Mitochondrial quality control (MQC) constitutes an evolutionarily conserved, multi-tiered system of molecular and organellar mechanisms that collectively preserve mitochondrial integrity, functionality, and population dynamics within eukaryotic cells.[@pickrell2015][@nunnari2012] As essential hubs of cellular metabolism, mitochondria serve as the primary site of oxidative phosphorylation (OXPHOS), producing the bulk of adenosine triphosphate (ATP) through the electron transport chain (ETC) PMID: 29462587. Beyond energy production, mitochondria are central to calcium homeostasis, reactive oxygen species (ROS) signaling, apoptosis regulation, and the synthesis of iron–sulfur clusters and steroid hormones.[@wallace2005] Given the breadth of their physiological contributions, the maintenance of mitochondrial health is a fundamental prerequisite for cellular viability, and this need is particularly acute in post-mitotic cells such as neurons PMID: 38812059.
Mitochondrial quality control (MQC) constitutes an evolutionarily conserved, multi-tiered system of molecular and organellar mechanisms that collectively preserve mitochondrial integrity, functionality, and population dynamics within eukaryotic cells.[@pickrell2015][@nunnari2012] As essential hubs of cellular metabolism, mitochondria serve as the primary site of oxidative phosphorylation (OXPHOS), producing the bulk of adenosine triphosphate (ATP) through the electron transport chain (ETC) PMID: 29462587. Beyond energy production, mitochondria are central to calcium homeostasis, reactive oxygen species (ROS) signaling, apoptosis regulation, and the synthesis of iron–sulfur clusters and steroid hormones.[@wallace2005] Given the breadth of their physiological contributions, the maintenance of mitochondrial health is a fundamental prerequisite for cellular viability, and this need is particularly acute in post-mitotic cells such as neurons PMID: 38812059.
Neurons present a uniquely demanding case for mitochondrial quality control for several interconnected reasons PMID: 36396497. First, neurons are among the most energetically消耗-intensive cell types in the mammalian body, maintaining resting potentials, trafficking organelles along elaborate axonal and dendritic arborizations, and sustaining synaptic activity—all of which demand a continuous and substantial supply of ATP.[@nicholls2005] Second, neurons are long-lived cells that must maintain their cellular architecture and functional identity for the entire lifespan of the organism, with limited capacity for cellular division and renewal. Third, the distal regions of neurons—particularly synaptic terminals—experience considerable distance from the soma, the primary site of most protein synthesis and organelle biogenesis, necessitating robust local quality control mechanisms to manage mitochondrial turnover at sites far from the cell body.[@sheng2012] Fourth, neurons generate substantial amounts of ROS as a byproduct of mitochondrial respiration, and because they are enriched in polyunsaturated fatty acids and metal ions, they are particularly vulnerable to oxidative damage—a process that directly impairs mitochondrial proteins, lipids, and mitochondrial DNA (mtDNA).[@federico2012]
The machinery of mitochondrial quality control operates at several distinct but interlinked levels. At the molecular level, mitochondria possess an array of proteases—including Lon protease (LONP1), ClpP, and the inner membrane AAA+ protease (AFG3L2 and PARL)—that recognize, unfold, and degrade misfolded or oxidized proteins within the mitochondrial matrix and inner membrane.[@levy2013] At the organellar level, quality control is mediated by the dynamic remodeling of the mitochondrial network through cycles of fusion and fission, processes that enable the mixing of mitochondrial contents, the equitable distribution of healthy mitochondria, and the segregation of damaged components for elimination.[@chan2020] The selective autophagic degradation of mitochondria, termed mitophagy, provides a dedicated pathway for the removal of severely damaged or dysfunctional mitochondria, while mitochondrial biogenesis—the de novo synthesis of mitochondria— replenishes the mitochondrial pool and adapts mitochondrial capacity to metabolic demand.[@palikaras2014] These processes are integrated with broader cellular stress responses, including the mitochondrial unfolded protein response (UPR<sup>mt</sup>), the integrated stress response (ISR), and ROS-dependent signaling cascades that coordinate mitochondrial quality control with nuclear gene expression.[@topalian2020]
The dysregulation of mitochondrial quality control has emerged as a central pathological theme in a growing number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and frontotemporal dementia (FTD).[@lin2006][^12] The accumulation of dysfunctional mitochondria within neurons is observed decades before the onset of overt clinical symptoms in many of these conditions, suggesting that mitochondrial quality control failure may represent an early upstream driver of neurodegeneration rather than a secondary consequence of protein aggregation. The present article provides a comprehensive examination of each major quality control pathway, their integration within neuronal systems, their specific roles in the pathogenesis of AD and PD, and the therapeutic strategies currently under development to restore or enhance mitochondrial quality control in the context of neurodegenerative disease.
Mitophagy is the process by which selective autophagy targets mitochondria for degradation through the lysosomal pathway, serving as a primary mechanism for the elimination of damaged, senescent, or superfluous mitochondria. Unlike bulk autophagy, which can be triggered by nutrient deprivation and proceeds in a relatively non-selective manner, mitophagy is a tightly regulated, receptor-mediated process that enables cells to specifically recognize and sequester damaged mitochondria for targeted destruction. The importance of mitophagy for neuronal health cannot be overstated: given the lifelong requirement for mitochondrial maintenance in post-mitotic neurons, the failure to remove defective mitochondria leads to the accumulation of ROS-generating, respiration-deficient organelles that propagate cellular damage in a feed-forward manner.[@chu2019]
The most extensively characterized mitophagy pathway in mammalian cells is the [PINK1](/genes/pink1)/[Parkin](/genes/parkin-prkn)-dependent pathway. Under conditions of mitochondrial homeostasis, the serine/threonine-protein kinase PINK1 (PTEN-induced kinase 1) is constitutively imported into mitochondria via the Translocase of the Outer Membrane (TOM) and Translocase of the Inner Membrane (TIM) complexes, where it undergoes proteolytic cleavage and degradation in the inner membrane.[@matsuda2010] However, when mitochondria sustain damage—whether through loss of membrane potential, mtDNA mutations, ROS-induced oxidation of proteins, or exposure to specific neurotoxins—the import of PINK1 is blocked, leading to its stable accumulation on the outer mitochondrial membrane (OMM). At the OMM, PINK1 phosphorylates ubiquitin and several OMM proteins, including mitofusin (MFN) 1 and 2, creating phospho-ubiquitin chains that serve as docking sites for the E3 ubiquitin ligase Parkin.[@kane2014] Activated Parkin then ubiquitinates a broad array of OMM proteins, labeling the damaged mitochondrion for recognition by autophagic receptors such as p62/SQSTM1, optineurin, and NDP52. These receptors bind to ubiquitin chains on the mitochondrion via their UBA domains and to LC3 (light chain 3) proteins on the forming phagophore via their LIR (LC3-interacting region) motifs, bridging the damaged organelle to the developing autophagosome.[@khaminets2015]
In addition to the PINK1/Parkin pathway, mitophagy can be mediated by a family of OMM-anchored receptor proteins that contain LIR motifs and function independently of Parkin. BNIP3 (BCL2/adenovirus E1A 19kDa interacting protein 3) and its paralog NIX (BNIP3L) are OMM proteins that serve as direct mitophagy receptors by binding to LC3/GABARAP family proteins through their LIR domains.[@lee2011] The BNIP3/NIX pathway is particularly important in certain cellular contexts, including erythropoiesis and hypoxia, and evidence suggests it may play a compensatory role in neurons when PINK1/Parkin signaling is compromised. Additionally, the FUNDC1 (FUN14 domain containing 1) receptor has been implicated in hypoxia-induced mitophagy, and the OMM protein CHCHD10, mutations in which are linked to ALS and FTD, has been shown to interact with Parkin and regulate mitophagy under stress conditions.[@genovese2021]
The regulation of mitophagy extends beyond the canonical pathway proteins to encompass a diverse array of post-translational modifications, lipid signaling events, and metabolic cues. Phosphorylation of mitophagy receptors by various kinases—including PINK1 itself, AMP-activated protein kinase (AMPK), and CaMKII—modulates their affinity for LC3 and their overall activity.[@egan2011] The OMM phospholipid cardiolipin, typically located in the inner mitochondrial membrane, externalizes to the OMM following mitochondrial damage and directly binds LC3, providing an additional layer of receptor-independent recognition.[@chu2013] The availability of nutrients, cellular energy status (as sensed by AMPK), and levels of NAD<sup>+</sup> also influence mitophagy through their effects on the autophagy initiation machinery, creating a bidirectional relationship between cellular metabolism and mitochondrial clearance.
In neurons, mitophagy operates with distinctive spatial dynamics. The distal nature of axonal and dendritic compartments necessitates that mitophagy occur not only within the soma but also locally within synapses and axonal varicosities, where mitochondria are actively turned over in response to synaptic activity and metabolic demand. The transport of mitochondria along microtubules, mediated by mitochondrial motor proteins (kinesins and dynein for anterograde and retrograde movement, respectively), is essential for delivering damaged mitochondria to lysosome-rich regions for degradation and for repositioning healthy mitochondria to energy-demanding sites.[@cai2012] Disruption of mitochondrial transport, as occurs in many neurodegenerative disease models, impairs the ability of neurons to clear damaged mitochondria from distal compartments, contributing to the focal accumulation of dysfunctional mitochondria observed in affected neurons.
Mitochondrial biogenesis is the process by which cells increase mitochondrial mass, expand the mitochondrial network, and replenish the population of functional mitochondria through the de novo synthesis of mitochondrial proteins, lipids, and mtDNA. It represents the anabolic counterpart to mitophagy and other mitochondrial clearance pathways, and the balance between these processes determines the net mitochondrial population within any given cell. In the context of neurodegeneration, mitochondrial biogenesis is of particular interest because it offers a potential strategy to offset the accumulation of defective mitochondria by promoting the generation of new, healthy organelles.[@wu2019]
The master regulator of mitochondrial biogenesis is the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), encoded by the PPARGC1A gene. PGC-1α functions as a transcriptional platform that co-activates a network of nuclear receptors and transcription factors governing the expression of genes required for mitochondrial DNA replication, transcription, and protein synthesis. Key downstream targets of PGC-1α include the nuclear respiratory factors NRF-1 and NRF-2 (nuclear respiratory factor 1 and 2), which regulate the expression of many nuclear-encoded mitochondrial proteins, and mitochondrial transcription factor A (TFAM), which drives the transcription and replication of mtDNA.[@scarpulla2011] PGC-1α also co-activates estrogen-related receptors (ERRs) and influences the expression of fatty acid oxidation enzymes, further integrating mitochondrial biogenesis with cellular energy metabolism.
The activity and expression of PGC-1α are regulated by multiple upstream signaling pathways that respond to cellular energetic demands. AMP-activated protein kinase (AMPK), the principal cellular energy sensor, is activated when the AMP:ATP ratio rises—such as during periods of increased energy demand or mitochondrial dysfunction—and directly phosphorylates PGC-1α, enhancing its transcriptional activity.[@jger2007] Similarly, the NAD<sup>+</sup>-dependent deacetylase sirtuin 1 (SIRT1) deacetylates PGC-1α in response to increases in the NAD<sup>+</sup>:NADH ratio, activating its coactivator function. The NAD<sup>+</sup> connection is particularly relevant to neurodegeneration because cellular NAD<sup>+</sup> levels decline with age and are further reduced in several neurodegenerative disease states, potentially contributing to impaired mitochondrial biogenesis.[@braidy2015] Additionally, PGC-1α can be induced by thyroid hormone, glucocorticoids, and β-adrenergic signaling, while its expression is suppressed by inflammatory cytokines and certain forms of cellular stress.
Beyond PGC-1α, several auxiliary pathways contribute to the orchestration of mitochondrial biogenesis. PGC-1β (PPARGC1B) shares functional redundancy with PGC-1α and can partially compensate for its loss, though tissue-specific differences in their regulation exist. The ERRα (estrogen-related receptor alpha) functions as a major downstream effector of PGC-1α signaling, and the TFB2M and TEFM proteins are involved in mtDNA transcription and replication.[@wredenberg2006] The import of nuclear-encoded mitochondrial proteins, mediated by the TOM and TIM complexes, is itself a regulated process influenced by the mitochondrial membrane potential and the availability of import machinery components.
In neurons, mitochondrial biogenesis must be precisely regulated to meet the spatially and temporally dynamic energy demands of synaptic activity. Synaptic activity itself can stimulate local mitochondrial biogenesis at presynaptic and postsynaptic sites, and the PGC-1α pathway has been implicated in the activity-dependent regulation of mitochondrial distribution and function at synapses. The failure of mitochondrial biogenesis has been documented in post-mortem brain tissue from patients with AD and PD, with reduced PGC-1α expression and target gene activity observed in affected brain regions.[@stpierre2006] Furthermore, genetic association studies have identified variants in the PPARGC1A gene as risk factors for PD, underscoring the relevance of this pathway to disease pathogenesis in humans.
The mitochondrial network is not a static structure but rather a highly dynamic, remodable continuum that undergoes continuous cycles of fusion and fission. These opposing processes, collectively termed mitochondrial dynamics, enable the mitochondrial population to adapt to metabolic conditions, distribute functional mitochondria equitably across cellular compartments, and segregate damaged mitochondrial segments for quality control elimination.[@westermann2010] The balance between fusion and fission is tightly regulated by a suite of GTPase proteins and adaptor molecules, and the disruption of this balance is a recurring theme in neurodegenerative disease.
Mitochondrial fusion is mediated by large GTPases of the dynamin superfamily that operate on the outer and inner mitochondrial membranes. Mitofusin 1 (MFN1) and mitofusin 2 (MFN2) are dynamin-like GTPases localized to the OMM that mediate outer membrane fusion by forming trans-oligomeric complexes between adjacent mitochondria. MFN2, in addition to its fusion function, serves as a molecular tether linking mitochondria to the endoplasmic reticulum (ER) at sites of mitochondrial ER contact (MERCs), facilitating calcium signaling and lipid exchange between the two organelles.[@rowland2012] The inner membrane fusion step is catalyzed by OPA1 (optic atrophy 1), a dynamin-like GTPase anchored to the inner mitochondrial membrane that also functions to maintain cristae structure and promote mitochondrial DNA maintenance. The fusion process mixes the matrix contents of adjacent mitochondria, enabling the sharing of proteins, metabolites, mtDNA, and, critically, the complementation of defective mitochondrial proteins by healthy ones—a form of functional rescue that can preserve respiration in mitochondria carrying partial defects.[@youle2012]
Mitochondrial fission is primarily executed by the cytosolic GTPase Drp1 (dynamin-related protein 1), which is recruited to the OMM by adaptor proteins including Fis1 (fission 1 protein), MFF (mitochondrial fission factor), and MiD49/50 (Mitochondrial Dynamics proteins). Drp1 assembles around the mitochondrion in a ring-like structure, and the hydrolysis of GTP drives the constriction and severing of the outer membrane. The inner membrane fission is less well understood but involves the inner membrane AAA+ protease PARL (presenilin-associated rhomboid-like protein), which may process OPA1 isoforms to facilitate inner membrane scission.[@chan2012] Fission can be triggered by multiple stimuli, including mitochondrial damage, ROS, elevated cytosolic calcium (which activates Drp1 through calcineurin-mediated dephosphorylation), and cellular stress signals. The division of a mitochondrion produces two daughter organelles, one of which typically retains a healthier membrane potential and is more likely to undergo fusion, while the other, often carrying a greater burden of damage, is preferentially targeted for mitophagy.
The importance of mitochondrial dynamics for neuronal function is underscored by the observation that mutations in the genes encoding MFN2, OPA1, and Drp1 are associated with distinct neurological disorders. Charcot–Marie–Tooth disease type 2A, caused by dominant MFN2 mutations, presents with peripheral neuropathy reflecting the dependence of long axonal projections on mitochondrial dynamics for distal organelle delivery. Autosomal dominant optic atrophy, resulting from heterozygous OPA1 mutations, illustrates the particular vulnerability of retinal ganglion cells to impaired mitochondrial fusion. In the context of neurodegenerative disease, alterations in mitochondrial dynamics are among the earliest observable mitochondrial abnormalities. In AD, neurons exhibit a shift toward excessive fission, with increased Drp1 recruitment to mitochondria and decreased MFN2 expression, changes that correlate with the severity of cognitive impairment.[@wang2013] In PD models, mutations in PINK1 and parkin disrupt the normal coupling between fission and mitophagy, leading to the accumulation of elongated, hyperfused mitochondria that fail to be properly cleared from distal axons. The fission inhibitor mdivi-1 has been explored as a pharmacological approach to restore mitochondrial morphology in PD models, with reported neuroprotective effects in cellular and animal systems.[@rappaport2019]
Beyond mitophagy and biogenesis, mitochondrial quality control encompasses a diverse array of molecular mechanisms that operate at the suborganellar level to preserve mitochondrial integrity. These mechanisms include the mitochondrial protein quality control system (mtPQC), the mitochondrial unfolded protein response (UPR<sup>mt</sup>), mtDNA repair and maintenance, and the surveillance of mitochondrial lipids and metabolic intermediates. Together, these systems provide a multi-layered defense against the various forms of damage that mitochondria accrue over their lifespan.
The mitochondrial protein quality control system is composed of molecular chaperones and proteases that recognize, refold, or degrade misfolded and damaged proteins within the mitochondrial compartments. The mitochondrial matrix houses the ATP-dependent chaperone Hsp60 (mortalin in mammals), which assists in the folding of imported proteins, and the Lon protease (LONP1), a AAA+ protease that degrades oxidized and misfolded proteins and has also been shown to regulate mtDNA transcription and replication.[@bezaworkgeleta2017] The inner membrane contains the AAA+ protease complex comprising AFG3L2 and its partner PARL, which processes misfolded inner membrane proteins and contributes to the regulation of OPA1 and mitophagy. The combined activity of these proteases ensures that damaged proteins do not accumulate within the mitochondrion to a level that compromises organellar function.
The mitochondrial unfolded protein response (UPR<sup>mt</sup>) is a retrograde signaling pathway through which mitochondria communicate the status of their protein-folding environment to the nucleus, leading to the transcriptional upregulation of mitochondrial chaperones, proteases, and antioxidant enzymes.[@haynes2010] The canonical mammalian UPR<sup>mt</sup> is mediated by the transcription factor ATFS-1 (activating transcription factor associated with stress 1), which harbors a mitochondrial targeting sequence and a nuclear localization domain. Under conditions of mitochondrial stress, the import of ATFS-1 into mitochondria is impaired, allowing it to translocate to the nucleus and activate the expression of mitochondrial protective genes. The UPR<sup>mt</sup> has been best characterized in C. elegans, where it is induced by mitochondrial dysfunction and extends lifespan, but evidence for its activation in mammalian cells and in the context of neurodegeneration is accumulating. In neurons, the UPR<sup>mt</sup> is activated in response to mitochondrial toxins and in disease models of PD and AD, and its activation has been associated with both protective and maladaptive outcomes depending on the duration and intensity of the stress.[@sorrentino2017]
Mitochondrial DNA (mtDNA) presents a unique challenge for quality control because it is packaged into nucleoids—protein complexes comprising TFAM, POLG (DNA polymerase gamma), and mtDNA itself—and is particularly vulnerable to ROS-induced mutation due to its proximity to the ETC. The mtDNA repair machinery is more limited than that of nuclear DNA, lacking certain repair pathways present in the nucleus, yet cells rely on mtDNA for the production of 13 essential subunits of the ETC. The maintenance of the mtDNA pool is mediated by processes including base excision repair, mismatch repair, and the selective degradation of mutant mtDNA species through a process termed mtDNA segregation.[@kazak2012] The accumulation of mtDNA mutations is a feature of aging and is accentuated in several neurodegenerative disorders; however, the precise contribution of mtDNA mutations to neurodegeneration versus other aspects of mitochondrial dysfunction remains an area of active investigation.
Mitochondrial lipids, particularly cardiolipin, are also subject to quality control. Cardiolipin is a unique dimeric phospholipid concentrated in the inner mitochondrial membrane where it supports cristae structure, ETC supercomplex formation, and apoptosis regulation. The peroxidation of cardiolipin by ROS disrupts its structural and signaling functions and serves as a signal for mitophagy initiation. The re-synthesis of cardiolipin and the turnover of other mitochondrial phospholipids are mediated by phospholipid transfer proteins and the mitochondrial phospholipid scramblase PLS3, adding another layer to the quality control repertoire.[@khlbrandt2015]
[Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease) represent the two most prevalent neurodegenerative disorders globally, and both are intimately linked to the dysfunction of mitochondrial quality control pathways. While the clinical phenotypes of AD (cognitive decline and memory loss) and PD (motor dysfunction and autonomic impairment) reflect the differential vulnerability of distinct brain regions—the [hippocampus](/brain-regions/hippocampus) and [entorhinal cortex](/brain-regions/entorhinal-cortex) in AD, the [substantia nigra pars compacta](/brain-regions/substantia-nigra) in PD—converging evidence indicates that mitochondrial quality control failure is a shared pathogenic mechanism that drives neurodegeneration in both conditions.
In [Alzheimer's disease](/diseases/alzheimers-disease), evidence for mitochondrial dysfunction is extensive and multifaceted. Histopathological studies of AD brain tissue reveal the presence of enlarged, structurally abnormal mitochondria within affected [neurons](/cell-types/neurons), and biochemical analyses consistently demonstrate reduced activities of ETC Complexes I and IV in the [hippocampus](/brain-regions/hippocampus) and [cerebral cortex](/brain-regions/cortex) of AD patients.[@mancuso2006] The amyloid-beta (Aβ) peptide, the principal component of amyloid plaques, has been shown to interact directly with mitochondria, binding to the mitochondrial protein ABAD (Aβ-binding alcohol dehydrogenase, also known as HSD17B10) and promoting mitochondrial dysfunction, ROS production, and the activation of apoptotic pathways.[@xie2010] Similarly, hyperphosphorylated tau, the protein that forms neurofibrillary tangles, disrupts mitochondrial transport by interfering with the microtubule-based motor machinery, preventing the delivery of mitochondria to energy-demanding synaptic sites. A feed-forward loop has been proposed in which Aβ and tau each impair mitochondrial quality control, leading to the accumulation of damaged mitochondria that generate additional ROS and release pro-apoptotic factors, thereby accelerating neuronal death.
The PINK1/Parkin mitophagy pathway is significantly impaired in AD, with reduced Parkin expression and diminished recruitment of autophagic vesicles to mitochondria reported in AD brain tissue and cellular models.[@sun2015] The accumulation of autophagic substrates within neurons in AD—including incompletely degraded mitochondria—indicates a bottleneck at the level of autophagosome-lysosome fusion, a defect that may reflect the broader dysregulation of autophagy observed in AD. Therapeutic strategies aimed at enhancing mitophagy, including the use of the natural compound urolithin A (a mitophagy inducer that acts through the inhibition of the mitochondrial ETC at Complex I), have shown promise in AD models, reducing Aβ accumulation and improving cognitive function in animal studies.[@liu2022]
[Parkinson's disease](/diseases/parkinsons-disease) provides perhaps the most direct genetic link between mitochondrial quality control and neurodegeneration. The identification of recessive mutations in [PINK1](/genes/pink1) (PARK6) and [parkin](/genes/parkin-prkn) (PARK2) as causes of early-onset familial PD established mitophagy as a biologically relevant pathway in dopaminergic neuron survival.[@kitada1998] Loss-of-function mutations in these genes abolish the ability of [neurons](/cell-types/neurons) to target damaged mitochondria for autophagic clearance, leading to the accumulation of dysfunctional mitochondria, increased ROS production, and the progressive degeneration of dopaminergic neurons in the [substantia nigra](/brain-regions/substantia-nigra). Post-mortem studies of PD brain tissue have confirmed the presence of mitochondrial abnormalities, including Complex I deficiency, in affected brain regions. Additionally, mutations in [LRRK2](/genes/lrrk2) (leucine-rich repeat kinase 2, PARK8), the most common genetic cause of autosomal dominant PD, have been associated with alterations in mitochondrial dynamics and mitophagy, further implicating mitochondrial quality control in disease pathogenesis.[@cookson2015]
The identification of additional PD risk genes with mitochondrial functions has reinforced the centrality of MQC in PD. DJ-1 (PARK7) encodes a mitochondrial protein with antioxidant functions, and loss-of-function mutations cause early-onset PD. ATP13A2 (PARK9), encoding a lysosomal P-type ATPase, is implicated in mitochondrial-lysosomal crosstalk, and its loss leads to Kufor–Rakeb syndrome, a form of parkinsonism with dementia. The mitochondrial protein CHCHD10, mutated in FTD-ALS and linked to PD, is involved in mitochondrial DNA maintenance and mitophagy regulation.[@bannwarth2014] These genetic findings collectively indicate that the spectrum of mitochondrial quality control—from biogenesis and dynamics to mitophagy and proteostasis—represents a critical node of vulnerability in PD pathogenesis.
Beyond the genetic forms of PD, environmental factors that impair mitochondrial function also increase disease risk. The mitochondrial toxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone, both used to generate animal models of PD, directly inhibit Complex I and trigger the death of dopaminergic neurons by overwhelming mitochondrial quality control capacity. These models have been instrumental in demonstrating that chronic mitochondrial dysfunction is sufficient to produce parkinsonian neurodegeneration, further validating the mechanistic link between MQC failure and PD.
The recognition that mitochondrial quality control dysfunction is a central pathogenic mechanism in neurodegeneration has spurred intense efforts to develop therapeutic interventions that restore or enhance these pathways. The strategies under investigation span pharmacological, genetic, and lifestyle approaches, and several have advanced to clinical testing, though the translation from preclinical success to disease-modifying therapies in humans remains challenging.
One of the most actively pursued strategies is the pharmacological induction of mitophagy. The natural ellagitannin urolithin A has been shown to stimulate mitophagy in cellular and animal models of PD and AD, improving mitochondrial function and extending lifespan in C. elegans models of neurodegeneration.[@ryu2016] A Phase II clinical trial of urolithin A in patients with PD (NCT04615910) has been completed, and the compound has demonstrated safety and tolerability in humans. The antibiotic rapamycin, which inhibits mTOR and thereby induces autophagy, has been explored in AD and PD models, though its pleiotropic effects and immunosuppressant properties complicate its clinical application. The small molecule nicotinamide riboside (NR), a NAD<sup>+</sup> precursor, has been shown to enhance mitophagy through the activation of SIRT1 and the improvement of mitochondrial bioenergetics, and it is under investigation in several neurodegenerative disease contexts.[@zhang2016]
Targeting mitochondrial dynamics represents another therapeutic avenue. The fission inhibitor mdivi-1 has demonstrated neuroprotective effects in cellular and animal models of PD, reducing dopaminergic neuron loss and improving motor function.[@itoh2013] However, because fission is also required for the generation of mitochondria destined for degradation, complete inhibition of fission may have unintended consequences on mitochondrial quality control. Similarly, promoting fusion through the upregulation of MFN1 or OPA1 has been proposed, though the therapeutic window for such interventions remains to be defined.
The enhancement of mitochondrial biogenesis through PGC-1α activation is a broadly applicable strategy with relevance to multiple neurodegenerative conditions. The AMPK activator metformin, widely used for type 2 diabetes, has been shown to increase PGC-1α expression and improve mitochondrial function in models of AD and PD, and epidemiological studies suggest reduced AD incidence in diabetic patients treated with metformin.[@kotake2019] The SIRT1 activator resveratrol and other sirtuin-activating compounds have also been explored for their ability to deacetylate and activate PGC-1α, though the bioavailability and target specificity of these compounds remain limitations.
Mitochondria-targeted antioxidants represent a conceptually straightforward approach to mitigating ROS-induced mitochondrial damage. The compounds MitoQ (mitochondria-targeted ubiquinone) and MitoTempo (mitochondria-targeted TEMPO) accumulate within mitochondria and scavenge ROS at the site of production, and both have shown efficacy in PD models.[@snow2010] The peptide SS-31 (elamipretide), which localizes to the inner mitochondrial membrane and stabilizes cardiolipin, has demonstrated promise in models of AD and PD and has reached clinical testing for other mitochondrial disorders.
Beyond pharmacological interventions, lifestyle factors known to influence mitochondrial quality control—including endurance exercise, caloric restriction, and intermittent fasting—have been shown to enhance mitophagy and mitochondrial biogenesis in humans and animal models.[@dietrich2010] Exercise upregulates PGC-1α and improves mitochondrial function in the brain, and epidemiologic evidence suggests that physical activity is associated with reduced risk for both AD and PD. These non-pharmacologic approaches, while requiring further mechanistic characterization, represent low-cost, accessible strategies that may complement pharmaceutical interventions.
Gene therapy approaches targeting mitochondrial quality control genes are also under development. Viral vector-mediated delivery of PINK1 or parkin has been explored in preclinical PD models, and CRISPR-based gene editing offers the potential to correct disease-causing mutations in patients with genetic forms of PD. However, the delivery of gene therapies to the appropriate neuronal populations and the achievement of therapeutically meaningful expression levels remain significant technical hurdles.
In summary, the therapeutic landscape for mitochondrial quality control in neurodegeneration is rapidly expanding, driven by a deep mechanistic understanding of the pathways involved and by a robust preclinical evidence base. The integration of biomarkers of mitochondrial health—including measurements of mitochondrial DNA copy number, plasma mitochondrial proteins, and imaging-based assessments of cerebral mitochondrial function—will be essential for patient stratification and the monitoring of treatment response in clinical trials. As the field advances, the development of combination therapies that simultaneously target multiple nodes of the mitochondrial quality control network may offer the greatest potential for disease modification in AD, PD, and related neurodegenerative conditions.