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Citation: Nunn, A.V.W.; Guy, G.W.;
Brysch, W.; Bell, J.D. Understanding
Long COVID; Mitochondrial Health
and Adaptation—Old Pathways,
New Problems. Biomedicines 2022,10,
3113. https://doi.org/10.3390/
biomedicines10123113
Academic Editor: Daniel L Galvan
Received: 14 November 2022
Accepted: 30 November 2022
Published: 2 December 2022
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biomedicines
Review
Understanding Long COVID; Mitochondrial Health and
Adaptation—Old Pathways, New Problems
Alistair V. W. Nunn 1, * , Geoffrey W. Guy 2, Wolfgang Brysch 3and Jimmy D. Bell 1
1Research Centre for Optimal Health, Department of Life Sciences, University of Westminster,
London W1W 6UW, UK
2The Guy Foundation, Chedington Court, Beaminster, Dorset DT8 3HY, UK
3MetrioPharm AG, Europaallee 41, 8004 Zurich, Switzerland
*Correspondence: a.nunn@westminster.ac.uk
Abstract:
Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as “brain
fog”, fatigue and clotting problems. Explanations for “long COVID” include immune imbalance,
incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-
optimal mitochondrial function are associated with initial severity of the disease, their prior health
could be key in resistance to long COVID and recovery. The SARs virus redirects host metabolism
towards replication; in response, the host can metabolically react to control the virus. Resolution is
normally achieved after viral clearance as the initial stress activates a hormetic negative feedback
mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial
function, the virus can “tip” the host into a chronic inflammatory cycle. This might explain the
main symptoms, including platelet dysfunction. Long COVID could thus be described as a virally
induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised
by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a
shift towards glycolysis. This would suggest that a sufferer’s metabolism needs to be “tipped” back
using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic
these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the
inflammatory response.
Keywords:
SARS-CoV-2; mitochondria; Kreb’s cycle; metabolic flexibility; hormesis; inflammation;
long COVID; lifestyle; platelets
1. Introduction
Long COVID, or post-acute sequelae of COVID-19 (PASC), could be affecting more
than two million people in the UK [
1
]. Globally up to 43% of people who had proven
infection display symptoms for 2–3 months or more [
2
]. However, due to “slippery” defini-
tions others have suggested the effectiveness of preventing long COVID with vaccination
could vary from 15 to 50%, while the overall prevalence could be anywhere between
5 and 50% [
3
]. What is clear is that however it is defined, severity of infection does seem to
be associated with an increased risk of long COVID, and although prior vaccination can
certainly reduce this risk, it does not completely in those who develop a break through
infection [
4
]. The most common symptom seems to be fatigue, closely followed by depres-
sion, anxiety and cognitive dysfunction, sleep disorders, breathlessness, and smell/taste
loss [
5
]. This is also linked to decreased exercise capacity, which is only partly explained by
the expected deconditioning that occurs when someone has been ill [
6
], additionally, there
is also evidence of persistent clotting problems [
7
]. It is therefore not surprising that long
COVID is clearly having a big impact on the quality of life for those that suffer from it [8].
A recent meta-analysis of 2020–2021 data suggests that globally, more than
14 million
people experienced one or more of the key symptoms three months post-infection, with
Biomedicines 2022,10, 3113. https://doi.org/10.3390/biomedicines10123113 https://www.mdpi.com/journal/biomedicines
Biomedicines 2022,10, 3113 2 of 33
most cases arising from people who had milder infections. At 12 months, 15.1% still
had not recovered [
9
]. Children can also develop it, and worryingly, even in those who
have had mild or no symptoms [
10
]. Thus, long COVID could be becoming a global
emergency [11]—especially
if many years later, it has accelerated the ageing process, lead-
ing to rising incidence of cancer, metabolic syndrome and Alzheimer’s. Certainly there is
evidence for long-term neurological complications after one year [
12
], which agrees with
data that the virus can infect brain cells [
13
]. Given the already huge cost burden associated
with obesity and dementia, this may be something that needs to be addressed.
There is thus a pressing need to truly understand the pathophysiology as it might
provide clues to treatment and prevention. To date, the candidate mechanisms include
persistence of the virus, reactivation of other viruses, induced autoimmunity, tissue damage
inducing persistent inflammation and formation of microthrombi [
5
]. With regards the
latter hypothesis, COVID-19 mortality is strongly related to coagulopathy and disseminated
intravascular coagulation (DIC) and cytokine storms, which are associated with thrombosis
and bleeding, as well as thrombocytopenia [
14
]. Critically, this could also play a role
in long COVID as even in those who have had mild symptoms, clotting problems still
occur and appear to be associated with increased circulating fibrinolytic resistance amyloid
complexes, in particular, the acute phase protein, serum amyloid A (SAA4) and
α
(2)-
antiplasmin (α2AP) [7].
There is thus a potentially informative overlap with the long-researched condition,
myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is also associated
with microclots [
15
]. CFS often occurs after viral infections and it has been proposed
that some of the same mechanisms, for instance, involving neuroinflammation, could
have common origins [
16
]. Furthermore, the severity of the initial disease is strongly
associated with metabolic perturbation, for instance in the Kreb’s cycle and central carbon
metabolism, which is associated with dysregulation and imbalance of the various cells
of the immune system [
17
]. Tellingly, CFS is potentially also associated with decreased
mitochondrial function [
18
]. As mitochondria are critical to platelet homeostasis [
19
], the
idea that preserving platelet mitochondrial function could be important in COVID-19
pathogenesis has also been raised in the context of microbiota dysfunction and extracellular
mitochondria swapping [20].
Interestingly, there is emerging evidence that many, maybe all cells, including platelets,
can either donate or receive mitochondria and that the mitochondria themselves act as
signals, for instance when damaged and inflammatory, or healthy, and potentially anti-
inflammatory [
21
]. Thus, as prior systemic mitochondrial health could be a strong factor
dictating the severity of the acute disease someone develops [
22
–
25
], it could also be
indicative of whether someone is more liable to develop long COVID.
Certainly, data are now indicating that the plasma proteomic signature in the acute
setting can predict who is more likely to develop long-term symptoms, even in those not
hospitalised. For instance, one of the most predictive components are raised levels of the
iron-sulphur cluster biogenesis protein (HSCB), which could hint at increased iron levels
and observed association with hyperferritinaemic state and tissue damage, suggesting
possible iron metabolism dysfunction [
26
]. Indeed, hepatic iron deposition in COVID-19
patients has been reported, with many of the increased number of ferritin particles being
associated with mitochondria [
27
]. As mitochondria are key in the synthesis of iron sulphur
proteins [
28
], and deficiencies in mitochondrial complex 1 can lead to iron metabolism
dysfunction [
29
], this might suggest compromised mitochondrial function could also help
explain these observations.
It is thus possible that the virus in some people “tips” their metabolism into a new
state, which is characterised by an inability to restore optimal mitochondrial function and
remains biased towards glycolysis. The reasons for this are likely many, but as indicated,
poor prior mitochondrial health and robustness are important. This could be the result of
prior low aerobic fitness, underlying inflammation related to the metabolic syndrome, as
well as other viral infections, co-morbidities or genetic defects that give rise to oxidative
Biomedicines 2022,10, 3113 3 of 33
stress. As to an explanation that might underpin this tipping point, the concept of mito-
chondrial DNA editing during oxidative stress to decrease the electron transport chain
(ETC) components and thus reactive oxygen species (ROS) [
30
], when combined with the
reasons why mitochondria retain their own genes [
31
] might provide a hint due to the
loss of mtDNA copy number as a marker for a lower mitochondrial reserve and loss of
metabolic flexibility.
Put simply, it could be possible that if somebody’s mitochondrial reserve is not great
enough, and the system gets overloaded, it tries to reduce oxidative stress by decreasing
mitochondrial function still further. For example, a reduced mtDNA copy number is
associated with increased incidence of type 2 diabetes and the metabolic syndrome and
thus, insulin resistance [
32
]. Certainly, the severity of the initial SARS-CoV-2 infection is
positively associated with greater circulating mtDNA, as this is a key marker of inflam-
matory processes [
33
]. Indeed, it has been suggested that excessive release of mtDNA
could be a key pathogenic mechanism with this virus [
34
], which could be related to the
observation that cells can expel damaged mitochondria via the process of mitocytosis [
35
].
In this light, it seems that corona viruses, including SARS-CoV-2, can directly inhibit and
modulate mitochondrial function, inhibiting energy production and inducing apoptosis; it
has been suggested that COVID-19 pneumonia is triggered by a SARS-CoV-2 mitochondri-
opathy [
36
]. This suggests that if someone’s initial mitochondrial reserve is compromised,
then the virus could make this worse.
In this regard, it could be informative that a fundamental piece of metabolism, the
mitochondrial Kreb’s cycle, which may have arisen in an alkaline thermal vent at the
very beginnings of life, highlights the importance of balancing energy production and
biosynthesis with the availability of oxygen. A key component of the evolution of complex
life is that different cells, and perhaps even different mitochondria within the same cell, can
have the Kreb’s cycle operating in a variety of different modes, which for the whole, are
synergistic [
37
]. The similarities between inflammation and growth are perhaps informative
here: there is much to be learnt from both the Warburg [
38
] and reverse Warburg effects,
which provides insight into both cancer and Alzheimer’s [
39
]. Indeed, components of the
Kreb’s cycle are not just central to energy and biosynthetic metabolism, but also signalling,
inflammation and immunity [
40
]. This could be especially important as these metabolites,
for instance, via epigenetics, could modulate the ageing process [
41
]. Critically, this virus
may also modulate epigenetics, as one of its proteins, encoded by ORF8, could be a histone
mimic [
42
]. This further suggests that SARS-CoV-2 is modulating, at a very basic level, the
core metabolism of its host.
However, interpreting what these changes in metabolism mean is difficult, as host
cells also modulate metabolism to fight pathogens. For example, altering lipids to prevent
pathogen entry, manipulating iron metabolism, and modulating mitochondria to starve
them of metabolites. What this suggests is the metabolic perturbations seen in infections
may not just be the direct effect of the pathogen, but the system’s response to it [
43
].
Certainly, cells rapidly alter mitochondrial structure in response to viruses, while viruses
themselves can also modulate mitochondrial dynamics [
44
]. Furthermore, for most infected
people, the immune system is not just fighting off COVID-19, but other pathogens too, as
well as managing its relationship with its more friendly microbiota. Mitochondria are also
key in modulating circadian rhythms, whose disruption is linked to disease [
45
]. In short,
in the evolutionary arms race between viruses and their hosts, not only have mitochondria
become a target, but they are also “weaponised” by the host.
In this paper, we discuss mitochondrial function and the evolutionary origins of
metabolism and the Kreb’s cycle and interlace it with the emerging literature that either
directly, or indirectly, SARS-CoV-2 is manipulating metabolism and suggest the possibility
that “long COVID” is a syndrome, in part, related to an overloaded mitochondrial com-
partment resulting in metabolic inflexibility and an inability to restore homeostasis. The
predisposing sub-optimal mitochondrial phenotype could be the result of either a comor-
bidity, age and/or a prior poor lifestyle resulting in a reduced mitochondrial reserve and
Biomedicines 2022,10, 3113 4 of 33
fitness. Worryingly, this phenotype could potentially be associated with an accelerated age-
ing process. Indeed, COVID-19 has already worsened period life expectancy, a measure of
population health—especially in countries already exhibiting a pre-existing mortality crisis,
such as the United States [
46
]. Given that vaccination seems to reduce visits to the doctor
with symptoms of long COVID [
47
], this further supports not just vaccination programs,
but also enhancing fitness and a reduction in obesity rates to prevent a possible future crisis.
Although we will not discuss genetics per se, the emerging link between APOE genotype
and the severity of COVID-19 could also be informative. For instance, the APOE2 and
APOE4 alleles are associated with alterations in lipid metabolism and a worse outcome [
48
].
The link here is that APOE4 is associated with reduced mitochondrial function [
49
]. An
important implication of the thesis in this paper is that enhancing mitochondrial health
could be key in both prevention and treatment of long COVID. Certainly, the concept of an
obesity/viral “syndemic” is becoming established, as there seems to be a clear link with
COVID-19 deaths and an unhealthy lifestyle [
50
]. We also apply the mitochondrial concept
to the platelet, which might also begin to explain the association with clotting problems.
2. From Alkaline Vents to Mitochondria and SARS-CoV-2
A key principle of extant, or modern-day biochemistry, is that its roots can be traced
nearly all the way back to the beginnings of life. Evidence is that life evolved based on
the earth’s early geochemistry [
51
], and can be viewed as the descent of the electron [
52
].
As to where, one of the strongest theories, due to the existence of the proton gradient and
universality of both the electron transport chain (ETC), and the existence of the Kreb’s
cycle, is the deep-sea alkaline thermal vent. One of the fundamental theories that falls out
of this is that originally, something like the Kreb’s cycle started as a biosynthetic system,
utilising hydrogen and carbon dioxide to create complex chemistry. At some point during
evolution, this system then evolved to work in reverse to extract energy from complex
molecules and generate a proton gradient. In short, the original “forward” mode of the
Kreb’s cycle was biosynthetic, not energy producing. Today, of course, it is viewed the
other way around [37].
This simple concept can have a profound impact on how we view what viruses, such
as COVID-19, might do to our metabolism and what our metabolism, in trying to defend
against the virus, might also do. For instance, at a very basic level, the virus needs to
reprogramme metabolism back to a biosynthetic mode, which could be a very ancient
strategy indeed, while manipulating the more modern immune system. If the original
direction of the Kreb’s cycle was biosynthetic, in effect, using the energy in a proton
gradient to build molecules, then a later evolutionary step was that it could go into reverse
by taking energy out of molecules to generate a gradient. A mechanism for doing this
relies on electrons flowing down to a highly electro-negative compound or element, such as
oxygen. This of course is reflected in modern day metabolism in the relationship between
inflammation, biosynthesis, and hypoxia, and thus, glycolysis and the mitochondrion.
2.1. Beyond the Powerhouse—Mitochondria Do a Lot More Than Produce Energy
An important aspect to understanding the virus is that mitochondria are not just
simply “powerhouses” of the cell but have many more functions (Figure 1), including
calcium and ROS homeostasis, which could be predicted from when they got together
with an Archean to become a eukaryote [
53
]. The Kreb’s cycle thus has many functions.
For example, succinate is involved in signalling, tumorigenesis, inflammation, redox and
epigenetics [
54
], and can suppress influenza viral replication by succinlyation of viral
nucleoproteins in the nucleus [
55
]. It is thus relevant that tumour necrosis factor (TNF) can
increase succinate production, driving reverse electron transport (RET) through complex 1
and generating ROS; this can be a powerful anti-pathogen mechanism, but also pathological
if not controlled and can be modulated by metformin, a known complex 1 inhibitor [56].
Biomedicines 2022,10, 3113 5 of 33
Biomedicines2022,10,xFORPEERREVIEW5of34
1andgeneratingROS;thiscanbeapowerfulanti‐pathogenmechanism,butalsopatho‐
logicalifnotcontrolledandcanbemodulatedbymetformin,aknowncomplex1inhibitor
[56].
Figure1.Someofthemanyrolesofthemitochondrionandthecentralityofglycolysisandthetri‐
carboxylicacidcycle(TCA,alsoknownastheKreb’scycle).
SuccinatebuildsupduringhypoxiaandisimportantingeneratingROS,forinstance,
duringheavyexercise—andisthusakeysignallingmoietywhenphosphorylationcannot
occur.ROSproductionisthuscloselyrelatedtomitochondrialmembranepotential.Crit‐
ically,muchoftheROSgeneratedisconvertedintohydrogenperoxide,whichisasignal‐
lingmoleculeandreadilydiffusible.However,lessappreciatedisthatmitochondriaalso
containseveralpowerfulROSreductionsystems(RDS),someofwhichrelyheavilyon
NADPH,indicatingtheycanactasnetROSsinks.Forexample,theycaneffectivelyre‐
moveexternalhydrogenperoxide,especiallyahigherconcentrations;theyaretherefore
centraltoROS‐basedsignallingastheycanactasbothaROSsinkandaproducer[57].
Critically,itseemsmitochondriafromdifferenttissueshavedifferentways,andabilities,
ofactingassinksofROS,suggestingcell‐specificfunctions[58,59].
Overall,thismeansthatmitochondriatightlycontrolROS,buttheextentmayvary
fromcelltocell.Itisthuspossiblethattheantioxidantsystemsarenotsimplythereto
offsetuncontrolledROSproduction,butareafundamentalpartofsignalling,andare
closelylinkedtobioenergeticstatus[60].Tellingly,itnowseemsthatthesesystemscould
beimportantindeterminingthelongevityofaspecies,ineffect,theabilityofanorgan‐
ism’smitochondriatoconsumeROSdetermineshowlongitlives[61].Akeywaytoview
thisisthattheredoxcouplesinthemitochondrionarecloselylinkedtosubstrateoxida‐
tion,andthustotheanti‐oxidantsystem(e.g.,generationofNADPH),whichhasledto
theredox‐optimisedROSbalancehypothesisandtheideathatmitochondriaevolvedto
operateatanintermediateredoxstate,whereenergyproductionismaximised,butROS
productionminimised—ifthesystemistoooxidised,orreduced,ROSincreases[62].In
thisregard,theabilityofbatstotolerateviruses,includingSARs,isperhapsrelevant,as
theyareextremelylonglived,yetveryactive;oneaspectoftheirmetabolismistheability
tomanageoxidativestressandinflammation—thiscouldberelatedtotheirflightcapacity
andmitochondrialfunction[63].
Thisdoesindicatethatnotonlyismitochondrialhealthanimportantdeterminator
ofresistancetothisvirus,butthatresistancetooxidativestressmightvaryfromcellto
cell,whichmaydeterminetheoutcomedependingonwhichorgansandcellsthevirus
Figure 1.
Some of the many roles of the mitochondrion and the centrality of glycolysis and the
tricarboxylic acid cycle (TCA, also known as the Kreb’s cycle).
Succinate builds up during hypoxia and is important in generating ROS, for instance,
during heavy exercise—and is thus a key signalling moiety when phosphorylation can-
not occur. ROS production is thus closely related to mitochondrial membrane potential.
Critically, much of the ROS generated is converted into hydrogen peroxide, which is a
signalling molecule and readily diffusible. However, less appreciated is that mitochondria
also contain several powerful ROS reduction systems (RDS), some of which rely heavily
on NADPH, indicating they can act as net ROS sinks. For example, they can effectively
remove external hydrogen peroxide, especially a higher concentrations; they are therefore
central to ROS-based signalling as they can act as both a ROS sink and a producer [
57
].
Critically, it seems mitochondria from different tissues have different ways, and abilities, of
acting as sinks of ROS, suggesting cell-specific functions [58,59].
Overall, this means that mitochondria tightly control ROS, but the extent may vary
from cell to cell. It is thus possible that the antioxidant systems are not simply there to
offset uncontrolled ROS production, but are a fundamental part of signalling, and are
closely linked to bioenergetic status [
60
]. Tellingly, it now seems that these systems could
be important in determining the longevity of a species, in effect, the ability of an organism’s
mitochondria to consume ROS determines how long it lives [
61
]. A key way to view this
is that the redox couples in the mitochondrion are closely linked to substrate oxidation,
and thus to the anti-oxidant system (e.g., generation of NADPH), which has led to the
redox-optimised ROS balance hypothesis and the idea that mitochondria evolved to operate
at an intermediate redox state, where energy production is maximised, but ROS production
minimised—if the system is too oxidised, or reduced, ROS increases [
62
]. In this regard, the
ability of bats to tolerate viruses, including SARs, is perhaps relevant, as they are extremely
long lived, yet very active; one aspect of their metabolism is the ability to manage oxidative
stress and inflammation—this could be related to their flight capacity and mitochondrial
function [63].
This does indicate that not only is mitochondrial health an important determinator
of resistance to this virus, but that resistance to oxidative stress might vary from cell to
cell, which may determine the outcome depending on which organs and cells the virus has
affected, either directly, or indirectly. It is well described that modulation of Kreb’s cycle
intermediates by viruses is key in how they replicate, as this supplies the metabolites they
need, such as citric acid, but it also controls the immune system. For instance, fumarate
and itaconate have anti-viral activity and are immunomodulators and can control the
nuclear factor erythroid 2–related factor 2 (Nrf2), a key regulator of resistance to oxidative
stress, while the latter can inhibit succinate dehydrogenase (SDH). In contrast, as discussed,
succinate is viewed as being pro-inflammatory [
64
]. Interestingly, activators of Nrf2, such
as dimethyl fumarate have indicated that SARS-CoV-2 suppresses the Nrf2 pathway, and
Biomedicines 2022,10, 3113 6 of 33
so indicate possible therapeutic approaches—as this pathway is not only anti-inflammatory
but appears to have a distinct anti-viral function [65].
Certainly, one metabolomic study of COVID-19 patients indicated that they had higher
succinate and lactic acid, but lower citric acid levels compared to healthy
controls [66]—which
is strongly suggestive of Kreb’s cycle modulation. Other metabolomic studies have also
shown changes in the Kreb’s cycle indicating mitochondrial dysfunction, with increases
in succinate [
67
,
68
]. One study did not show any change, but could have been explained
as the patients were receiving intense respiratory therapy, suggesting hypoxia may be
important [
69
]. Considering this latter study, another showed that in more severe cases there
was an indication of modified amino acid metabolism that was commensurate with hypoxia
and a shift in mitochondrial metabolism [
70
]. It may therefore be relevant that platelets
express the succinate receptor, SUCNR1, which can stimulate platelet activation [
71
]. We
will discuss platelet metabolism in more detail later in the paper.
2.2. SARS-CoV-2 Can Modulate Mitochondria and Glycolysis
Data suggest that a SARS-CoV-2 membrane protein can directly cause mitochondrial
apoptosis, which may lead to enhanced lung injury [
72
]. In general, coronaviruses including
SARS-CoV-2 have been found to modulate mitochondria. In several models involving lung
cells, the virus was found to inhibit the formation of components of the ETC, in particular
complex 1, and induce mitochondrial permeability transition (MTP), reduce mitochondrial
membrane potential, disrupt ATP synthase function, enhance mitochondrial fission, and
induce apoptosis. In the lungs, this could inhibit the hypoxic pulmonary constriction
response (HPV) by inhibiting oxygen sensing. In short, in severe COVID-19, the hypoxemia
associated with lung injury could be a viral mitochondriopathy [36].
It has also been found that in the leukocytes of patients with post COVID-19 sequalae
there is evidence of decreased mitochondrial membrane potential [
73
], while in an elderly
population, a decreased mitochondrial membrane potential seemed to associate with an
increased susceptibility and vulnerability to the virus [
74
]. Another observation is that in
placental samples from infected patients, SARS-CoV-2 RNA co-localised with mitochon-
dria, which was associated with altered mitochondrial networks [
75
] and although one
study did not find any changes in mitochondrial long non-coding RNAs during infection,
during recovery, there was a persistence change in small mitochondrial RNAs [
76
]. This of
course might suggest that there might be host mitochondrial transcriptome responses to
SARS-CoV-2
, as there are in response to other viruses. In one study, the virus did not appear
to significantly alter mtDNA gene or mitochondrial antiviral signalling protein (MAVs)
expression but did seem to downregulate nuclear encoded mitochondrial genes [77].
The role of SARS-CoV-1 protein ORF3b is also suggestive, as it has been found to target
mitochondria and modulate interferon production [
78
], while ORF3a from SARS-CoV-2,
via its effects on mitochondria, seems to play a role in activation of the hypoxia-inducible
factor-1
α
(HIF-1
α
) that enhances viral infectivity [
79
]. Interestingly, researchers using a fruit
fly model found that the viral Nsp6 protein can damage hearts, which is of great clinical
interest because of the association of COVID-19 with cardiovascular problems. Their key
finding was that it induced a switch to glycolysis, which was associated with mitochondrial
damage, and activation of the Myc pathway. Critically, inhibitors of glycolysis could reduce
the severity of the damage both to Drosophila hearts and mouse cardiomyocytes, suggesting
a potential clinical strategy [80].
Considering the ability of the virus to induce metabolic reprogramming of its host,
a further link is also suggested by the emerging pleiotropic roles of vacuolar-ATPase
(V-ATPase) and viruses. V-ATPase is a large proton pumping turbine consisting of many
different, and interchangeable subunits that vary according to its place in and the function of
a particular cell. Its most readily identifiable function is to use ATP to acidify compartments,
but it has many more roles. For example, its association with the mammalian target of
rapamycin (mTOR), the AMP-activated protein kinase (AMPK) and transient receptor
potential V-type channels (TRPV) indicate a role in nutrient sensing and modulating energy
Biomedicines 2022,10, 3113 7 of 33
levels. In essence, with increased glucose, it is involved in activating mTOR, but when
glucose levels fall, it can inactivate mTOR, activating AMPK and via TRPV, interact with
the endoplasmic reticulum. Equally, when amino acid levels rise, it can also activate
mTOR, but when they fall, it can inactivate it [
81
]. In effect, it seems to be part of the
system for switching from glycolysis to oxidative phosphorylation when the organism is
under starvation and vice versa, thus shifting from anabolism and catabolism and back
again. These pathways are intimately coupled to control of mitochondrial function [
82
].
Furthermore, it also seems to be modulated by oxidative stress via Oxr1, which induces
its disassembly [
83
], while the targeting of the different isoforms is dependent on their
phosphatidylinositol lipid composition, which is related to the pH of the organelle [84].
It is thus relevant that data are indicating that the virus can manipulate V-ATPase—
increasing its levels [
85
] and that its entry into cells can be synergistically blocked by
inhibiting both V-ATPase, using bafilomycin A1, and the cell surface transmembrane
protease serine 2 (TMPRSS2), using Camostat. Hence, viral entry can be achieved by both
the plasma membrane route involving TMPRSS2 and an endosomal route, which explains
why some inhibitors, such as chloroquine, have not been that effective [
86
]. So, although
this could be explained by a mechanism that simply inhibits endosomal acidification, it
might also hint that it could affect metabolic reprogramming. In this light, given that
COVID-19 seems to be associated with a hyper-ferritinaemia and in some cases, hepatic
failure associated with iron overload [
27
], it may be relevant that V-ATPase is also key
in controlling HIF1
α
by modulating iron levels; V-ATPase depletion/inhibition enhances
HIF1
α
activity by depleting transferrin uptake [
87
]. However, the effects V-ATPase on
HIF, and thus glycolysis, are nuanced; although its inhibition can activate glycolysis, so
enhancing cell survival, it can also kill cancer cells due to proton build up in the cytosol [
88
].
So, as HIF is known to be important in viral defence [
89
], this might suggest that this could
be a viral defence mechanism. A somewhat sobering thought is that most oncogenic viruses
seem to upregulate HIF as well—although the direction of the causality is unclear [
90
],
but it does suggest that SARS-CoV-2 might heighten the risk of cancer. Overall, the
emerging data, both about viruses in general, and this one, do seem to support it can
modulate mitochondrial function. Figure 2summarises the link between the virus and
mitochondrial function.
Biomedicines2022,10,xFORPEERREVIEW8of34
Figure2.Potentialviralmanipulationofmitochondrialfunctioninmultiplecelltypescouldbeal‐
liedwithsymptomsoflongCOVID;thevirusmanipulatesthesystemtowardsgrowthpathways
thataresimilartoinflammatorypathways,whicharealsohowthehosttriestogetridofthevirus.
2.3.TakingtheViralViewpoint;IsHypoxiaGoodorBadfortheVirus?
Asindicated,oxygenlevelsandmetabolismareverytightlyintegrated.Interestingly,
manyvirusesaresensitivetooxygentension,buttheoutcomeisverycontextdependent,
andtheresponsevarieswiththespeciesandthehostcell:hypoxiaenhancesEBVbutsup‐
pressesinfluenzareplication.Ithasbeenshown,atleastinrespiratorytractcells,thatac‐
tivationoftheHIFpathwaycandownregulatetheangiotensinconvertingenzyme(ACE2)
andthatpost‐entrystepsintoacellareoxygensensitiveforCOVID‐19—hinderingits
replication,atleastinthesecells[91].However,othershavefoundthatHIFcanpromote
COVID‐19infection,worseninginflammation,withasuggestedmechanisminvolving
ORF3adirectlydamagingmitochondria[79].Thisisperhapsfurtherreinforcedbythe
findingthatelevatedglucoselevelsalsofavourinfection,whichisaccentuatedbyaHIF‐
dependentmechanisminlungmonocytesthatenhancesglycolysisthatcaninhibitTcell
responses[92].Thissuggeststhatwhileinsomecellsananti‐viralHIFmechanismisacti‐
vated,inothercells,itcouldfavourthevirus.
Giventheimmenseamountoftimethatvirusesandtheirhostshavebeenco‐evolv‐
inginanalmosteternalarmsrace,itwouldbenosurprisethatthevirushasevolvedto
utilisetheverymetabolicreprogrammingthatitshostusestotryandgetridofit.This
wouldsuggestthattryingtountanglewhatthehost’smetabolicdefenceprogramisand
whatistheviruses’manipulationofitisdifficult.Forexample,aWarburgshiftcould
benefitboththehostandthevirus,dependingoncontext,butitdoesraisethepossibility
thatinductionofmildhypoxiamightalsofavourthevirus,andhasthusbeenadoptedby
thevirusthroughevolution.However,intermsoftheKreb’scycle,thisdoessuggesta
biastowardsabiosyntheticmodethatcouldaidthevirus.Whetherthiseffectisenhanced
inthepresenceofpre‐existingsub‐optimalmitochondrialfunctionisthusperhapsanin‐
terestingquestion,ascellularmetabolismmightbeslightlymorereliantonglycolysisin
thesecircumstances.Theclearthromboticstateseeninmanypatientscouldbeanexample
ofapositivereinforcementfeedbackloopthatperpetuatesaverydamaginginflammatory
cycle,hinting,potentiallyatatippingpoint.Thiswouldespeciallybethecaseifthevirus
damagesmitochondria.
Figure 2.
Potential viral manipulation of mitochondrial function in multiple cell types could be allied
with symptoms of long COVID; the virus manipulates the system towards growth pathways that are
similar to inflammatory pathways, which are also how the host tries to get rid of the virus.
Biomedicines 2022,10, 3113 8 of 33
2.3. Taking the Viral Viewpoint; Is Hypoxia Good or Bad for the Virus?
As indicated, oxygen levels and metabolism are very tightly integrated. Interestingly,
many viruses are sensitive to oxygen tension, but the outcome is very context dependent,
and the response varies with the species and the host cell: hypoxia enhances EBV but
suppresses influenza replication. It has been shown, at least in respiratory tract cells,
that activation of the HIF pathway can downregulate the angiotensin converting enzyme
(ACE2) and that post-entry steps into a cell are oxygen sensitive for COVID-19—hindering
its replication, at least in these cells [
91
]. However, others have found that HIF can promote
COVID-19 infection, worsening inflammation, with a suggested mechanism involving
ORF3a directly damaging mitochondria [
79
]. This is perhaps further reinforced by the
finding that elevated glucose levels also favour infection, which is accentuated by a HIF-
dependent mechanism in lung monocytes that enhances glycolysis that can inhibit T cell
responses [
92
]. This suggests that while in some cells an anti-viral HIF mechanism is
activated, in other cells, it could favour the virus.
Given the immense amount of time that viruses and their hosts have been co-evolving
in an almost eternal arms race, it would be no surprise that the virus has evolved to utilise
the very metabolic reprogramming that its host uses to try and get rid of it. This would
suggest that trying to untangle what the host’s metabolic defence program is and what
is the viruses’ manipulation of it is difficult. For example, a Warburg shift could benefit
both the host and the virus, depending on context, but it does raise the possibility that
induction of mild hypoxia might also favour the virus, and has thus been adopted by the
virus through evolution. However, in terms of the Kreb’s cycle, this does suggest a bias
towards a biosynthetic mode that could aid the virus. Whether this effect is enhanced
in the presence of pre-existing sub-optimal mitochondrial function is thus perhaps an
interesting question, as cellular metabolism might be slightly more reliant on glycolysis in
these circumstances. The clear thrombotic state seen in many patients could be an example
of a positive reinforcement feedback loop that perpetuates a very damaging inflammatory
cycle, hinting, potentially at a tipping point. This would especially be the case if the virus
damages mitochondria.
2.4. Viruses, Mitochondria and Lipids; a Nutritional Arms Race
The previous discussion touches upon a possible problem in dissecting out what is a
direct viral effect, and potentially, a host reaction. It is thus perhaps worth remembering
that the host versus virus is a very old arm’s race, and both sides modulate metabolism,
especially the Kreb’s cycle and mitochondrial function; this has been called “nutritional
immunity” from the host’s perspective. One mechanism is not only to try and starve
pathogens of lipids, but for the host to alter membrane structure to make entry more
difficult, for instance, by modulating cholesterol and other lipids, such as sphingolipids [
43
].
One of the functions of a more biosynthetic Kreb’s cycle mode is to produce lipids. It
certainly seems that viruses have evolved to usurp this mechanism. It now appears that
SARS-CoV-2 is no different as it comprehensively rewires its host lipid metabolism, with a
key feature being the formation of lipid droplets. This is supported by clinical observations
at the systemic level, which include changes in the apolipoprotein system. Critically, viral
replication could be inhibited by small molecule glycerolipid biosynthesis inhibitors [
93
].
Interestingly, as mentioned in the introduction, the APOE4 allele seems to be associated
with impaired neuron-astrocyte coupling of fatty acid metabolism, which is associated
with mitochondrial dysfunction and an inability to form lipid droplets and a shift towards
glycolysis [
94
]. This would suggest that differences in lipid metabolism genotype could
affect outcome.
So could the virus, by modulating mitochondrial function, affect lipid metabolism?
Mitochondria play a key role in lipid metabolism, for instance, via Kreb’s cycle intermedi-
ates and NADPH, or by burning fatty acids in respiration, but perhaps less appreciated
is that their function is very dependent on their own lipid system, which seems to ex-
plain why they contain their own fatty acid synthase (mtFAS), which utilises acetyl CoA
Biomedicines 2022,10, 3113 9 of 33
to build C8 fatty acids. In fact, it seems that mitochondrial fatty acid synthesis coordi-
nates oxidative metabolism, and its loss leads to severe problems with the production
of ETC complexes [
95
,
96
], while defects in mitochondrial fatty synthesis are associated
with neurodegeneration [
97
]. Furthermore, NAD kinase (NADK) supports lipogenesis
by maintaining a pool of NADPH, which in concert with mtFAS, is key in maintaining
mitochondrial mass by controlling acetyl-CoA and peroxisome proliferator-activated re-
ceptor gamma one alpha (PGC-1
α
). As a central component of cellular lipid storage is
the lipid droplet, defective mitochondria can lead to lipid accumulation—although this is
balanced by their role in both providing energy and precursors for cytosolic fatty acid syn-
thesis [
98
]. It may also be relevant that isocitrate dehydrogenase 2 (IDH2) deficiency, a key
mitochondrial enzyme, seems to be critical in myogenesis and fatty acid metabolism [99].
Putting this together, this virus could induce a shift in mitochondrial function that is
linked to altered lipid metabolism. Whether this is direct, or indirect, is not clear; it could
again be a phenotype generated by host adaptation to get rid of the virus. It has long been
known that one of the trades offs of defence against pathogens is “friendly fire” damage.
A classic example of this is perhaps the dyslipidemia and insulin resistance associated
with activation of the acute phase response, and thus inflammation, with conditions like
atherosclerosis and the metabolic syndrome and lifestyle-induced disease, and the role of
peroxisomal proliferating-activated receptors (PPARs) [100].
In this light, there is, perhaps, another relevant observation, and that is that in the
kidneys of diabetic mice, peroxisomal succinate production is increased leading to in-
creased lipid accumulation and oxidative stress via suppression of mitochondrial fatty acid
oxidation [
101
]. It seems that succinate is a suppressor the antiviral immune response by
modulating the MAVs complex [102].
In summary, there is an evolutionary rationale as to why SARS-CoV-2 would modulate
Kreb’s cycle intermediates and lipid metabolism, equally there is also a good reason why
the host may do it to get rid of the virus. However, this could be truly ancient indeed, as
theories on the earliest proto-metabolism that gave rise to life, certainly indicate that it can
lead to the formation of lipids [103].
3. Long COVID and Mitochondria—A Tipping Point
The above discussions do seem to support the idea the both the virus, and the host,
will manipulate mitochondrial function; the former to help it replicate, the latter to get rid
of the virus. Is there a point where if both operate in the same direction, and mitochondrial
function is sub-optimal, the system ends up in a vicious spiral?
Current thinking suggests that long COVID pathology is associated with five key
perturbations: persistence of the virus; reactivation of other viruses; induced autoimmu-
nity; tissue damage inducing persistent inflammation; and formation of microthrombi [5].
Certainly, all of these could be involved. However, what is clear is that the metabolic
phenotype remains in a sub-optimal homeostatic state, which is commensurate with low
grade inflammation. Whether or not this is caused by persistent virus, or other viruses,
or even bits of virus, or simply that the host is “stuck” in a kind of “defence” mode, and
cannot for some reason resolve itself, is unclear. Whatever is happening, it appears to be
associated with a reprogramming of mitochondrial function, which is likely linked, because
of the importance of mitochondria in epigenetics, to a kind of epigenetic stress state. As to
why the system in some people “tips” into this state could be due to a prior and already
altered mitochondrial status, perhaps coupled to chronic inflammation induced by a poor
lifestyle, age and/or another co-morbidity.
In this section, we review the evidence linking mitochondrial function and the longer-
term effects of COVID-19 and highlight some less obvious links. One possibility is that
through evolution, the virus has evolved to utilise the very metabolic phenotype that
the host normally uses to defend against the virus. For example, it thrives, in some
tissues, due to a mildly hypoxic inflammatory environment where the Kreb’s cycle is more
Biomedicines 2022,10, 3113 10 of 33
likely to be in biosynthetic mode, which is very similar to what happens in some cells
during inflammation.
Figure 3outlines a simple concept in relation to a see saw tipping point; without
sufficient starting metabolic flexibility, a host can get stuck in an inflammatory state. In
contrast, Figure 4indicates that with good mitochondrial health and metabolic flexibility,
resistance to long COVID might be more likely.
Biomedicines2022,10,xFORPEERREVIEW10of34
3.LongCOVIDandMitochondria—ATippingPoint
Theabovediscussionsdoseemtosupporttheideatheboththevirus,andthehost,
willmanipulatemitochondrialfunction;theformertohelpitreplicate,thelattertogetrid
ofthevirus.Isthereapointwhereifbothoperateinthesamedirection,andmitochondrial
functionissub‐optimal,thesystemendsupinaviciousspiral?
CurrentthinkingsuggeststhatlongCOVIDpathologyisassociatedwithfivekey
perturbations:persistenceofthevirus;reactivationofotherviruses;inducedautoimmun‐
ity;tissuedamageinducingpersistentinflammation;andformationofmicrothrombi[5].
Certainly,allofthesecouldbeinvolved.However,whatisclearisthatthemetabolicphe‐
notyperemainsinasub‐optimalhomeostaticstate,whichiscommensuratewithlow
gradeinflammation.Whetherornotthisiscausedbypersistentvirus,orotherviruses,or
evenbitsofvirus,orsimplythatthehostis“stuck”inakindof“defence”mode,and
cannotforsomereasonresolveitself,isunclear.Whateverishappening,itappearstobe
associatedwithareprogrammingofmitochondrialfunction,whichislikelylinked,be‐
causeoftheimportanceofmitochondriainepigenetics,toakindofepigeneticstressstate.
Astowhythesysteminsomepeople“tips”intothisstatecouldbeduetoapriorand
alreadyalteredmitochondrialstatus,perhapscoupledtochronicinflammationinduced
byapoorlifestyle,ageand/oranotherco‐morbidity.
Inthissection,wereviewtheevidencelinkingmitochondrialfunctionandthe
longer‐termeffectsofCOVID‐19andhighlightsomelessobviouslinks.Onepossibilityis
thatthroughevolution,thevirushasevolvedtoutilisetheverymetabolicphenotypethat
thehostnormallyusestodefendagainstthevirus.Forexample,itthrives,insometissues,
duetoamildlyhypoxicinflammatoryenvironmentwheretheKreb’scycleismorelikely
tobeinbiosyntheticmode,whichisverysimilartowhathappensinsomecellsduring
inflammation.
Figure3outlinesasimpleconceptinrelationtoaseesawtippingpoint;without
sufficientstartingmetabolicflexibility,ahostcangetstuckinaninflammatorystate.In
contrast,Figure4indicatesthatwithgoodmitochondrialhealthandmetabolicflexibility,
resistancetolongCOVIDmightbemorelikely.
Figure3.WhyapoorlifestylemightleadtoagreaterlikelihoodoflongCOVID.Poormetabolic
flexibility,asaresultofalifestylethatdoesnotstimulateoptimalmitochondrialfunction,canresult
inlowgradeinflammationthatmaywellfurtherstressmitochondrialfunction.Onexposuretothe
virus,thesystemisfurthertippedtowardsaninflammatoryphenotype,whichcoupledwithsub‐
Figure 3.
Why a poor lifestyle might lead to a greater likelihood of long COVID. Poor metabolic
flexibility, as a result of a lifestyle that does not stimulate optimal mitochondrial function, can result
in low grade inflammation that may well further stress mitochondrial function. On exposure to
the virus, the system is further tipped towards an inflammatory phenotype, which coupled with
sub-optimal mitochondrial function in the immune system, may take longer to either clear the virus
and/or resolve the proinflammatory state.
3.1. The Sub-Optimal Mitochondrial Function Theory and Acute SARS-CoV-2 Severity
Several groups, including us, have been suggesting that prior sub-optimal mitochon-
drial function could be contributing to the morbidity when infected with SARS-CoV-2
as many viruses, including this one, can affect bioenergetics as it is a key part of their
infectious modus operandi. The people thus most affected will likely be those who already
have compromised mitochondria, for instance the elderly and those with underlying mor-
bidities [
22
–
25
,
104
,
105
]. This could include a link to the reactivation of viruses like the
Epstein–Barr Virus (EBV), which is well known to modulate mitochondrial function; we
have suggested that this could result in a mitochondrial “double whammy” [
106
]. Indeed,
data are beginning to support a link between long COVID and EBV reactivation [
107
].
There is also evidence that patients with primary mitochondrial defects (PMD) are also at
greater risk, although they often have many other co-morbidities, including respiratory
dysfunction [
108
]. The link between ageing and poor mitochondrial function has long
been discussed, although the role of mitochondrial dynamics and hormesis indicate the
relationship is more complex than thought [109].
Biomedicines 2022,10, 3113 11 of 33
Biomedicines2022,10,xFORPEERREVIEW11of34
optimalmitochondrialfunctionintheimmunesystem,maytakelongertoeitherclearthevirus
and/orresolvetheproinflammatorystate.
Figure4.WhyagoodlifestylemayhelpagainstthelongCOVID.Withmitochondriainoptimal
health,theyhaveplentyofreservecapacitytoensurethemetabolicflexibilitytobothensureagood
immuneresponse,andalso,forinstance,viaeffectiveantioxidantcapability,ensureinflammation
isresolved.
3.1.TheSub‐OptimalMitochondrialFunctionTheoryandAcuteSARS‐CoV‐2Severity
Severalgroups,includingus,havebeensuggestingthatpriorsub‐optimalmitochon‐
drialfunctioncouldbecontributingtothemorbiditywheninfectedwithSARS‐CoV‐2as
manyviruses,includingthisone,canaffectbioenergeticsasitisakeypartoftheirinfec‐
tiousmodusoperandi.Thepeoplethusmostaffectedwilllikelybethosewhoalready
havecompromisedmitochondria,forinstancetheelderlyandthosewithunderlyingmor‐
bidities[22–25,104,105].Thiscouldincludealinktothereactivationofviruseslikethe
Epstein–BarrVirus(EBV),whichiswellknowntomodulatemitochondrialfunction;we
havesuggestedthatthiscouldresultinamitochondrial“doublewhammy”[106].Indeed,
dataarebeginningtosupportalinkbetweenlongCOVIDandEBVreactivation[107].
Thereisalsoevidencethatpatientswithprimarymitochondrialdefects(PMD)arealsoat
greaterrisk,althoughtheyoftenhavemanyotherco‐morbidities,includingrespiratory
dysfunction[108].Thelinkbetweenageingandpoormitochondrialfunctionhaslong
beendiscussed,althoughtheroleofmitochondrialdynamicsandhormesisindicatethe
relationshipismorecomplexthanthought[109].
3.2.Temporal‐CompartmentalEffectsoftheVirusvstheHostonMetabolicReprogramming
Oneproblemwithscientificacceptanceofasignificantroleformitochondrialfunc‐
tioninCOVID‐19isthatitseffectsonmetabolismareoftenvariedindifferenttissues.
However,newdataarenowprovidingsomeanswers;itmaywelldependonwhenand
wheresamplesaretakenfrompatients.Forexample,itappearsthatwhilemitochondrial
bioenergeticsisrepressedinthenasopharynx,itisupregulatedinthelungs.Whatseems
tobehappeningisthatthevirusdownregulatessomeaspectsofoxidativephosphoryla‐
tion,butinresponse,thehosttriestoupregulatethem.Insometissues,suchastheheart,
theconsequencesofthisrepressioncanbeseverebecauseoftherelianceonoxidative
phosphorylation.Thusthetimingduringtheinfectioniskey—duringactiveviral
Figure 4.
Why a good lifestyle may help against the long COVID. With mitochondria in optimal
health, they have plenty of reserve capacity to ensure the metabolic flexibility to both ensure a good
immune response, and also, for instance, via effective antioxidant capability, ensure inflammation
is resolved.
3.2. Temporal-Compartmental Effects of the Virus vs. the Host on Metabolic Reprogramming
One problem with scientific acceptance of a significant role for mitochondrial function
in COVID-19 is that its effects on metabolism are often varied in different tissues. However,
new data are now providing some answers; it may well depend on when and where samples
are taken from patients. For example, it appears that while mitochondrial bioenergetics is
repressed in the nasopharynx, it is upregulated in the lungs. What seems to be happening
is that the virus downregulates some aspects of oxidative phosphorylation, but in response,
the host tries to upregulate them. In some tissues, such as the heart, the consequences of
this repression can be severe because of the reliance on oxidative phosphorylation. Thus
the timing during the infection is key—during active viral infection, it suppresses certain
aspects of mitochondrial function to ensure production of metabolites for viral replication,
for instance, upregulation of glycolysis and production of nucleotides, but as the virus is
cleared, the system rebounds to repair [110].
This metabolic “Warburg” switch would be predicted to occur and does have simi-
larities to what happens in cancer, and thus, why, potentially, anti-cancer and anti-viral
strategies have some cross over as potential treatments [
22
]. A potentially interesting ex-
ample of this may occur in the brain; data indicate that the virus can infect both astrocytes
and neurons, but in astrocytes, it seems to enhance oxidative phosphorylation, depriving
neurons of lactate and pyruvate. This seems to be tightly linked to the cognitive problems
associated with this virus [
13
]. The reverse or inverse Warburg effect and metabolic cou-
pling is critical in brain function, and its modulation could well be key in the development
of Alzheimer’s [111].
Why this virus infects brain tissue is perhaps an interesting question. It could simply
be a non-specific effect, but it could also be that by centrally modulating brain function,
which can control inflammation, it may help in viral survival. For instance, by enhancing
insulin resistance, so making more glucose and lipids available. Altering the behaviour of
its host could also be an evolved strategy. It is certainly true that viruses have evolved to
utilise their host’s machinery to make more viruses, which has gone hand in hand with
modulation of mechanisms that control the immune system and metabolism to provide
the materials, and energy that are needed. How they affect mitochondria depends on their
replication rate, for instance, whether they induce, or prevent, apoptosis, and modulate
Biomedicines 2022,10, 3113 12 of 33
metabolism. Some switch from one to the other to enable long-term infection, but most
result in oxidative stress. It is likely that each virus has a different way of doing it [112].
However, if we accept that the host will reprogram its metabolism to try and get
rid of the virus [
43
], which is likely linked to more general systemic effects related to the
inflammatory-driven acute phase response (APR) and insulin resistance and alterations
in lipid metabolism [
113
], then the boundary between “directly virus induced” vs. “host
response to virus” becomes less clear. This definition becomes even more blurred with
evidence that some proteins released during the APR can actually suppress inflamma-
some activation, hinting at the host trying to suppress excessive inflammation [
114
]. The
metabolic link is perhaps further strengthened as COVID-19 not only worsens existing
diabetes but can trigger it in people who did not previously have it; although some of the
mechanisms mentioned above could be important, there is also some evidence of direct
damage to the pancreas [115].
At the organ level this might mean that any tissue that has a high reliance on oxidative
phosphorylation, which means in conventional terms that the Kreb’s cycle is running in
the forward direction, could we well be at risk, especially if the virus can infect it, but
also indirectly, if it is also susceptible to metabolic reprogramming during a generalised
inflammatory response, or its supply of oxygen becomes compromised. Thus, the heart,
neurons and the kidneys are likely to be very vulnerable. Certainly, renal problems associ-
ated with this virus are being increasingly recognised, especially, somewhat worryingly, in
children [116].
In some respects, this could be viewed as a collateral non-specific metabolic repro-
gramming effect, for instance, of both the virus’s target cells and the immune system. At
the cellular level, not only does this alter the death threshold of a cell, but it could well
affect things like the generation of ATP to fuel autophagy. The potential problems of this
latter point are perhaps highlighted by the mitochondrial-lysosomal theory of ageing. In
effect, as mitochondrial function decreases and thus ATP production to drive the V-ATPase,
the ability to remove damaged components, including sub-functional mitochondria by
autophagy decreases—could lead to a vicious cycle. Post-mitotic long lived cells could well
be particularly vulnerable, such as neurons, retinal pigment epithelium, cardiac myocytes
and even skeletal muscle [
117
]. Proteomic studies of blood samples certainly indicating
alterations in the autophagic pathway, which can, it seems predict long COVID [
26
]. In
fact, it now seems that eye problems are becoming an increasing concern—even in the
longer term [
118
]. Likewise, the link between skeletal muscle problems and COVID-19 are
well recognised, and are associated with weakness and exercise intolerance, and could be
related to direct and indirect effects, including motoneuron problems; the similarities to CFS
are suggesting further investigational avenues. There is evidence of early mitochondrial
dysfunction, akin to what happens to sepsis, and certainly, recovery from critical illness is
strongly correlated with restoration of oxidative phosphorylation [
119
]. The root of this
probably lies in the fact that mitochondria are central to the immune response [120].
The virus has also been associated with gastro-intestinal problems, which are partly re-
lated to acute severity, and in the longer term, disordered gut-brain interaction (DGBI) [
121
].
There are many similarities with COVID-19 infection and inflammatory bowel disease, in
particular dysbiosis and its perpetuation after viral clearance—critically, it is thought that
the gut could also be trophic for the virus as well. There are also similarities in metabolomic
profiles, for instance in tryptophan as well as in some related to Kreb’s cycle compounds,
including succinate [
122
]. The importance here is that it is now well recognised that there
is bidirectional communication between the gut microbiota and mitochondria, for instance,
via short chain fatty acids (SCFA), and other microbiota metabolites, including secondary
bile products that can modulate mitochondrial energy and inflammatory function. In turn,
mitochondrial function regulates gut function, inflammation, and gut wall integrity. Criti-
cally, the right amount of endurance exercise can beneficially modulate the gut microbiota,
while excessive exercise can have the opposite effect [123].
Biomedicines 2022,10, 3113 13 of 33
Overall, this might suggest that much of the pathology could be related to a contextual
metabolic reprogramming of different organ systems. Some could be related to a gen-
eralised immune response, but direct effects of the virus on some tissues would also be
relevant, such as in the brain or the gut.
3.3. The Importance of Mitochondrial DNA Copy Number—A Tipping Point?
If we assume that one of the precipitating factors for long COVID is existing sub-
optimal mitochondrial function, then one marker might be mitochondrial DNA copy
number. One of the key themes emerging from this viral-attack/host-defence tug of war
with regards metabolic reprogramming is that the host defence system has evolved, as a
countermeasure, to induce destruction of some of its own components to help remove a
pathogen. For example, programmed cell death (PCD) has evolved both as a mechanism
to stop the spread of viruses, while, depending on the type of death, it can also act as a
powerful inflammatory signal. This of course mirrors what happens in response to stress.
The flipside is that viruses also manipulate PCD for their own purposes; mitochondria,
because of the central role in many forms of PCD, are thus intimately evolved in this
ancient arms race [
124
]. For instance, there are data suggesting that certainly in yeast,
there is a programmed response that quite deliberately deletes mtDNA genes in response
to oxidative stress in the short term to restrict production of ROS; this process could
become maladaptive in the long term [
30
]. Certainly, it seems that mtDNA copy number
(mtDNAcn) is important in overcoming heteroplasmic mtDNA mutation, which could
be become a problem if not diluted out enough; in effect, the absolute levels of wild type
mtDNA are key in determining pathology, especially in post-mitotic tissues, but not in
rapidly dividing tissues [125].
Although there are some confounding data, the majority points towards mtDNAcn de-
creasing with age, which is probably associated with increasing mutation and heteroplasmy,
and certainly, in contrast, healthy mitochondrial mass is associated with longevity [
126
].
This certainly fits with the mitochondrial bottleneck inheritance concept, in effect, a smaller
number of heteroplasmic mitochondria when passed on during fertilisation will enable
natural selection to take place between embryos, which may have relevance to the sus-
ceptibility and importance of mtDNA mutation in cancer [
127
]. When combined with the
overall origins, and function of mitochondria throughout evolution, for instance, their role
in longevity and apoptosis [
128
], their health could be pivotal in whether or not homeostasis
is restored.
The implication is that for someone with poor mitochondrial health, the virus could
easily precipitate an exaggerated inflammatory response, for instance, because their mi-
tochondrial death threshold is lower, so more cells release mtDNA, which in turn, drives
oxidative stress with further suppresses mtDNA gene expression, so tipping the system
towards hypoxia and glycolysis. This would then lower mtDNAcn, and the effects of any
detrimental mtDNA haplotypes could be become amplified.
Where this occurs is thus critical, for instance in organs with low replicative potential,
such as in the nervous system, heart or brain, but it could also occur in the blood, in
particular, in platelets (see below). This could result in a tipping point relating to a threshold.
It could be argued that this could be determined, in part, by the prior mtDNA reserve.
Evidence is that mtDNAcn change is associated with pathology, for instance, increased
mtDNA copy number can be associated with better aerobic fitness (VO
2max
) and an active
lifestyle and is greater than in someone living a sedentary lifestyle, with the lowest being
seen in patients with T2D [
32
]. Of relevance is that negative effects of mitochondrial
heteroplasmy because of mutations can be offset to some degree by increasing overall
mtDNAcn [
125
]. Simply put, if a tissue contains low levels of mtDNA, some of which
is mutated, then the likelihood of this mutation having a negative effect becomes more
pronounced if there is a viral mitochondriopathy.
Biomedicines 2022,10, 3113 14 of 33
4. Mitochondrial Health and Platelets in Long COVID
In this section, we discuss, as it could be important in relation to clotting disorders,
the potential role of mitochondrial health in relation to platelet function. Overall, the
underlying concept being discussed in this paper is that of metabolically flexibility and
reserve, and the ability of an organism to adapt to stress, which will be dependent on its
mitochondrial health. This could include platelets.
In tissues such as the heart, brain or the immune system, poor mitochondrial health
could clearly induce much of the pathology seen in these tissues. However, the platelet
has also been identified as playing a role in the pathology of COVID-19. For instance,
COVID-19
can directly induce platelet activation enhancing thrombosis [
129
]. Indeed,
circulating mtDNAcn is being used to study mitochondrial health, with mitochondria
coming from most circulating cells, including platelets. The pathology is associated with
a “U” shaped numbers curve, which most likely reflects haematopoiesis. Although it
has to be borne in mind mtDNA does not necessarily represent mitochondrial biology, as
other factors can influence it [
130
]. Interestingly, genome-wide association studies (GWAS)
of blood mtDNA have picked up associations with platelet activation, megakaryocyte
proliferation and mtDNA metabolism [
131
], while platelet mtDNA methylation seems to
be able to predict cardiovascular outcome in obesity [132].
Some of the most devastating pathologies associated with this virus, especially with
hospitalisation, are associated with the increased risk of cardiovascular problems and
venous thromboembolism (VTE) [
133
]. The risk of thrombosis is linked to platelet function,
suggesting that if their mitochondria are unhealthy, then many of symptoms associated
with both acute viral infection and long COVID, could be explained.
4.1. Platelets and Health
In humans, platelets are short lived anucleate cells that usually contain several mito-
chondria, which are essential for their haemostatic and immunological function. Critically,
their activation can lead to apoptosis. Hence mitochondrial damage or dysfunction reduces
their survival and can lead to an increased risk of thrombovascular events [19].
A key activating mechanism involves calcium modulation of the mitochondrial per-
meability transition pore (mPTP), which can lead to a loss of the mitochondrial membrane
potential and exposure of negatively charged phosphatidyl serine (PS) at the platelet surface.
Due to the heterogeneity of the platelet population, this process can be reversible in some,
indicating that the overall response can be finely tuned [
134
]. They also, on activation, seem
to activate aerobic glycolysis—but maintain mitochondrial function [
135
]. Suggestively,
evidence indicates that the increased risk of coagulation in patients with Wiskott–Aldrich
syndrome could be associated with smaller platelets and less mitochondria, and thus,
less capacity to buffer calcium [
136
]. This is in keeping with the well described role of
mitochondria in calcium homeostasis and signalling and certainly in platelets, fits with
the data indicating the mitochondrial calcium uniporter (MCU) plays a role in regulat-
ing procoagulant platelet formation [
137
]. It also appears that dynamin-related protein-1
(Drp1), which is a GTPase involved in mitochondrial dynamics, is important in controlling
platelet exocytosis [
138
]. A key point here is that as individual platelets only contain a small
number of mitochondria, if any of them are damaged, or possibly, have mutations, then
their health could dramatically affect platelet function. Data are showing that migrating
cells can export damaged mitochondria via a newly described process called “mitocytosis”
encapsulated in a in a “migrasome” [
35
]; whether platelets do this as well is an interesting
question, but it seems likely (see below).
It is therefore suggestive that free mitochondria derived from platelets also modulate
immune cells, suggesting that healthy mitochondria could have a translational treatment
potential; this supports the emerging evidence that cells, in general, swap mitochondria
as part of a homeostatic mechanism [
139
]. An interesting example of this is that activated
platelets can transfer functional mitochondria to mesenchymal stem cells, enhancing their
healing ability [
140
]. In contrast, mitochondria released from damaged brain tissue can
Biomedicines 2022,10, 3113 15 of 33
induce platelet procoagulant activity [
141
]. It also seems that cancer chemotherapy can
induce platelet dysfunction associated with mitochondrial damage [
142
]. Furthermore,
cardiovascular disease is also linked to heightened platelet activation, but regular exercise
reduces this effect [
143
]. In fact, it has now been shown that platelet mitochondrial function
reflects systemic mitochondrial function following interventions such as physical activity
training [
144
]. This reinforces the finding that mitochondria communicate with each other,
for instance, via myokines, and play a key role in the systemic response to exercise [145].
In short, we should consider platelets as being part of the global mitochondrial sys-
tem, which might suggest that their dysfunction could be important in say, disseminated
intravascular coagulation (DIC), if, in general, a person’s mitochondrial function is sub-
optimal. Equally, someone with an athletic disposition might well be protected, which does
seem to be born out with the data [
146
]. In effect, it is possible that a healthy mitochon-
drial population engendered by exercise is likely reflected in platelets, while an unhealthy
population as result of a poor lifestyle, is also reflected in these cells.
4.2. SARS-CoV-2, Platelets and Mitochondria
As indicated, a common finding in COVID-19 patients is hyperactivation of platelets.
This could be due to increased inflammatory factors, but many viruses are also known
to directly activate platelets and megakaryocytes, or indirectly via immune complexes.
SARS-CoV-2 mRNA has been found in platelets, but there has been some discussion as
to whether platelets express its main receptor, ACE2, although there are other platelet
proteins it could bind to, such as CD147. Another route of uptake could be virus particles
within extracellular vesicles (EVs) [
147
,
148
]. Indeed, new evidence seems to suggest that
platelets from hospitalised patients can take up the virus via several routes, which does not
always require ACE2. Intriguingly, this seems to result in PCD via apoptosis or necroptosis,
but not pyroptosis; pyroptosis and necroptosis can be inflammatory, but apoptosis is
normally not. Both viral proteins and fragmented RNA were detected, as well as ACE2
protein. Interestingly, it seems that the virus ended up in vacuoles, where it was digested,
furthermore, there was no evidence of viral replication. It also seems that the virus induced
platelets to release EVs. One explanation is that platelet uptake of this virus, and perhaps
other viruses, is a way of neutralising these pathogens [149].
Given the well described role of mitochondria in several forms of cell death [
150
],
this would indicate how mitochondrial health could determine outcome. Platelets have
autophagic machinery, indicating they can remove dysfunctional components [
151
]; dis-
ruption of autophagy, for instance, due to poor mitochondrial function, could be pivotal
in how they respond to stress. It is possible the virus could induce the platelet to release
damaged mitochondria. Perhaps less appreciated, platelets, like most other cells, can also
undergo apoptosis, which can also be modulated by mitochondrial health. They are also
involved in multiple other functions, including immune surveillance, and are modulated
by multiple compounds, including polyphenols [152].
If, as has been suggested, platelets are acting as a means of neutralising the virus,
this raises the interesting possibility that this has been selected for during evolution as
these cells do not have nuclei. Many viruses modulate nuclear traffic, and as 99% of
mitochondrial protein is coded for in the nucleus [
153
]; this could be important. Thus, this
evolutionary strategy perhaps reduces the ability of the virus to reprogram this organelle.
Certainly, it seems that like many viruses, SARS-CoV-2 can metabolically reprogramme
many cells towards glycolysis, in effect, a kind of Warburg shift (aerobic glycolysis) that
enhances viral replication—which may explain why diabetes can predispose to worse
disease [
92
,
154
]. This suggests that a Warburg shift in COVID-19 could be critical [
22
]. It
may therefore be relevant, as indicated, that platelet activation results in a switch to aerobic
glycolysis and an upregulation of the pentose phosphate pathway (PPP) and increased
ROS generation via NADPH oxidase (NOX), where mitochondrial function remains viable
but inhibition of respiration does not inhibit activation; suppression of aerobic glycolysis
Biomedicines 2022,10, 3113 16 of 33
is thus a developing approach to preventing excessive platelet activation and thrombus
formation [135]. This of course represents changes in how the Kreb’s cycle is functioning.
In terms of a possible mitochondrial swapping between cells, data suggest that SARS-
CoV-2 can infect brain endothelial cells where internalised spike protein components can
directly damage mitochondria [
155
]. In turn, extracellular mitochondria released from
damaged brains can induce platelet activation via binding to phospholipid-CD36 [
141
].
Furthermore, in COVID-19 patients, peripheral blood mononuclear cells (PBMC) are repro-
grammed, displaying compromised mitochondrial function [
156
]. In contrast, platelet
mitochondria can reprogramme CD4+ T cells, which could be important in the sup-
pression of the proliferation of PBMCs [
139
]. Overall, this seems to suggest there is an
inflammatory/anti-inflammatory feedback system involving mitochondria, platelets, and
infected cells.
Perhaps a further clue may come from the observation that mitochondria contain com-
ponents of the renin-angiotensin system (RAS), which includes ACE2—the antioxidant and
anti-inflammatory component of the RAS that produces Ang (1–7). In neurons, this is in-
volved in generating nitric oxide (NO), and the whole system, including ACE2 and a newly
identified receptor, the mitochondrial Mas-related receptor (MrgE), seems to decrease with
age [
157
]. Interestingly, ACE2, delivered via exosomes, can restore endothelial function by
restoring mitochondrial health following exposure to angiotensin II [
158
]. It is thus perhaps
noteworthy that as serious COVID-19 disease is thrombotic it can be viewed through the
prism of Virchow’s triad of vascular damage, altered blood flow and hypercoagulability,
where the RAS plays a central role. Of relevance is the fact that ACE2 is a key negative
regulator of this system, including in platelets via production of NO [159].
Overall, this might suggest that if platelets are not functioning properly due to sub-
optimal mitochondria, this could be part of a positive feedback loop driving continual
inflammation in someone with long COVID. If, as is becoming clear, mitochondria are
being swapped between cells and tissues, then this could reflect a systemwide sub-optimal
mitochondrial population, which is expressed in platelets as well.
4.3. The Optimal Platelet Mitochondrion—Exercise as a Medicine
A key question of course is if the platelets in people with long COVID do, in part,
reflect a persistent sub-optimal systemic mitochondrial induced pathology, how might
it be reversed? One universal treatment that seems to help in multiple indications is
physical activity.
Acute exercise can activate platelets, but regular exercise diminishes this response,
and favourably modifies their function at rest—and likely plays a key role in prevention
against cardiovascular disease [
143
]. Critically, platelet mitochondrial function seems to
reflect their overall systemic status [
144
]. In short, exercise results in a healthier platelet
mitochondrial population. However, the truth is that exercise is a key component of
maintaining mitochondrial health throughout the body, not just in skeletal muscle [160].
A healthy mitochondrial system results in good control of their potential to elicit an
immune response. Due to their bacterial ancestry, release of both mitochondrial RNA,
DNA, and proteins can amplify an immune response; this often occurs during oxidative
stress [
161
]. A key modulator of this is mitophagy [
117
]. This system is tightly integrated
with the immune system, for instance, via the production of interferons to defend against
viruses [
162
], of which MAVS are central following activation of pathogen pattern recogni-
tion receptors [
163
]. MAVs also interact with the NOD-like receptor pyridine containing
(NLRP) 3 inflammasome, which also detects pathogenic nucleotides, and can generate
ROS and IL-1
β
[
164
]. Mitochondrial function is thus key in viral defence, in particular, in
relation to interferon signalling.
Of relevance in relation to a poor lifestyle possibly leading to worse acute disease
and long COVID, is that sterile activation of NLRP3 may occur in the metabolic syndrome,
leading to generalised inflammation (“metainflammation”), which is also associated with
mitochondrial dysfunction [
165
]. Platelets contain NLRP3, so it is interesting that its
Biomedicines 2022,10, 3113 17 of 33
activation by the Dengue virus might result in thrombocytopenia [
166
], as well as in primary
immune thrombocytopenia; tellingly, this is also associated with reduced anti-oxidant
capacity [
167
]. As there is an association between the metabolic syndrome and severity
of COVID-19 [
168
], this might suggest that a heightened activity of NLRP3 caused by a
pre-existing condition might further worsen platelet function when infected by the virus.
Conversely, not only does exercise protect against the metabolic syndrome, but aerobic
fitness seems to provide a measure of protection against developing severe
COVID-19—which
is likely related to mitochondrial fitness [
169
,
170
]. Exercise stimulates adaptive improve-
ment of mitochondrial function in muscle, and via myokines, in other tissues through-
out the body [
145
]; acute exercise is inflammatory, but following recovery, enhances an
overall anti-inflammatory phenotype [
171
]. The underlying principle is hormesis; stim-
ulating mitochondrial function can be associated with oxidative stress, which in turn,
induces an adaptive increase in both mitochondrial and anti-oxidant capacity—which
seems to be essential for a balanced inflammatory response [
172
]. Data seem to suggest
that macrophage mitochondrial function is key during injury, for instance, mitochondrial
ROS is pro-inflammatory to begin with, but via hormesis, results in an anti-inflammatory
milieu enabling resolution [173].
This would seem to suggest that to some extent, sub-optimal mitochondrial function in
platelets may well reflect that of the entire body and potentially be associated with clotting
imbalances. Critically, it would also hint that exercise could well play a key role in both
prevention and treatment of conditions like long COVID.
5. Discussion and Implications
Given the evolutionary roots of eukaryotic cells, it is no surprise that mitochondria are
central to every aspect of modern cell functioning and have thus been part of a billion year
plus arms race with viruses. Most of the symptoms of long COVID can be explained, to
varying degrees, by sub-optimal mitochondrial function in multiple organs, including, we
suggest, in platelets. In some respects, the metabolic/inflammatory phenotype is not too
dissimilar to that induced by a poor lifestyle, which might explain why this population is
more susceptible [
22
]. The potential scale of this interaction is perhaps indicated by data
that suggest in the USA, between 2017 and 2018, only 6.8% of adults displayed optimal
cardiometabolic health [
174
]. What is a normal metabolic system and what is an optimally
healthy one may not be the same thing in this modern world.
It has been said that as an ancient oxidative symbiont, if not constantly stimulated, the
mitochondrion slowly loses its ability to handle oxidative and macronutrient stress, leading
to the palette of lifestyle induced disorders we see today, which hints at why endurance
exercise is so important [
175
]. Hormesis is in fact a vital component of maintaining health,
as it is this very process that has driven evolution and adaptation, and without it, large
sections of society appear to be experiencing accelerated ageing phenotype [176]. It could
therefore be argued that long COVID, at the broader level, is simply what happens when
this new virus meets a metabolically unprepared host.
In this last section, we look at long-term health, a possible mitochondrial definition
of long COVID, and how we might approach treatment. The simple observation is that
just about all strategies that have been used to improve functional longevity, and thus, a
healthy lifespan and potentially slow the ageing process, may well help in long COVID. It
is quite possible that any mild stressor, if applied in the right way, could be beneficial. This
of course not only includes exercise, but also calorie restriction, as well as diet, but also
things like acute temperature stress—both hot and cold. Indeed, one of very first insights
into hormesis came from heat stress and the role of heat shock proteins [
177
], which is
perhaps supported by data on sauna use, coupled with cold stress (e.g., rolling in snow),
and longevity [
178
]. Figure 5, which combines components from Figures 3and 4, illustrates
one way of viewing how improving mitochondrial health and thus metabolic flexibility,
can resolve inflammation restoring system homeostasis.
Biomedicines 2022,10, 3113 18 of 33
Biomedicines2022,10,xFORPEERREVIEW18of34
toodissimilartothatinducedbyapoorlifestyle,whichmightexplainwhythispopulation
ismoresusceptible[22].Thepotentialscaleofthisinteractionisperhapsindicatedbydata
thatsuggestintheUSA,between2017and2018,only6.8%ofadultsdisplayedoptimal
cardiometabolichealth[174].Whatisanormalmetabolicsystemandwhatisanoptimally
healthyonemaynotbethesamethinginthismodernworld.
Ithasbeensaidthatasanancientoxidativesymbiont,ifnotconstantlystimulated,
themitochondrionslowlylosesitsabilitytohandleoxidativeandmacronutrientstress,
leadingtothepaletteoflifestyleinduceddisordersweseetoday,whichhintsatwhyen‐
duranceexerciseissoimportant[175].Hormesisisinfactavitalcomponentofmaintain‐
inghealth,asitisthisveryprocessthathasdrivenevolutionandadaptation,andwithout
it,largesectionsofsocietyappeartobeexperiencingacceleratedageingphenotype[176].
ItcouldthereforebearguedthatlongCOVID,atthebroaderlevel,issimplywhathappens
whenthisnewvirusmeetsametabolicallyunpreparedhost.
Inthislastsection,welookatlong‐termhealth,apossiblemitochondrialdefinition
oflongCOVID,andhowwemightapproachtreatment.Thesimpleobservationisthat
justaboutallstrategiesthathavebeenusedtoimprovefunctionallongevity,andthus,a
healthylifespanandpotentiallyslowtheageingprocess,maywellhelpinlongCOVID.
Itisquitepossiblethatanymildstressor,ifappliedintherightway,couldbebeneficial.
Thisofcoursenotonlyincludesexercise,butalsocalorierestriction,aswellasdiet,but
alsothingslikeacutetemperaturestress—bothhotandcold.Indeed,oneofveryfirstin‐
sightsintohormesiscamefromheatstressandtheroleofheatshockproteins[177],which
isperhapssupportedbydataonsaunause,coupledwithcoldstress(e.g.,rollinginsnow),
andlongevity[178].Figure5,whichcombinescomponentsfromFigures3and4,illus‐
tratesonewayofviewinghowimprovingmitochondrialhealthandthusmetabolicflexi‐
bility,canresolveinflammationrestoringsystemhomeostasis.
Figure5.Tippingthesystembacktohealth.AslongCOVIDmightberepresentedbytheuppersee
sawwherebythemetabolicflexibilityfulcrumistoofartotherighttoenabletherestorationof
homeostasis,thesystemhaseffectivelypassedatippingpointandgotstuck.Resolutionmayre‐
volvearoundenhancingmetabolicflexibilityand/orsuppressinginflammatorypathwaystoshift
thefulcrumtotheleft,asinthelowerseesaw.Atthesimplestlevel,someonestartingwithareduced
populationofslightlystressedmitochondriacouldwellbemorelikelytodeveloplongCOVID—
whichimplies,forresolution,thatthesystemneedstobeinducedtoadapttowardsnormalby
Figure 5.
Tipping the system back to health. As long COVID might be represented by the upper
see saw whereby the metabolic flexibility fulcrum is too far to the right to enable the restoration
of homeostasis, the system has effectively passed a tipping point and got stuck. Resolution may
revolve around enhancing metabolic flexibility and/or suppressing inflammatory pathways to shift
the fulcrum to the left, as in the lower see saw. At the simplest level, someone starting with a
reduced population of slightly stressed mitochondria could well be more likely to develop long
COVID—which implies, for resolution, that the system needs to be induced to adapt towards normal
by hormetic approaches known to stimulate renewal of a healthy population of mitochondria. The
most obvious of these is a carefully balanced prescription of physical activity.
5.1. Can We Say What Long COVID Is?
At its simplest, it could be described as a chronic and self-perpetuating metabolically
imbalanced dyshomeostatic state induced by the virus that fails to resolve. It perhaps has
all the hallmarks of an accelerated ageing syndrome and thus similarities to inflammaging.
It could be argued that this occurs because the original system was not robust enough, and
because the virus might induce a particular set of metabolic conditions associated with
inflammation, it can tip a weakened system into a positive feedback spiral—which might be
made worse because part of the host’s defence system against the virus also acts in a similar
metabolic direction. The key here is that the capacity of a single system, represented by
the Kreb’s cycle and thus, mitochondria, must have enough reserve to operate in multiple
modes in different tissues. In a few words, it requires metabolic flexibility.
Inflammation is triggered in several ways, but oxidative stress, and thus, ROS, are
pivotal, and initially work, beyond a threshold, as a feed forward amplification loop. It
could be said that resolution occurs because the very same stress activates a feedback
suppressive anti-inflammatory/antioxidant system that engenders repairing damage once
the threat is removed—the right amount of exercise is a good example of how this can be
induced [
179
]. One chronic driver of inflammation could be that damaged mitochondria
are releasing bits of oxidised DNA, which is thought to be an inflammatory mechanism as
it can activate the NLPR3 inflammasome [
180
]. Again, this could come back to a vicious
cycle outlined in the mitochondrial/lysosomal theory of ageing [
117
]. Of course, where the
line is drawn between chronic inflammation, and say, adaptive immunity is perhaps less
clear. A key component of immunity is its ability to remember past challenges, for instance,
via epigenetics, but this can become maladaptive [
181
]. Does this virus somehow alter the
epigenetic memory?
Biomedicines 2022,10, 3113 19 of 33
One possibility is that the human homeostatic system evolved over many generations
where its metabolically flexible state was reliant on stimulation from a hormetic environ-
ment, for instance, lots of physical activity, occasional fasting, temperature extremes and
a diet high in bioactive plant compounds. In effect, the system became “canalised” to a
particular environment. In a modern world, for large sections of the population because of
technology, this stimulus has been lost, resulting in reduced antioxidant capacity and ten-
dency for the immune system to over-react in response to infections. Without the induced
metabolic flexibility, the memory signal becomes much stronger and chronic, so potentially
becoming maladaptive. As organisms age, this restorative pathway naturally declines
and robustness decreases, and they become increasingly frail and less able to adapt. Thus,
the concept of “inflammaging” emerged, which also explains how immunosenescence
develops; mitochondrial function and hormesis are pivotal in modulating this [182].
This would certainly suggest an inability to restore redox balance, which has similari-
ties to what happens in CFS [
183
], could play an age-related role in developing long COVID.
Certainly, evidence is that nutrient sensing, mitochondrial function, stem cell exhaustion
and altered cellular communication are all linked to the epigenetic aging process, although
interestingly, it appears that cellular senescence, telomere shortening and genomic instabil-
ity may not be [
184
]. However, there is some evidence that shorter telomeres are linked to
worse COVID-19 severity in relation to T cell expansion [
185
]. It also seems that the DNA
damage response (DDR) increases with age-related telomere shortening, which seems to
increase ACE2 expression [
186
]. In contrast, genetically predicted short telomere lengths
have also been shown not to be related to severity [
187
]. This may indicate that telomere
length alone, especially if genetically determined, is not enough to explain it—indicating
there is a strong age and environmental element.
Clearly, loss of immune system function is an important factor in ageing, and “im-
munosenescence” is a well described ageing problem, as it results in a reduced ability to
resist pathogens and cancer cells and critically, can drive senescence in other organs [
188
].
Loss of mitochondrial function is part of the process in immunosenescence, but it is
likely that mild mitochondrial stress, via the production of mitokines, does have an anti-
inflammatory function and can limit immunosenescence overall [
189
]—which fits well with
the importance of hormesis in keeping an optimally functional immune system. Indeed, it
is becoming clear that skeletal muscle plays a vital role in maintaining a healthy immune
system [
190
]. For instance, it can harbour anti-viral CD8
+
T cells, so preventing T cell
exhaustion [191].
Ultimately, it could argued that as a result of an “intelligence paradox”, whereby
humans have all but removed all the stressors required to induce an adaptable and flex-
ible metabolism [
192
], they have shifted their overall metabolic phenotype to one that
favours the virus, and even if they manage to clear the virus, the system cannot always
reset properly.
5.2. Restoring Metabolic Flexibility—A Hormetic Approach?
The implication of hormesis is that our systems do require stimulus from the occasional
right kind of mild stress to be optimally healthy. If long COVID is fundamentally a
chronic and self-perpetuating metabolically imbalanced dyshomeostatic state/syndrome
induced by the virus that fails to resolve, can the right stimulus, or inhibition of feed-
forward inflammatory pathways help in recovery? This could take the form of drug-based
therapy, exercise, calorie restriction, or even, electromagnetic and light-based modulation
of metabolism. The goal would be to restore mitochondrial health.
In fact, because of the lack of consensus on the underlying causal pathology and a
plethora of definitions, there are already many trials underway trying different approaches
targeting both individual symptoms, such as fatigue or lung problems, or more generalised
approaches, which, because of the inflammatory component are centred around suppress-
ing inflammation. For instance, approaches include hyperbaric oxygen and radiofrequency-
based therapies, corticosteroids and statins, anti-inflammatory biologics, dietary supple-
Biomedicines 2022,10, 3113 20 of 33
ments ranging from vitamin C, nicotinamide to coenzyme Q10 and melatonin, polyphenols
and targeting Nrf2, to exercise and breathing classes [
193
,
194
]. Interestingly, a Kreb’s cycle
intermediate, oxaloacetate, has also been tried, with some success in both ME/CFS and long
COVID associated fatigue [
195
]. Even an endocannabinoid due to its anti-inflammatory
potential have been studied—with some evidence of efficacy [196].
In this section, we review some of the main approaches being tried, many of which are
known to enhance functional longevity and health. Some of these are likely to be reliant to
some degree on hormetic mechanisms, while the mechanism of others relies more on direct
modulation of wayward pathways.
5.2.1. A Healthy Plant-Based Diet?
It has been suggested that a healthy plant-based diet could be important in treat-
ing long COVID [
197
]. Plant rich diets contain lots of phenolic compounds, which are
well known to modulate mitochondrial function in a number of ways, including being
“hormetic” [
198
]. Why many plant compounds act as medicines is perhaps a much deeper
question, but a clue may be that they may have started out as sunscreens, in effect, dis-
sipating solar potential, which meant during evolution they became integrated into a
generalised stress response. This would explain why they modulate so many intracellular
targets, including mitochondria, and have clear dose-related differential effects, as well as
anti-pathogen actions, and the ability to control host cell fate. It also explains why they can
be both direct antioxidants and oxidants [
198
]. In effect, they can buffer a potentially highly
damaging redox situation, and turn it into an adaptive signal, and tip the organism out of a
vicious cycle.
5.2.2. Antioxidants and Oxidants—The Metformin Experience
Aside from anti-viral drugs, the concept that biology relies on hormetic stressors to
maintain optimal health may provide some insight to the success, or not, of some treatments.
For instance, many “antioxidant” drugs have been given to restore redox balance, but they
have had limited success in COVID-19 [
183
]. One reason could be that direct antioxidants
simply inhibit the hormetic response. Modulation of redox, however, is still a potential
approach, especially if targeted to the right intracellular location to manage the balance
between adaptive signalling and suppression of excessive, and potentially damaging,
oxidative stress. This is of course could be one way of viewing how plant-derived phenolic
compounds might work. However, there are some more traditional drugs that may work
in a similar way, for example, metformin.
Metformin has several intracellular targets, a primary one is complex 1 of the ETC
with some reports suggesting it can inhibit ROS production at this complex [
199
]. However,
it has also been shown to be mitohormetic via enhancement of ROS, leading to increased
longevity [
200
]. It has been investigated in COVID-19 and has shown some benefit in
hospitalised patients [
201
–
203
]. A possible mechanism has been suggested involving
inhibition of mitochondrial function and inflammasomes, which could help to reduce
pulmonary inflammation [
204
]. Perhaps significantly, it has also been shown that metformin
can reduce platelet hyper-activity in patients with polycystic ovary syndrome, which also
appears to involve stabilising mitochondrial function [
205
]. Metformin is therefore an
example of a mitochondrially targeted compound with several effects; the outcome is likely
to depend on dose and the metabolic/inflammatory status of the cell and its mitochondria.
This is pivotal, as it provides an insight into how to suppress oxidative stress-driven
inflammation, while also potentially, stimulating ROS-based adaptation. Thus, the finding
that RET can be induced by TNF, which generates mtROS at complex 1 from succinate, is
perhaps significant, as the effect can be blocked by metformin [
56
]. Given that different
compartments in the body could be experiencing different grades of inflammation and
resolution and have variable metabolic flexibility due to where the virus has infected,
it is possible to explain how one compound could, in theory, both inhibit inflammation
in one place, while stimulating mitochondrial regeneration in another compartment. If
Biomedicines 2022,10, 3113 21 of 33
mitochondria and their components are indeed undergoing a constant “do-si-do” amongst
cells, then as long as one compartment can start to regenerate healthy mitochondria,
then this could be key in regenerating metabolic flexibility and resolution throughout the
entire body.
5.2.3. Learnings from Physical Activity
The global mitochondrial health concept does suggest the enhancing mitochondrial
health and capacity in one organ could result in enhancement in other parts of the body.
One of the problems of a drug-based approach is that even if many of these compounds do
act pleiotropically, for instance, modulating inflammation, they are unlikely to be able to
induce a global adaptive response. In contrast, it is now becoming recognised that one of
the most generic and powerful medicines is exercise, especially as overall it can enhance
anti-inflammatory mechanisms [169,170,206–208].
However, like all medicines, it needs to be prescribed carefully, as getting the “dose”
right could be critical. The uncertainties over its use is perhaps highlighted as NICE has
advised against graded exercise for patients recovering from COVID-19 [
209
]. However,
many clinical practitioners have suggested its use should be based on risk stratification [
210
].
The clue here is that exercise is hormetic [
211
], and thus follows a “U” shaped curve—if the
system is very heavily compromised, it will be unable to adapt quickly, and too much will
clearly induce inflammation without adaptation and make it worse.
It could therefore be argued that COVID related exercise intolerance is just an extreme
example of a bad case of delayed onset muscle soreness (DOMS). In many respects, the
approach is thus no different to standard athletic training practices, whereby untrained
individuals need to build up capacity by carefully managing exercise bout intensity with
sufficient rest periods to enable adaptation, so, with time, enhancing their ability to resist
the oxidative stress induced by increasing amounts of heavy exercise. This would certainly
suggest that at least initially, high intensity interval training (HIIT) is not a good idea, but
low-level endurance training, keeping within the aerobic threshold, is optimal, especially
after a period of rest. Determining when to do this is maybe key, so may require measuring
both more standard biochemical parameters to determine physiological status, as well as
performance metrics, such as VO2max, balance, grip strength and walking speed.
Related to this is perhaps a line of research that investigates those biochemical path-
ways involved in the exercise response to identify targets for new “exercise mimetics” [
212
].
The concept of “exercise in a pill” has been around for a while, in particular, for compounds
that modulate the AMPK-SIRT1-PGC1
α
pathway, for instance, metformin, epcatechin,
resveratrol and AICAR [
213
]. Again, however, the dose of this compound is probably key
in its actions and how it modulates mitochondrial function as they are biphasic [214].
5.2.4. Calorie Restriction and the Ketogenic Diet—Sirtuins to the Rescue?
Another approach is to restrict calories, as this is well-known to reverse many metabolic
dysfunctions. For instance, a ketogenic diet stimulates mitochondrial function [
215
]. Indeed,
calorie restriction, which is not only a way to enhance lifespan, but also has a whole slew
of other beneficial effects, including stimulating autophagy and mitochondrial renewal,
has been suggested as a possible way to help in COVID-19 [216].
Calorie restriction and autophagy are pivotal for ageing research. Many calorie re-
striction mimetics show similar metabolic effects, some of which, like rapamycin, directly
modulate a key pathway involving mTOR that is key in controlling autophagy in response
to calories [
217
]. One of the pivotal pathways underlying the benefits of calorie restriction
involves Sirt1, the sirtuins and NAD. This has led to the investigation of using NAD
+
precursors as calorie restriction mimetics, which can have anti-inflammatory effects, such
as nicotinamide mononucleotide (NMN) in various indications, especially in ageing in-
dividuals as NAD
+
production decreases with age [
218
]. Another NAD
+
precursor is
nicotinamide riboside (NR), which has also been shown to have many benefits, and has
been investigated for SARS-CoV-2 [
219
]. Sirtuins are NAD-dependent deacetylases that act
Biomedicines 2022,10, 3113 22 of 33
as metabolic sensors, and are key in modulating mitochondrial function and antioxidant
systems in response to nutrient stress, for instance, Sirt1 activates PGC1
α
, which is a key
regulator of energy metabolism and master regulator of mitochondrial biogenesis [220].
What is perhaps less appreciated is that sirtuins are also highly conserved anti-viral
factors [
221
]. One group in the anti-viral response are members of the poly (ADP-ribose)
polymerases (PARP), that use NAD as a source of ADP-ribose (ADPR) which they covalently
link to target proteins. They are upregulated by interferon. Critically, it seems that SARS-
CoV-2 genome encodes for an ADPR hydrolase, hence reversing the output of the PARPs.
This therefore dramatically upsets the cell’s NAD metabolome, driving down levels of
NAD
+
and NADP
+
, which would explain why compounds like NMN and NR could have
antiviral activity [
222
]. It has been suggested that COVID-19-induced sepsis could be
associated with severe mitochondrial dysfunction, in which suppression of sirtuin activity
and enhancement of HIF-
α
activity could play a key role [
223
]. This would certainly fit
with this imbalance, if the person survived, being a causative factor in long COVID.
5.2.5. Emerging Nonchemical Modalities
There are also emerging new treatments, such as photobiomodulation (PBM), which
uses low intensity longer wavelengths of light to modulate metabolism via absorption at
various complexes in the ETC of mitochondria, such as cytochrome C oxidase, or possibly,
in ion channels. Hormesis seems to be one mode of action, and it is now being used
for several conditions, but a commonality is as an anti-inflammatory intervention [
224
].
However, the dose, timing and wavelength are going to be important, for example, light
at 980 nm shows some very interesting dose effects and seems to work via complexes III
and IV, inhibiting ATP production at low power, but stimulating at higher power (0.1 vs.
0.8 watts, respectively), inversely, it stimulated superoxide production at the lower power to
a much greater extent than the high power [
225
]. Its use in wound healing is also becoming
accepted, including treating orals lesions in patients with COVID-19 [226].
Then there is the use of static magnetic and electric fields, which when applied in the
right way, seem to be able to suppress inflammation—possibly via a hormetic mechanism
based on altering quantum spin-states. For example, this technique has been used to
control aberrant redox signalling and inflammation in a mouse model of T2D [
227
]. Indeed,
because of the emergence of new technologies, the concept of “quantum biology” and
the observation that life is both using, and is sensitive to, electromagnetic fields is rapidly
gaining acceptance [
228
]. Because of their ability to have anti-inflammatory and tissue
healing effects, which seem to be partly reliant on modulating mitochondrial function, it
could well have application in long COVID as well.
5.2.6. Mitochondrial Transplant
However, what if a person’s “healthy” mitochondrial population is so depleted that
they simply cannot tip back into health—even in their muscles? Is it possible that a person
could simply lose enough healthy mtDNA that the system may never recover? Mito-
chondrial transplantation has been tried for several disease associated with mitochondrial
dysfunction, and is certainly an area of interest, but there are many challenges to overcome,
not least induction of an inflammatory response, the source and preservation, and the
delivery method. Although autologous transplantation is the preferred option, allogenic
mitochondria would be more readily available, but potentially more problematic [
229
]. As
far as the authors are aware, it has not been tried for diseases like COVID-19.
5.2.7. Can We Measure Mitochondrial Health?
A key underlying aspect of this paper is that sub-optimal mitochondrial health prior
to infection may, to some degree, determine the likelihood of developing long COVID
and potentially, also be a biomarker of recovery and guide treatment. Showing that
there is a correlation with the clinical phenotype, especially as someone recovers, could
be very informative. For example, comparing mitochondrial function with markers of
Biomedicines 2022,10, 3113 23 of 33
inflammation, oxidative stress and symptoms, and physical functionality, may well help
in determining the dose and timing of treatment. The problem is not only defining what
mitochondrial health is, but also accurately measuring it to produce a distribution curve
across a population in, ideally, a way that is non-invasive, or at the very least, from a
blood sample. For example, determining the ATP/ROS ratio in say, peripheral blood
mononuclear cells (PBMCs).
Would studying Kreb’s cycle intermediates and other blood metabolites help to
track mitochondrial function in long COVID? The data outlined in this paper do sug-
gest that there are clear changes in the metabolic profile. One interesting observation is the
comorbidity-associated glutamine deficiency that predisposes to severe COVID-19 as it
compromises many immunological functions [
230
]. The main source of glutamine is active
muscle, although it can be produced by other tissues such as the liver—and it has been
long known that physical activity is key to proper immune function and stress resistance. It
is also vital for fast growing cells as it provides carbon for the Kreb’s cycle, as well as being
a precursor for glutathione production and thus protection of mitochondrial function [
231
].
However, the Kreb’s cycle is also a source of glutamine, although it can be produced by
branched chain amino metabolism, plus, its production can also be manipulated (limited)
as an anti-pathogen strategy, as well as to suppress inflammation, in turn, pathogens also
manipulate its metabolism for their own ends [
232
]. In short, mitochondrial function plays
a key role in glutamine metabolism.
Studies have compared permeabilised skeletal muscle cell mitochondrial function
with circulating blood cells, such as PBMCs and platelets. The underlying premise being
that mitochondrial respiration in circulating cells can indicate a person’s overall metabolic
health. Although in one study it seemed that circulating cells could not replace muscle
biopsies, it did suggest that some parameters of platelet cell mitochondria did reflect
muscle cell mitochondria, such as complex 1 leak and oxidative phosphorylation coupling
efficiency—so could be of some value [233].
In fact, is has been suggested that the link between cardiometabolic risk factors and
altered immune cell function is via reduced respiratory capacity, and a recent study did
show this in apparently healthy individuals with some risk markers—hinting at immune
cell reprogramming towards glycolysis [
234
]. Platelets can also be used to measure mito-
chondrial function, are easier to isolate than PBMCs, and they do seem to reflect overall
systemic mitochondrial function; initial studies in runners before and after an event do
seem to support this [
144
,
235
]. So mitochondrial health in platelets could well be something
that could be measured and relevant.
Totally non-invasive ways of measuring mitochondrial function are still not available.
However, autofluorescence and lifetime imaging, say, of NADH and FAD
+
, which can not
only give good images, but also tell us a great deal about bioenergetics of live cells is an
emergent technology that is being rapidly developed [
236
]. Having a handheld device that
could measure bioenergetics of blood flow in capillaries under exposed skin may eventually
provide us with a possible way forward.
6. Conclusions
Long COVID is likely, for many people, to be the result of a viral challenge to an
already less robust system that is itself the outcome of the removal of environmental factors
that are required to maintain mitochondrial health through stress adaptation, or poten-
tially, have been compromised by a co-morbidity. There will also be gene–environment
interaction—everybody’s
immune system is different, not just genetically, but also be-
cause of the challenges they have faced from injuries, infections, and other trauma during
their lifetime.
As a generalisation, it could well be that many people can be “tipped” into a chronic
dysmetabolic/inflammatory cycle. The similarities to an accelerated ageing phenotype
suggest that approaches used to slow the ageing process, and enhance functional longevity
and a healthy lifespan, can be applied by understanding the underlying pathways and the
Biomedicines 2022,10, 3113 24 of 33
concept of hormesis. However, because the system only has so much capacity to recover,
which decreases with age, treatments need to be measured and commensurate with the
person’s current mitochondrial health status and ability to adapt. They could range from
calorie restriction to exercise and natural products, and some drugs, but also new emerging
therapies such as photobiomodulation. In some cases, direct inhibition of some pathways
may be required to break the system out of a vicious cycle, for instance, by suppressing
inflammatory pathways, or potentially, supporting antioxidant systems.
Author Contributions:
A.V.W.N. developed the concept and wrote the manuscript: G.W.G., W.B.
and J.D.B. contributed equally to critiquing the original drafts and the concept therein and approved
the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding:
The first author is the Director of Science for and is supported by the Guy Foundation. The
project received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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