Mitochondrial Dysfunction In Parkinson's Disease Research Articles

Mitochondrial dysfunction in Parkinson's disease.

The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD.

CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease.

Mitochondrial dysfunction is a significant pathological alteration that occurs in Parkinson's disease (PD), and the Thr61Ile (T61I) mutation in coiled-coil helix coiled-coil helix domain containing 2 (CHCHD2), a crucial mitochondrial protein, has been reported to cause Parkinson's disease. F1F0-ATPase participates in the synthesis of cellular adenosine triphosphate (ATP) and plays a central role in mitochondrial energy metabolism. However, the specific roles of wild-type (WT) CHCHD2 and T61I-mutant CHCHD2 in regulating F1F0-ATPase activity in Parkinson's disease, as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1F0-ATPase activity, remain unclear. Therefore, in this study, we expressed WT CHCHD2 and T61I-mutant CHCHD2 in an MPP+-induced SH-SY5Y cell model of PD. We found that CHCHD2 protected mitochondria from developing MPP+-induced dysfunction. Under normal conditions, overexpression of WT CHCHD2 promoted F1F0-ATPase assembly, while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1F0-ATPase assembly. In addition, mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1F0-ATPase. Three weeks after transfection with AAV-CHCHD2 T61I, we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model. These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.

Longitudinal Changes in Mitochondrial DNA Copy Number and Telomere Length in Patients with Parkinson's Disease.

Parkinson's disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) are biological aging markers with inconclusive results regarding their association with PD. A case-control study was used to measure TL and mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) and followed-up at one (T1) and two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines were determined by ELISA in all participants, along with clinical parameters of patients at T0. While TL was shorter in patients vs. controls at all time points evaluated (p < 0.01), mtDNA-CN showed no differences. An increase in mtDNA-CN and TL was observed in treated patients vs. naive ones (p < 0.001). Our statistical model analyzed both aging markers with covariates, showing a strong correlation between them (r = 0.57, p < 0.01), and IL-17A levels positively correlating with mtDNA-CN only in untreated patients (r = 0.45, p < 0.05). TL and mtDNA-CN could be useful markers for monitoring inflammation progression or treatment response in PD. DRT might modulate TL and mtDNA-CN, reflecting a compensatory mechanism to counteract mitochondrial dysfunction in PD, but this needs further investigation.

Mitochondrial Complex I Inhibition in Dopaminergic Neurons Causes Altered Protein Profile and Protein Oxidation: Implications for Parkinson's disease.

Mitochondrial dysfunction and oxidative stress are critical to neurodegeneration in Parkinson's disease (PD). Mitochondrial dysfunction in PD entails inhibition of the mitochondrial complex I (CI) in the dopaminergic neurons of substantia nigra. The events contributing to CI inhibition and downstream pathways are not completely elucidated. We conducted proteomic analysis inadopaminergic neuronal cell line exposed individually to neurotoxic CI inhibitors: rotenone (Rot), paraquat (Pq) and 1-methyl-4-phenylpyridinium (MPP+). Mass spectrometry (MS) revealed the involvement of biological processes including cell death pathways, structural changes and metabolic processes among others, most of which were common across all models. The proteomic changes induced by Pq were significantly higher than those induced by Rot and MPP+. Altered metabolic processes included downregulated mitochondrial proteins such as CI subunits. MS of CI isolated from the models revealed oxidative post-translational modifications with Tryptophan (Trp) oxidation as the predominant modification. Further, 62 peptides in 22 subunits of CI revealed Trp oxidation with 16 subunits common across toxins. NDUFV1 subunit had the greatest number of oxidized Trp and Rot model displayed the highest number of Trp oxidation events compared to the other models. Molecular dynamics simulation (MDS) of NDUFV1 revealed that oxidized Trp 433 altered the local conformation thereby changing the distance between the Fe-S clusters, Fe-S 301(N1a) to Fe-S 502 (N3) and Fe-S 802 (N4) to Fe-S 801 (N5), potentially affecting the efficiency of electron transfer. The events triggered by the neurotoxins represent CI damage, mitochondrial dysfunction and neurodegeneration in PD.

Mitochondrial electron transport chain defects modify Parkinson's disease phenotypes in a Drosophila model

IntroductionMitochondrial defects have been implicated in Parkinson's disease (PD) since complex I poisons were found to cause accelerated parkinsonism in young people in the early 1980s. More evidence of mitochondrial involvement arose when many of the genes whose mutations caused inherited PD were discovered to be subcellularly localized to mitochondria or have mitochondrial functions. However, the details of how mitochondrial dysfunction might impact or cause PD remain unclear. The aim of our study was to better understand mitochondrial dysfunction in PD by evaluating mitochondrial respiratory complex mutations in a Drosophila melanogaster (fruit fly) model of PD. MethodsWe have conducted a targeted heterozygous enhancer/suppressor screen using Drosophila mutations within mitochondrial electron transport chain (ETC) genes against a null PD mutation in parkin. The interactions were assessed by climbing assays at 2–5 days as an indicator of motor function. A strong enhancer mutation in COX5A was examined further for L-dopa rescue, oxygen consumption, mitochondrial content, and reactive oxygen species. A later timepoint of 16–20 days was also investigated for both COX5A and a suppressor mutation in cyclope. Generalized Linear Models and similar statistical tests were used to verify significance of the findings. ResultsWe have discovered that mutations in individual genes for subunits within the mitochondrial respiratory complexes have interactions with parkin, while others do not, irrespective of complex. One intriguing mutation in a complex IV subunit (cyclope) shows a suppressor rescue effect at early time points, improving the gross motor defects caused by the PD mutation, providing a strong candidate for drug discovery. Most mutations, however, show varying degrees of enhancement or slight suppression of the PD phenotypes. Thus, individual mitochondrial mutations within different oxidative phosphorylation complexes have different interactions with PD with regard to degree and direction. Upon further investigation of the strongest enhancer (COX5A), the mechanism by which these interactions occur initially does not appear to be based on defects in ATP production, but rather may be related to increased levels of reactive oxygen species. ConclusionsOur work highlights some key subunits potentially involved in mechanisms underlying PD pathogenesis, implicating ETC complexes other than complex I in PD.

236 Systemic mitochondrial dysfunction in monogenic Parkinson’s disease as a potential biomarker for stratification

To investigate the use of PBMCs as a biomarker of mitochondrial dysfunction in Parkinson disease (PD) fresh peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll gradient separation from PD patients with pathogenic biallelic parkin mutations as well as healthy controls (HC). PBMC mitochondrial function was analysed using Seahorse XF respirometry and flow cytometric assessment of mitochondrial membrane potential (Δψm) using TMRE staining.Nine parkin PD patients (average age 45.2yrs, 66% male) and 41 healthy controls (average age 57.8yrs, 58% female) were sampled for the study. Parkin patients had increased oxygen consumption related to proton leak, reduced maximal respiration and reduced spare respiratory after correction for age (p&lt;0.01). Additionally Parkin patients were found to have reduced resting Δψm and reduced oxygen consumption related to ATP production (p&lt;0.01). Basal oxygen consumption was similar between Parkin patients and healthy controls.These findings are in keeping with parkin’s role in removing dysfunctional mitochondria through mitophagy. The finding of normal basal oxygen consumption suggests that dysfunction is most pronounced when cells are under stress, during high ATP demand. This ‘signature’ of mitochondrial dysfunction could be applied to idiopathic PD patients to define a mitochondrial subgroup, in which personalised, stratified therapeutics could be targeted.p.campbell@ucl.ac.uk

Nuclear Genes Associated with Mitochondrial DNA Processes as Contributors to Parkinson's Disease Risk.

Over the past four decades, mitochondrial dysfunction has been a recurring theme in Parkinson's disease (PD) and is hypothesized to play a central role in its disease pathogenesis. Given the instrumental role of mitochondria in cellular energy production, their dysfunction can be detrimental to highly energy-dependent dopaminergic neurons, known to degenerate in PD. Mitochondria harbor multiple copies of their own genomes (mtDNA), encoding critical respiratory chain complexes required for energy production. Consequently, mtDNA has been investigated as a source of mitochondrial dysfunction in PD. As seen in multiple mitochondrial diseases, deleterious mtDNA variation and mtDNA copy number depletion can impede mtDNA protein synthesis, leading to inadequate energy production in affected cells and the onset of a disease phenotype. As such, high burdens of mtDNA defects but also mtDNA depletion, previously identified in the substantia nigra of PD patients, have been suggested to play a role in PD. Genetic variation in nuclear DNA encoding factors required for replicating, transcribing, and translating mtDNA, could underlie these observed mtDNA changes. Herein we examine this possibility and provide an overview of studies that have investigated whether nuclear-encoded genes associated with mtDNA processes may influence PD risk. Overall, pathway-based analysis studies, mice models, and case reports of mitochondrial disease patients manifesting with parkinsonism all implicate genes encoding factors related to mtDNA processes in neurodegeneration and PD. Most notably, cumulative genetic variation in these genes likely contributes to neurodegeneration and PD risk by acting together in common pathways to disrupt mtDNA processes or impair their regulation. © 2021 International Parkinson and Movement Disorder Society © 2021 International Parkinson and Movement Disorder Society.

Activation of transcription factor Nrf2 to counteract mitochondrial dysfunction in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, for which no disease-modifying therapies are available to date. Although understanding of the precise aetiology of PD is incomplete, it is clear that age, genetic predispositionand environmental stressors increase the risk. At the cellular level, oxidative stress, chronic neuroinflammation, mitochondrial dysfunctionand aberrant protein aggregation have been implicated as contributing factors. These detrimental processes are counteracted by elaborate networks of cellular defence mechanisms, one of which is orchestrated by transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2; gene name NFE2L2). A wealth of preclinical evidence suggests that Nrf2 activation is beneficial in cellular and animal models of PD. In this review, we summarise the current understanding of mitochondrial dysfunction in PD, the role of Nrf2 in mitochondrial functionand explore the potential of Nrf2 as a therapeutic target for mitochondrial dysfunction in PD.

Quantifying mechanisms in neurodegenerative diseases (NDDs) using candidate mechanism perturbation amplitude (CMPA) algorithm

BackgroundLiterature derived knowledge assemblies have been used as an effective way of representing biological phenomenon and understanding disease etiology in systems biology. These include canonical pathway databases such as KEGG, Reactome and WikiPathways and disease specific network inventories such as causal biological networks database, PD map and NeuroMMSig. The represented knowledge in these resources delineates qualitative information focusing mainly on the causal relationships between biological entities. Genes, the major constituents of knowledge representations, tend to express differentially in different conditions such as cell types, brain regions and disease stages. A classical approach of interpreting a knowledge assembly is to explore gene expression patterns of the individual genes. However, an approach that enables quantification of the overall impact of differentially expressed genes in the corresponding network is still lacking.ResultsUsing the concept of heat diffusion, we have devised an algorithm that is able to calculate the magnitude of regulation of a biological network using expression datasets. We have demonstrated that molecular mechanisms specific to Alzheimer (AD) and Parkinson Disease (PD) regulate with different intensities across spatial and temporal resolutions. Our approach depicts that the mitochondrial dysfunction in PD is severe in cortex and advanced stages of PD patients. Similarly, we have shown that the intensity of aggregation of neurofibrillary tangles (NFTs) in AD increases as the disease progresses. This finding is in concordance with previous studies that explain the burden of NFTs in stages of AD.ConclusionsThis study is one of the first attempts that enable quantification of mechanisms represented as biological networks. We have been able to quantify the magnitude of regulation of a biological network and illustrate that the magnitudes are different across spatial and temporal resolution.

Cardiolipin Promotes Pore-Forming Activity of Alpha-Synuclein Oligomers in Mitochondrial Membranes.

Aggregation of the amyloid-forming α-synuclein (αS) protein is closely associated with the etiology of Parkinson's disease (PD), the most common motor neurodegenerative disorder. Many studies have shown that soluble aggregation intermediates of αS, termed oligomers, permeabilize a variety of phospholipid membranes; thus, membrane disruption may represent a key pathogenic mechanism of αS toxicity. Given the centrality of mitochondrial dysfunction in PD, we therefore probed the formation of ion-permeable pores by αS oligomers in planar lipid bilayers reflecting the complex phospholipid composition of mitochondrial membranes. Using single-channel electrophysiology, we recorded distinct multilevel conductances (100-400 pS) with stepwise current transitions, typical of protein-bound nanopores, in mitochondrial-like membranes. Crucially, we observed that the presence of cardiolipin (CL), the signature phospholipid of mitochondrial membranes, enhanced αS-lipid interaction and the membrane pore-forming activity of αS oligomers. Further, preincubation of isolated mitochondria with a CL-specific dye protected against αS oligomer-induced mitochondrial swelling and release of cytochrome c. Hence, we favor a scenario in which αS oligomers directly porate a local lipid environment rich in CL, for instance outer mitochondrial contact sites or the inner mitochondrial membrane, to induce mitochondrial dysfunction. Pharmacological modulation of αS pore complex formation might thus preserve mitochondrial membrane integrity and alleviate mitochondrial dysfunction in PD.

Mitochondrial Stress Modulates Elongator Protein 3 (ELP3) Function to Enhance Dopaminergic Neurotoxicity in Cell Culture and Animal Models of Parkinson's Disease

Mitochondrial dysfunction is well established in Parkinson's disease (PD). Exposure to mitochondria‐targeting neurotoxicants, e.g., those neurotoxic pesticides that act as mitochondrial complex I inhibitors, has been linked to the pathogenesis of environmentally linked PD, but the molecular mechanisms underlying the enhanced vulnerability of dopaminergic neurons to mitochondrial toxicants are not fully understood. The histone acetyltransferase ELP3 (Elongator Protein 3) is the catalytic subunit of the RNA polymerase II elongator complex and plays an essential role in transcript elongation and maturation of projection neurons. Dysregulation of ELP3 has been implicated in a number of human disorders, but its potential role in the pathogenesis of PD remains elusive. In a serendipitous finding, we observed that mitochondria‐targeting pesticides can disrupt ELP3's function in dopaminergic neurons in cell culture and rodent models of PD. In this study, we further characterized ELP3 expression in the mouse brain and found high expression of full‐length ELP3 (62 kDa) in cytosolic fractions from different brain regions, while high levels of short‐form ELP3 (~40 kDa) were detected in the olfactory bulb (OB). Interestingly, immunohistochemical analyses revealed that ELP3 is highly expressed in TH‐positive neurons of the OB. Furthermore, OB slice cultures treated with the mitochondrial complex‐I inhibiting pesticide tebufenpyrad (Tebu) showed a reduced level of short‐form ELP3 in mitochondrial fractions. Consistently, we also found that ELP3 levels were significantly downregulated in the OB of transgenic MitoPark mice, a model which recapitulates mitochondrial dysfunction in PD. Collectively, our results indicate that ELP3 is a novel cellular target that can modulate the susceptibility of dopaminergic neurons to neurotoxic mitochondria‐targeting stressorsSupport or Funding InformationNIH grants ES026892 and ES027245 and Eugene and Linda Lloyd Endowed ChairThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Potential Role of Mic60/Mitofilin in Parkinson's Disease.

There are currently no treatments that hinder or halt the inexorable progression of Parkinson’s disease (PD). While the etiology of PD remains elusive, evidence suggests that early dysfunction of mitochondrial respiration and homeostasis play a major role in PD pathogenesis. The mitochondrial structural protein Mic60, also known as mitofilin, is critical for maintaining mitochondrial architecture and function. Loss of Mic60 is associated with detrimental effects on mitochondrial homeostasis. Growing evidence now implicates Mic60 in the pathogenesis of PD. In this review, we discuss the data supporting a role of Mic60 and mitochondrial dysfunction in PD. We will also consider the potential of Mic60 as a therapeutic target for treating neurological disorders.

Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the nigrostriatal pathway. The etiology of PD remains unclear and most cases are sporadic, however genetic mutations in more than 20 proteins have been shown to cause inherited forms of PD. Many of these proteins are linked to mitochondrial function, defects in which are a central characteristic of PD. Post-translational modifications (PTMs) allow rapid and reversible control over protein function. Largely focussing on mitochondrial dysfunction in PD, here we review findings on the PTMs phosphorylation, SUMOylation and ubiquitination that have been shown to affect PD-related proteins.

Translational approaches to restoring mitochondrial function in Parkinson's disease.

There is strong evidence of a key role for mitochondrial dysfunction in both sporadic and all forms of familial Parkinson's disease (PD). However, none of the clinical trials carried out with putative mitochondrial rescue agents have been successful. Firm establishment of a wet biomarker or a reliable readout from imaging studies detecting mitochondrial dysfunction and reflecting disease progression is also awaited. We will provide an overview of our current knowledge about mitochondrial dysfunction in PD and related drug screens. We will also summarise previously undertaken mitochondrial wet biomarker studies and relevant imaging studies with particular focus on 31P-MRI spectroscopy. We will conclude with an overview of clinical trials which tested putative mitochondrial rescue agents in PD patients.

Mitochondria in the context of Parkinson's disease.

Mitochondria in the context of Parkinson's disease.

Mitochondrial dysfunction in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of α-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we provide a detailed overview of the mechanisms that can cause mitochondrial dysfunction in PD. We bring to the forefront, new signaling pathways such as the retromer-trafficking pathway and its implication in the disease and also provide a brief overview of therapeutic strategies to improve mitochondrial defects in PD. Bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations, alterations in mitochondrial dynamics, alterations in trafficking/transport and mitochondrial movement, abnormal size and morphology, impairment of transcription and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we focus on the mechanisms underlying mitochondrial dysfunction in PD and bring to the forefront new signaling pathways that may be involved in PD. We also provide an overview of therapeutic strategies to improve mitochondrial defects in PD. This article is part of a special issue on Parkinson disease.

IDH2 deficiency promotes mitochondrial dysfunction and dopaminergic neurotoxicity: implications for Parkinson’s disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and its pathogenesis is under intense investigation. Substantial evidence indicates that mitochondrial dysfunction and oxidative stress play central roles in the pathophysiology of PD, through activation of mitochondria-dependent apoptotic molecular pathways. Several mitochondrial internal regulating factors act to maintain mitochondrial function. However, the mechanism by which these internal regulating factors contribute to mitochondrial dysfunction in PD remains elusive. One of these factors, mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2), has been implicated in the regulation of mitochondrial redox balance and reduction of oxidative stress-induced cell injury. Here we report that IDH2 regulates mitochondrial dysfunction and cell death in MPP+/MPTP-induced DA neuronal cells, and in a mouse model of PD. Down-regulation of IDH2 increased DA neuron sensitivity to MPP+; lowered IDH2 levels facilitated induction of apoptotic cell death due to elevated mitochondrial oxidative stress. Deficient IDH2 also promoted loss of DA SNpc neurons in an MPTP mouse model of PD. Interestingly, Mito-TEMPO, a mitochondrial ROS-specific scavenger, protected degeneration of SNpc DA neurons in the MPTP model of PD. These findings demonstrate that IDH2 contributes to degeneration of the DA neuron in the neurotoxin model of PD and establish IDH2 as a molecular target of potential therapeutic significance for this disabling neurological illness.

MTERF2 contributes to MPP+-induced mitochondrial dysfunction and cell damage

Parkinson's disease (PD) is a common neurodegenerative disorder whose pathogenesis is under intense investigation. Substantial evidence indicates that mitochondrial dysfunction plays a central role in the pathophysiology of PD. Several mitochondrial internal regulating factors act to maintain the mitochondrial function. However, how these internal regulating factors contribute to mitochondrial dysfunction in PD remains elusive. One of these factors, mitochondrial transcription termination factor 2 (MTERF2), has been implicated in the regulation of oxidative phosphorylation by modulating mitochondrial DNA transcription. Here, we discovered a new role of MTERF2 in regulating mitochondrial dysfunction and cell damage induced by MPP+ in SH-SY5Y cells. We found that MPP+ treatment elevated MTERF2 expression, induced mitochondrial dysfunction and cell damage, which was alleviated by MTERF2 knockdown. These findings demonstrate that MTERF2 contributes to MPP+-induced mitochondrial disruption and cell damage. This study indicates that MTERF2 is a potential therapeutic target for environmentally induced Parkinson's disease.

Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.

Impairment of the autophagy–lysosome pathway is implicated with the changes in α‐synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resulting in ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH‐SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock‐down cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB knockdown. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC‐1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain autophagy–lysosome pathway and mitochondrial biogenesis. Therefore, strategies to increase TFEB may improve both the clearance of α‐synuclein and mitochondrial dysfunction in PD. Damaged mitochondria are degraded by the autophagy–lysosome pathway and is termed mitophagy. Following mitophagy induction, the transcription factors Nrf2 and TFEB translocate to the nucleus, inducing the transcription of genes encoding for autophagic proteins such as p62, as well as lysosomal and mitochondrial proteins. We propose that these events maintain autophagic flux, replenish lysosomes and replace mitochondria.

Somatic mtDNA variation is an important component of Parkinson's disease

There is a growing body of evidence linking mitochondrial dysfunction, mediated either through inherited mitochondrial DNA (mtDNA) variation or mitochondrial proteomic deficit, to Parkinson's disease (PD). Yet, despite this, the role of somatic mtDNA point mutations and specifically point-mutational burden in PD is poorly understood. Here, we take advantage of recent technical and methodological advances to examine the role of age-related and acquired mtDNA mutation in the largest study of mtDNA in postmortem PD tissue to date. Our data show that PD patients suffer an increase in mtDNA mutational burden in, but no limited to, the substantia nigra pars compacta when compared to matched controls. This mutational burden appears increased in genes encoding cytochrome c oxidase, supportive of previous protein studies of mitochondrial dysfunction in PD. Accepting experimental limitations, our study confirms the important role of age-related mtDNA point mutation in the etiology of PD, moreover, by analyzing 2 distinct brain regions, we are able to show that PD patient brains are more vulnerable to mtDNA mutation overall.