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Fluorescent assays for mitophagy. A. mito-Keima is a pH-sensitive fluorescent biosensor, which fluoresces green at neutral pH in the cytosol, and red upon entry into acidic autolysosomes. B. mito-QC comprises two mitochondrially-targeted tandem fluorescent proteins, EGFP and mCherry. Both EGFP and mCherry fluoresce in the cytosol. However, in the lysosome, the fluorescence of mCherry is retained, while that of GFP is lost. C. mito-SRAI consists of two mitochondrially-targeted tandem fluorescent proteins, TOLLES and YPet. Unlike YPet, which is pH sensitive, TOLLES evades both acid-denaturation and proteolysis inside the lysosomal lumen and retains fluorescence.
Source publication
The best-known hallmarks of Parkinson’s disease (PD) are the motor deficits that result from the degeneration of dopaminergic neurons in the substantia nigra. Dopaminergic neurons are thought to be particularly susceptible to mitochondrial dysfunction. As such, for their survival, they rely on the elaborate quality control mechanisms that have evol...
Context in source publication
Context 1
... methods of mitophagy detection assess mitochondrial alterations using fluorescent dyes, such as MitoTracker Deep Red or nonyl acridine orange (NAO), or by using transmission electron microscopy [162][163][164]. In addition, fluorescent reporters have been developed to measure the final steps of mitophagy, namely, the fusion of mitophagosomes with lysosomes, which we discuss in detail below (Figure 3). ...
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Methods
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Citations
... PD is among the most common progressive neurodegenerative disorders and characterized by the progressive loss of dopaminergic neurons in the substantia nigra and basal ganglia. Lewy bodies, associated with progressive dopaminergic neuronal death, and the presence of distinctive granular α-synuclein aggregates in spherical pale bodies, are the hallmark neuropathological features of PD (Goiran et al., 2022). PD is typically recognized for its major motor symptoms, such as resting tremor, muscle rigidity, bradykinesia, and postural instability (Tansey et al., 2022). ...
Non-motor symptoms are prevalent among individuals with Parkinson’s disease (PD) and seriously affect patient quality of life, even more so than motor symptoms. In the past decade, an increasing number of studies have investigated non-motor symptoms in PD. The present study aimed to comprehensively analyze the global literature, trends, and hotspots of research investigating non-motor symptoms in PD through bibliometric methods. Studies addressing non-motor symptoms in the Web of Science Core Collection (WoSCC), published between January 2013 and December 2022, were retrieved. Bibliometric methods, including the R package “Bibliometrix,” VOS viewer, and CiteSpace software, were used to investigate and visualize parameters, including yearly publications, country/region, institution, and authors, to collate and quantify information. Analysis of keywords and co-cited references explored trends and hotspots. There was a significant increase in the number of publications addressing the non-motor symptoms of PD, with a total of 3,521 articles retrieved. The United States was ranked first in terms of publications (n = 763) and citations (n = 11,269), maintaining its leadership position among all countries. King’s College London (United Kingdom) was the most active institution among all publications (n = 133) and K Ray Chaudhuri was the author with the most publications (n = 131). Parkinsonism & Related Disorders published the most articles, while Movement Disorders was the most cited journal. Reference explosions have shown that early diagnosis, biomarkers, novel magnetic resonance imaging techniques, and deep brain stimulation have become research “hotspots” in recent years. Keyword clustering revealed that alpha-synuclein is the largest cluster for PD. The keyword heatmap revealed that non-motor symptoms appeared most frequently (n = 1,104), followed by quality of life (n = 502), dementia (n = 403), and depression (n = 397). Results of the present study provide an objective, comprehensive, and systematic analysis of these publications, and identifies trends and “hot” developments in this field of research. This work will inform investigators worldwide to help them conduct further research and develop new therapies.
... Regulating autophagy is a proposed treatment strategy for PD (Rakowski et al., 2022). Another process called mitophagy removes damaged mitochondria from cells and protects brain cells in PD (Goiran et al., 2022). ...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non‐motor symptoms. Several cellular and molecular mechanisms such as alpha‐synuclein (α‐syn) accumulation, mitochondrial dysfunction, oxidative stress and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post‐transcriptional gene regulation. They are typically about 21–25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. miRNAs like miR‐221 play important roles in various biological processes, including development, cell proliferation, differentiation and apoptosis. miR‐221 promotes neuronal survival against oxidative stress and neurite outgrowth and neuronal differentiation. Additionally, the role of miR‐221 in PD has been investigated in several studies. According to the results of these studies, (1) miR‐221 protects PC12 cells against oxidative stress induced by 6‐hydroxydopamine; (2) miR‐221 prevents Bax/caspase‐3 signalling activation by stopping Bim; (3) miR‐221 has moderate predictive power for PD; (4) miR‐221 directly targets PTEN, and PTEN over‐expression eliminates the protective action of miR‐221 on p‐AKT expression in PC12 cells; and (5) miRNA‐221 controls cell viability and apoptosis by manipulating the Akt signalling pathway in PD. This review study suggested that miR‐221 has the potential to be used as a clinical biomarker for PD diagnosis and stage assignment.
... Further, levels of mitophagy-related proteins such as BCL2-like 13 (apoptosis facilitator) (Bcl2L13) and PTEN-induced kinase 1 (PINK1) downregulated in the hippocampal area of AD patient brains, in induced pluripotent stem cells (iPSC) derived cortical neuronal cultures generated from AD patients, indicative of a defective mitophagy pathway [169]. In the case of PD, mutations in PINK1 and Parkin, which are the predominant proteins involved in mitophagy, were shown to contribute to the early onset of autosomal recessive PD [170,171]. Moreover, in the case of ALS levels of mitophagy, proteins like Parkin, PINK1, Bcl-2 interacting protein 3 (BNIP3), and p62 were also found to be reduced in SOD1G93A mice [172]. ...
Neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs.
... Although there are many studies that suggest that mitochondrial dysfunction is essential in PD, there are many studies about LID in PD, and the relationship between mitophagy and PD is highly recognized, more recently in a therapeutic context [7,[23][24][25], no studies are found in the global literature on mitophagy specifically in the treatment of LD. Thus, because genetic alterations can lead to dysfunctions in mitophagy, which in turn are related to PD, it is important to investigate potential biomarkers from the perspective of this mitochondrial process. ...
Mitophagy is an important process that participates in mitochondrial quality control. Dysfunctions in this process can be caused by mutations in genes like PRKN and are associated with the development and progression of Parkinson’s Disease (PD). The most used drug in the treatment of PD is levodopa (LD), but it can cause adverse effects, such as dyskinesia. Currently, few studies are searching for biomarkers for an effective use of lLD for this disease, especially regarding mitophagy genetics. Thus, this work investigates the association of 14 variants of the PRKN gene with LD in the treatment of PD. We recruited 70 patients with PD undergoing treatment with LD (39 without dyskinesia and 31 with dyskinesia). Genotyping was based on Sanger sequencing. Our results reinforce that age at onset of symptoms, duration of PD, and treatment and dosage of LD can influence the occurrence of dyskinesia but not the investigated PRKN variants. The perspective presented here of variants of mitophagy-related genes in the context of treatment with LD is still underexplored, although an association has been indicated in previous studies. We suggest that other variants in PRKN or in other mitophagy genes may participate in the development of levodopa-induced dyskinesia in PD treatment.
... Regulating autophagy is a proposed treatment strategy for PD (72). Another process called mitophagy, which helps remove damaged mitochondria from cells, may also play a role in protecting brain cells in PD (73). ...
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non-motor symptoms. Several cellular and molecular mechanisms such as alpha-synuclein accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post-transcriptional gene regulation. They are typically about 21-25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. MicroRNAs like miR-221 play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. miR-221 is also implicated in promoting neuronal survival against oxidative stress and in promoting neurite outgrowth and neuronal differentiation. Additionally, the role of miR-221 in PD has been investigated in several studies. According to the results of this study; 1) miR-221 protects against oxidative stress in 6-hydroxydopamine-induced PC12 cells; 2) miR-221 prevents Bax/caspase-3 signaling activation by stopping Bim; 3) miR-221 has moderate predictive power for PD; 4) miR-221 directly targets PTEN, and PTEN over-expression eliminates the protective action of miR-221 on p-AKT expression in PC12 cells; 5) miRNA-221, by manipulating the Akt signaling pathway, performs in controlling cell viability and apoptosis in PD. This review study suggests that miR-221 may provide an imperative insight for understanding the underlying mechanisms of PD and could possibly be targeted as a biomarker for therapeutic interventions in the future.
... [2,135] Mitochondrial quality control also includes mitophagy, a mitochondrion-selective autophagic process to degrade dysfunctional or defective mitochondria. [136,137] α-Syn not only localizes in the cytosol but also at or in mitochondria of DA neurons in different systems, including cell cultures, rodent midbrain, and human subjects with PD. [5,138] Tom40 is an essential protein-conducting pore that directly interacts with α-syn for its import into mitochondria. [138] Protein levels of Tom40 (but not TOM20) were significantly attenuated in PD brains and transgenic mice overexpressing wild-type human αsyn. ...
The brain is a complex organ that controls body functions and homeostasis through the action of neuronal and glial cells. Neuronal activity is highly energy-dependent and requires large numbers of functional mitochondria to provide substantial amount of energy via mitochondrial oxidative phosphorylation (OXPHOS), the most efficient metabolic process to generate adenosine triphosphate (ATP). Under stress conditions, neurons are particularly vulnerable to mitochondrial dysfunction, leading to decreased ATP synthesis, excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and intracellular Ca2+ dyshomeostasis, although not necessarily in this order. Alzheimer's disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly and are characterized by the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that compromised mitochondrial energy metabolism along with a depleted antioxidant system play a vital role in the pathophysiology of these neurological disorders. Toxic accumulation of proteins such as amyloid β peptides (Aβ) or amyloid precursor protein (APP) in AD and α-synuclein (α-syn) or leucine-rich repeat kinase 2 (LRRK2) in PD cause mitochondrial deficits through direct inhibition of electron transport chain (ETC) assembly and function, thereby resulting in further generation of ROS/RNS and disturbance of Ca2+ influx. Due to the improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. There is no effective protective treatment or therapy available but rather only very limited palliative treatment. There is an urgent need for the development of preventive strategies and disease-modifying therapies (both neuroprotective and neurorestorative interventions) to treat AD/PD. Here, we review the capability of some heterocyclic compounds to modulate Ca2+ homeostasis and signaling with a potential role in regulating mitochondrial function and associated free radical production during the development and onset of AD or PD. Moreover, we have included the chemical synthesis of a series of heterocycles and their derivatives.
... Activated microglia produce nitric oxide (NO) and superoxide, which may mix to create peroxynitrite, a highly reactive and toxic oxidant that damages and kills cells by interacting with DNA, proteins, and lipids [40][41][42]. Furthermore, NO generated by active microglia may traverse cell membranes and enter dopaminergic neurons in order to communicate with superoxide generated inside the neuron and cause oxidative damage that inevitably results in neuronal death [43]. This has been established in MPTP-induced PD animal models and is postulated to happen in PD [43]. ...
... Furthermore, NO generated by active microglia may traverse cell membranes and enter dopaminergic neurons in order to communicate with superoxide generated inside the neuron and cause oxidative damage that inevitably results in neuronal death [43]. This has been established in MPTP-induced PD animal models and is postulated to happen in PD [43]. ...
Infections represent a possible risk factor for parkinsonism and Parkinson’s disease (PD) based on information from epidemiology and fundamental science. The risk is unclear for the majority of agents. Moreover, the latency between infection and PD seems to be very varied and often lengthy. In this review, the evidence supporting the potential involvement of infectious microorganisms in the development of Parkinson’s disease is examined. Consequently, it is crucial to determine the cause and give additional treatment accordingly. Infection is an intriguing suggestion regarding the cause of Parkinson’s disease. These findings demonstrate that persistent infection with viral and bacterial microorganisms might be a cause of Parkinson’s disease. As an initiating factor, infection may generate a spectrum of gut microbiota dysbiosis, engagement of glial tissues, neuroinflammation, and alpha-synuclein accumulation, all of which may trigger and worsen the onset in Parkinson’s disease also contribute to its progression. Still uncertain is the primary etiology of PD with infection. The possible pathophysiology of PD infection remains a matter of debate. Furthermore, additional study is required to determine if PD patients develop the disease due to infectious microorganisms or solely since they are more sensitive to infectious causes.
... The PINK1/Parkin-mediated ubiquitin pathway is the main pathway that drives mitophagy. 51 In Alzheimer's disease, Aβ1- In our study, we found that the expression of PINK1 and Parkin was increased after TBI, treatment of exosome further increased the expression of PINK1 and Parkin. Interestingly, we found that knockdown of PINK1 partly inhibited mitophagy and reversed the neuroprotection of exosome, suggesting that there might be other pathways involved in the activation of mitophagy by exosome. ...
Aims
Recently, human umbilical cord mesenchymal stem cell (HucMSC)‐derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC‐derived exosome in both in vivo and in vitro TBI models.
Methods
We established both mouse and neuron TBI models in our study. After treatment with HucMSC‐derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI.
Results
We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI‐induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome‐activated phosphatase and tensin homolog‐induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin–protein ligase (PINK1/Parkin) pathway‐mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway‐mediated mitophagy after TBI in vitro.
Conclusion
Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway‐mediated mitophagy.
... Subsequently, Parkin ubiquitinates mitochondrial outer membrane proteins and Optineurin interacts with these proteins tagged by ubiquitin and targets the isolation membrane to damaged mitochondria, which are eventually sent to lysosomes for degradation (Wei et al., 2015;Rasool et al., 2018;Goiran et al., 2022;Pradeepkiran et al., 2022). ...
Neurodegenerative diseases (NDDs) are disorders in which neurons are lost owing to various factors, resulting in a series of dysfunctions. Their rising prevalence and irreversibility have brought physical pain to patients and economic pressure to both individuals and society. However, the pathogenesis of NDDs has not yet been fully elucidated, hampering the use of precise medication. Induced pluripotent stem cell (IPSC) modeling provides a new method for drug discovery, and exploring the early pathological mechanisms including mitochondrial dysfunction, which is not only an early but a prominent pathological feature of NDDs. In this review, we summarize the iPSC modeling approach of Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis, as well as outline typical mitochondrial dysfunction and recapitulate corresponding therapeutic strategies.
... Along with antioxidant enzymes, MCh rely on mitophagy, which is a specialized type of autophagy that mediates the selective removal of damaged MCh from cells, with the net effect of dampening the toxicity arising from these dysfunctional organelles [8]. There are three pathways at the crossroads of mitophagy. ...
... The second, receptor-mediated mitophagy involves the direct binding of mitophagy receptors NIX/BNIP3L or FUNCD1 to LC3 on the autophagosomes, which then deliver the engulfed damaged mitochondria to the lysosome. In the third pathway, which is known as lipid-mediated mitophagy, cardiolipin is externalized from the inner mitochondrial membrane (IMM) to the OMM, where it binds to LC3 on mitophagosomes [8]. Impairment of mitophagy was observed in several PD models and found in the brains of PD patients [120,121]. ...
An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson's disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). In this review, genetic, epigenetic and environmental factors that cause these disorders and their cause-and-effect relationships are considered. As a constituent of environmental factors, the example of organophosphates (OPs) is also reviewed. The role of endothelial damage in the pathogenesis of PD is discussed, and a 'triple hit hypothesis' is proposed as a modification of Braak's dual hit one. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.
