Figure 8 - available from: BMC Biology
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ATP synthase dimer rows shape the mitochondrial cristae. At the cristae ridges, the ATP synthases (yellow) form a sink for protons (red), while the proton pumps of the electron transport chain (green) are located in the membrane regions on either side of the dimer rows. Guiding the protons from their source to the proton sink at the ATP synthase, the cristae may work as proton conduits that enable efficient ATP production with the shallow pH gradient between cytosol and matrix. Red arrows show the direction of the proton flow. (Adapted from 17 )
Source publication
Biological energy conversion in mitochondria is carried out by the membrane protein complexes of the respiratory chain and the mitochondrial ATP synthase in the inner membrane cristae. Recent advances in electron cryomicroscopy have made possible new insights into the structural and functional arrangement of these complexes in the membrane, and how...
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Energy exchange in the cell is associated with mitochondria, which play an important role in vital processes. The Oxidative Phosphorylation System (OxРhoS), localized in the inner mitochondrial membrane, consists of five membrane enzymes. Four of the five protein complexes make up the "respiratory chain" and are involved in the transfer of electron...
Citations
... The inner boundary membrane follows the OMM closely at a distance of ∼20 nm. The IMM sharply turns at the crista junctions, where the cristae join the inner boundary membrane [35]; B. The proportions of orthodox, intermediate and condensed mitochondria (p < 0.01, chi-square test); C. The distributions of the area ratio of ICS/(ICS + matrix). The distributions were fitted by Gaussian curves; D. Quantitative analysis of the area ratio of ICS/(ICS + matrix). ...
Extensive studies have demonstrated the diverse impacts of electromagnetic waves at gigahertz and terahertz (THz) frequencies on cytoplasmic membrane properties. However, there is little evidence of these impacts on intracellular membranes, particularly mitochondrial membranes crucial for mitochondrial physiology. In this study, human neuroblast-like cells were exposed to continuous 0.1 THz radiation at an average power density of 33 mW/cm². The analysis revealed that THz exposure significantly altered the mitochondrial ultrastructure. THz waves enhanced the enzymatic activity of the mitochondrial respiratory chain but disrupted supercomplex assembly, compromising mitochondrial respiration. Molecular dynamics simulations revealed altered rates of change in the quantity of hydrogen bonds and infiltration of water molecules in lipid bilayers containing cardiolipin, indicating the specific behavior of cardiolipin, a signature phospholipid in mitochondria, under THz exposure. These findings suggest that THz radiation can significantly alter mitochondrial membrane properties, impacting mitochondrial physiology through a mechanism related to mitochondrial membrane, and provide deeper insight into the bioeffects of THz radiation.
... Beyond the involvement of NOS in nitro-oxidative stress, the nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme family also plays a significant role in ischemic and diabetic conditions. These enzymes, classified into seven isoforms (NOX1-5 and DUOX1-2), facilitate the transfer of electrons from cytosolic NADPH to molecular oxygen, producing superoxide [41]. In ischemic retinopathy, dedicated investigations have pinpointed the involvement of specific isoforms such as NOX1, NOX2, and NOX4, which mediate glial activation and contribute to vascular injuries [42][43][44]. ...
Nitric oxide synthases (NOS) are essential regulators of vascular function, and their role in ocular blood vessels is of paramount importance for maintaining ocular homeostasis. Three isoforms of NOS-endothelial (eNOS), neuronal (nNOS), and inducible (iNOS)-contribute to nitric oxide production in ocular tissues, exerting multifaceted effects on vascular tone, blood flow, and overall ocular homeostasis. Endothelial NOS, primarily located in endothelial cells, is pivotal for mediating vasodilation and regulating blood flow. Neuronal NOS, abundantly found in nerve terminals, contributes to neurotransmitter release and vascular tone modulation in the ocular microvasculature. Inducible NOS, expressed under inflammatory conditions, plays a role in response to pathological stimuli. Understanding the distinctive contributions of these NOS isoforms in retinal blood vessels is vital to unravel the mechanisms underlying various ocular diseases, such diabetic retinopathy. This article delves into the unique contributions of NOS isoforms within the complex vascular network of the retina, elucidating their significance as potential therapeutic targets for addressing pathological conditions.
... Mitochondria are double-membraned organelles that play crucial roles in cellular energy (ATP) production through oxidative phosphorylation. In addition, mitochondria also function in cell metabolism and regulate apoptosis (Kuhlbrandt, 2015). Oxidative phosphorylation occurs in mitochondrial respiratory chain complexes, including electron transport complexes I-IV and ATP synthase (also named complex V), located in the inner membrane cristae. ...
Influenza A virus can infect respiratory tracts and may cause severe illness in humans. Proteins encoded by influenza A virus can interact with cellular factors and dysregulate host biological processes to support viral replication and cause pathogenicity. The influenza viral PA protein is not only a subunit of influenza viral polymerase but also a virulence factor involved in pathogenicity during infection. To explore the role of the influenza virus PA protein in regulating host biological processes, we performed immunoprecipitation and LC‒MS/MS to globally identify cellular factors that interact with the PA proteins of the influenza A H1N1, 2009 pandemic H1N1, and H3N2 viruses. The results demonstrated that proteins located in the mitochondrion, proteasome, and nucleus are associated with the PA protein. We further discovered that the PA protein is partly located in mitochondria by immunofluorescence and mitochondrial fractionation and that overexpression of the PA protein reduces mitochondrial respiration. In addition, our results revealed the interaction between PA and the mitochondrial matrix protein PYCR2 and the antiviral role of PYCR2 during influenza A virus replication. Moreover, we found that the PA protein could also trigger autophagy and disrupt mitochondrial homeostasis. Overall, our research revealed the impacts of the influenza A virus PA protein on mitochondrial function and autophagy.
... This lateral asymmetric effect translates to a TELP associated liquid-membrane interface pH difference of about one pH unit between the crista tip (ridge) and the flat region within the same crista. It is now known that the proton-pumping "respiratory supercomplexes" (complexes I, III and IV) are situated at the relatively flat membrane 8 regions where the TELP concentration ( ) is relatively lower whereas the ATP synthase dimer rows are located at the cristae ridges (tips) where the TELP concentration ( ) is significantly higher as shown in Figure 2 [7,[32][33][34][35][36][37]. Consequently, even if the protonic outlets of the complexes I, III and IV are somehow in contact with the TELP layer at the crista flat membrane region so that their activities would be equilibrated with the redox potential chemical energy limit (−22.0 kJ mol −1 ), the total protonic Gibbs free energy ( ) at the crista tip can still be as high as −27.9 kJ mol −1 since the TELP density at the crista tip can be as high as 10 times that of the crista flat region, equivalent to an additional effective protonic Gibbs free energy of −5.89 kJ mol −1 owning to the crista geometric effect on TELP at the liquid-membrane interface [7]. ...
We have now identified two thermodynamically distinct types (A and B) of energetic processes naturally occurring on Earth. Type A energy processes such as the classical heat engines, apparently well follow the second law of thermodynamics; Type B energy processes, such as the newly discovered thermotrophic function that isothermally utilizes environmental heat energy to do useful work in driving ATP synthesis, which follows the first law of thermodynamics (conservation of mass and energy) but does not have to be constrained by the second law, owing to their special asymmetric functions. Several Type-B energy processes such as asymmetric-function-gated isothermal electricity and epicatalysis have been created through human efforts. The innovative efforts on Type-B processes to enable isothermally utilizing endless environmental heat energy could help to liberate all peoples from their dependence on fossil fuel energy, thus helping to reduce greenhouse gas CO2 emissions and control climate change towards a sustainable future for the humanity on Earth.
... When compared to intracellular mitochondria, mitovesicles differ in size, as mitovesicle diameter is 50-350 nm [2,8], while the minor mitochondria axis is 200-700 nm and the major axis is several µm in vivo [15]. They also differ in morphology, as mitovesicles lack cristae and the intermembrane space is narrower, ~ 6 nm in mitovesicles [2,8] vs. ~ 20 nm in mitochondria [16]. Furthermore, mitovesicles carry only a restricted, mostly catabolic set of mitochondrial constituents, roughly ~ 24% of the total brain mitochondrial proteome [2], and lack several proteins that are abundant in mitochondria, including TOMM20, mitofusin-2 (MFN2), and the polymerase-γ (POL-γ) subunits [2,8]. ...
... In this study, we tested these hypotheses in the murine model of DS Ts[Rb(12.17 16 )]2Cje, hereafter called Ts2 [28], an archetype of the interrelationship between mitochondrial dysfunctions, cognitive decline, and mitovesicle abnormalities, given (i) the mitochondrial dynamics alterations found in DS, both in humans and in mouse models [22][23][24][25]27], (ii) the importance of DS as a model for the pathogenesis of AD, with the progression to AD in DS correlating with mitochondrial and metabolic dysfunctions [25], and (iii) findings demonstrating that the same abnormalities in mitovesicle secretion are found in the brains of 12-month-old Ts2 mice and in human DS frontal cortices [2], suggesting that the Ts2 model is an ideal surrogate of the human counterpart to study mitovesicle biology. We found that Ts2 mitovesicles perturb long-term potentiation (LTP) of otherwise normal murine hippocampi, while microvesicles and exosomes isolated from the same brains and mitovesicles isolated from control brains do not impair LTP. ...
Background
Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved.
Methods
Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices.
Results
Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP.
Conclusions
Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.
... Thus it is important for oxidative phosphorylation and cellular respiratory function. 149,150 Cytochrome C is a multifunctional protein. 151 It acts as a scavenger of ROS and H 2 O 2 inside the mitochondrion. ...
Common for major surgery, multitrauma, sepsis, and critical illness, is a whole-body inflammation. Tissue injury is able to trigger a generalized inflammatory reaction. Cell death causes release of endogenous structures termed damage associated molecular patterns (DAMPs) that initiate a sterile inflammation. Mitochondria are evolutionary endosymbionts originating from bacteria, containing molecular patterns similar to bacteria. These molecular patterns are termed mitochondrial DAMPs (mDAMPs). Mitochondrial debris released into the extracellular space or into the circulation is immunogenic and damaging secondary to activation of the innate immune system. In the circulation, released mDAMPS are either free or exist in extracellular vesicles, being able to act on every organ and cell in the body. However, the role of mDAMPs in trauma and critical care is not fully clarified. There is a complete lack of knowledge how they may be counteracted in patients. Among mDAMPs are mitochondrial DNA, cardiolipin, N-formyl peptides, cytochrome C, adenosine triphosphate, reactive oxygen species, succinate, and mitochondrial transcription factor A. In this overview, we present the different mDAMPs, their function, release, targets, and inflammatory potential. In light of present knowledge, the role of mDAMPs in the pathophysiology of major surgery and trauma as well as sepsis, and critical care is discussed.
... MMP is generated via proton pumps housed within the membranes of mitochondria [157]. MMP plays a vital role in energy production during oxidative phosphorylation (OXPHOS) reactions [158,159]. ...
Phthalates' pervasive presence in everyday life poses concern as they have been revealed to induce perturbing health defects. Utilized as a plasticizer, phthalates are riddled throughout many common consumer products including personal care products, food packaging, home furnishings, and medical supplies. Phthalates permeate into the environment by leaching out of these products which can subsequently be taken up by the human body. It is previously established that a connection exists between phthalate exposure and cardiovascular disease (CVD) development; however, the specific mitochondrial link in this scenario has not yet been described. Prior studies have indicated that one possible mechanism for how phthalates exert their effects is through mitochondrial dysfunction. By disturbing mitochondrial structure, function, and signaling, phthalates can contribute to the development of the foremost cause of death worldwide, CVD. This review will examine the potential link among phthalates and their effects on the mitochondria, permissive of CVD development.
... Митохондриялардың негізгі жасушалық қызметі аденозинүшфосфат (АҮФ) түріндегі энергияны өндіру болып табылады. Жасушадағы митохондриялардың саны бір мыңнан бірнеше мыңға дейін өзгереді және бұл сан ұлпалар мен ағзаның түріне байланысты [1,2]. ...
... Митохондрияда әртүрлі архитектуралық екі мембрана бар екенін жоғарыда атап өттік, сыртқы мембрана органоидты қоршайды, ал ішкі мембрана екі доменнен (аймақтан) тұрады [1,2]. Сыртқы мембранаға іргелес жатқан ішкі шектеуші мембранада көптеген ақуыздар -транслоказалар бар. ...
Mitochondria are one of the main sources of reactive oxygen species (ROS) and therefore they are actively involved in the regulation of cellular redox processes and ROS signalling. Mitochondrial dysfunction plays a critical role in bioenergy metabolism and the pathogenesis of many lung diseases. The processes of mitochondrial oxidative phosphorylation and their cellular functions are specific to different cells and tissues and can be heterogeneous even within a single cell due to the existence of subpopulations of mitochondria with distinct functional and structural properties. Mitochondrial function can change in response to changes in cellular metabolism. Damage to mitochondrial DNA (mtDNA) causes mitochondrial dysfunction, including disruption of the electron transport chain and loss of mitochondrial membrane potential. In addition, damaged mtDNA also acts as a damage-associated molecular pattern that triggers inflammatory and immune responses. Asbestos causes various lung diseases, the cellular and molecular mechanisms of which are not fully understood. Asbestos fibers can induce the production of mitochondrial ROS in lung epithelial cells and macrophages. This review article examines the molecular mechanisms of mitochondrial functioning when exposed to asbestos, as well as the formation and damage of mtDNA, reactive oxygen species, the effect of asbestos on ultrastructural changes in lung tissue mitochondria, and the role of microRNA in the functional activity of mitochondria.
... Mitochondria are double-membrane surrounded organelles: the outer mitochondrial membrane (OMM), freely permeable due to the presence of a large number of porins [10], and the inner mitochondrial membrane (IMM), structured in cristae, so highly impermeable that almost all ions and molecules require membrane transporters to cross it [11]. The IMM is the primary site of adenosine triphosphate (ATP) synthesis, and it has a high percentage content of proteins involved in OXPHOS and transport of metabolites between the cytosol and the mitochondria [12]. The double-membrane system demarcates two independent compartments: the intermembrane space and the mitochondrial matrix. ...
Carnosic acid (CA), a diterpene obtained mainly from Rosmarinus officinalis and Salvia officinalis, exerts antioxidant, anti-inflammatory, and anti-apoptotic effects in mammalian cells. At least in part, those benefits are associated with the ability that CA modulates mitochondrial physiology. CA attenuated bioenergetics collapse and redox impairments in the mitochondria obtained from brain cells exposed to several toxicants in both in vitro and in vivo experimental models. CA is a potent inducer of the major modulator of the redox biology in animal cells, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of a myriad of genes whose products are involved with cytoprotection in different contexts. Moreover, CA upregulates signaling pathways related to the degradation of damaged mitochondria (mitophagy) and with the synthesis of these organelles (mitochondrial biogenesis). Thus, CA may be considered an agent that induces mitochondrial renewal, depending on the circumstances. In this review, we discuss about the mechanisms of action by which CA promotes mitochondrial protection in brain cells.
... The role of energy deprivation in the induction and pathogenesis of heart failure (HF) is well supported by clinical evidence, in which therapeutic measures to reduce energy consumption have been demonstrated to improve survival while treatment increasing energy demand is detrimental [38]. In the mitochondria, the synthesis of ATP takes place in the electron transport chain (ETC) [39]. Reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH 2 ) generated from the Krebs cycle, and from β-oxidation, transfer protons and electrons through the ETC, creating an electrochemical gradient that is then used to activate ATP synthase and produces ATP. ...
Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disability. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, an increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to an even greater health and economic burden as the global average life expectancy increases and consequently the world’s population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction including energy starvation and oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.
