Mitochondria-derived Vesicles Research Articles

Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?

Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.

Mitochondrial dysfunction in the pathophysiology of renal diseases.

Mitochondria are essential organelles in the human body, serving as the metabolic factory of the whole organism. When mitochondria are dysfunctional, it can affect all organs of the body. The kidney is rich in mitochondria, and its function is closely related to the development of kidney diseases. Studying the relationship between mitochondria and kidney disease progression is of great interest. In the past decade, scientists have made inspiring progress in investigating the role of mitochondria in the pathophysiology of renal diseases. This article discusses various mechanisms for maintaining mitochondrial quality, including mitochondrial energetics, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial DNA repair, mitochondrial proteolysis and UPR, mitochondrial autophagy, mitochondria-derived vesicles, and mitocytosis. The article also highlights the crosstalk between mitochondria and other organelles, with a focus on kidney diseases. Finally, the article concludes with an overview of mitochondrial-related clinical research.

Defects of mitochondria-lysosomes communication induce secretion of mitochondria-derived vesicles and drive chemoresistance in ovarian cancer cells

BackgroundAmong the mechanisms of mitochondrial quality control (MQC), generation of mitochondria-derived vesicles (MDVs) is a process to avoid complete failure of mitochondria determining lysosomal degradation of mitochondrial damaged proteins. In this context, RAB7, a late endocytic small GTPase, controls delivery of MDVs to late endosomes for subsequent lysosomal degradation. We previously demonstrated that RAB7 has a pivotal role in response to cisplatin (CDDP) regulating resistance to the drug by extracellular vesicle (EVs) secretion.MethodsWestern blot and immunofluorescence analysis were used to analyze structure and function of endosomes and lysosomes in CDDP chemosensitive and chemoresistant ovarian cancer cell lines. EVs were purified from chemosensitive and chemoresistant cells by ultracentrifugation or immunoisolation to analyze their mitochondrial DNA and protein content. Treatment with cyanide m-chlorophenylhydrazone (CCCP) and RAB7 modulation were used, respectively, to understand the role of mitochondrial and late endosomal/lysosomal alterations on MDV secretion. Using conditioned media from chemoresistant cells the effect of MDVs on the viability after CDDP treatment was determined. Seahorse assays and immunofluorescence analysis were used to study the biochemical role of MDVs and the uptake and intracellular localization of MDVs, respectively.ResultsWe observed that CDDP-chemoresistant cells are characterized by increased MDV secretion, impairment of late endocytic traffic, RAB7 downregulation, an increase of RAB7 in EVs, compared to chemosensitive cells, and downregulation of the TFEB-mTOR pathway overseeing lysosomal and mitochondrial biogenesis and turnover. We established that MDVs can be secreted rather than delivered to lysosomes and are able to deliver CDDP outside the cells. We showed increased secretion of MDVs by chemoresistant cells ultimately caused by the extrusion of RAB7 in EVs, resulting in a dramatic drop in its intracellular content, as a novel mechanism to regulate RAB7 levels. We demonstrated that MDVs purified from chemoresistant cells induce chemoresistance in RAB7-modulated process, and, after uptake from recipient cells, MDVs localize to mitochondria and slow down mitochondrial activity.ConclusionsDysfunctional MQC in chemoresistant cells determines a block in lysosomal degradation of MDVs and their consequent secretion, suggesting that MQC is not able to eliminate damaged mitochondria whose components are secreted becoming effectors and potential markers of chemoresistance.

Mitochondria-derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.

Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether MDV deregulation causes mitochondrial dysfunction in PH is unknown. The aim of this study was to determine MDV regulation in ECs and to elucidate how MDV deregulation in ECs leads to PH. MDV formation and mitochondrial morphology/dynamics were examined in ECs of EC-specific liver kinase B1 (LKB1) knockout mice (LKB1ec-/-), in monocrotaline-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of patients with PH and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of the cristae network, together with defective MDV shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDV shedding, and disequilibrium of the mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intratracheal delivery of adeno-associated virus LKB1 reversed PH, together with improved MDV shedding and mitochondrial function in rats invivo. We conclude that LKB1 regulates MDV shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defects of LKB1-mediated MDV shedding from parental mitochondria instigate EC dysfunction and PH.

Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation

Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.

Zika virus modulates mitochondrial dynamics, mitophagy, and mitochondria-derived vesicles to facilitate viral replication in trophoblast cells.

Zika virus (ZIKV) remains a global public health threat with the potential risk of a future outbreak. Since viral infections are known to exploit mitochondria-mediated cellular processes, we investigated the effects of ZIKV infection in trophoblast cells in terms of the different mitochondrial quality control pathways that govern mitochondrial integrity and function. Here we demonstrate that ZIKV (PRVABC59) infection of JEG-3 trophoblast cells manipulates mitochondrial dynamics, mitophagy, and formation of mitochondria-derived vesicles (MDVs). Specifically, ZIKV nonstructural protein 4A (NS4A) translocates to the mitochondria, triggers mitochondrial fission and mitophagy, and suppresses mitochondrial associated antiviral protein (MAVS)-mediated type I interferon (IFN) response. Furthermore, proteomics profiling of small extracellular vesicles (sEVs) revealed an enrichment of mitochondrial proteins in sEVs secreted by ZIKV-infected JEG-3 cells, suggesting that MDV formation may also be another mitochondrial quality control mechanism manipulated during placental ZIKV infection. Altogether, our findings highlight the different mitochondrial quality control mechanisms manipulated by ZIKV during infection of placental cells as host immune evasion mechanisms utilized by ZIKV at the placenta to suppress the host antiviral response and facilitate viral infection.

Role of VPS39, a key tethering protein for endolysosomal trafficking and mitochondria-lysosome crosstalk, in health and disease.

The coordinated interaction between mitochondria and lysosomes, mainly manifested by mitophagy, mitochondria-derived vesicles, and direct physical contact, is essential for maintaining cellular life activities. The VPS39 subunit of the homotypic fusion and protein sorting complex could play a key role in the regulation of organelle dynamics, such as endolysosomal trafficking and mitochondria-vacuole/lysosome crosstalk, thus contributing to a variety of physiological functions. The abnormalities of VPS39 and related subunits have been reported to be involved in the pathological process of some diseases. Here, we analyze the potential mechanisms and the existing problems of VPS39 in regulating organelle dynamics, which, in turn, regulate physiological functions and disease pathogenesis, so as to provide new clues for facilitating the discovery of therapeutic targets for mitochondrial and lysosomal diseases.

Evidence of mitochondria origin of SARS-CoV-2 double-membrane vesicles: a review.

Coronavirus Disease-19 (COVID-19) pandemic is caused by SARS-CoV-2 that has infected more than 600 million people and killed more than 6 million people worldwide. This infection affects mainly certain groups of people that have high susceptibility to present severe COVID-19 due to comorbidities. Moreover, the long-COVID-19 comprises a series of symptoms that may remain in some patients for months after infection that further compromises their health. Thus, since this pandemic is profoundly affecting health, economy, and social life of societies, a deeper understanding of viral replication cycle could help to envisage novel therapeutic alternatives that limit or stop COVID-19. Several findings have unexpectedly discovered that mitochondria play a critical role in SARS-CoV-2 cell infection. Indeed, it has been suggested that this organelle could be the origin of its replication niches, the double membrane vesicles (DMV). In this regard, mitochondria derived vesicles (MDV), involved in mitochondria quality control, discovered almost 15 years ago, comprise a subpopulation characterized by a double membrane. MDV shedding is induced by mitochondrial stress, and it has a fast assembly dynamic, reason that perhaps has precluded their identification in electron microscopy or tomography studies. These and other features of MDV together with recent SARS-CoV-2 protein interactome and other findings link SARS-CoV-2 to mitochondria and support that these vesicles are the precursors of SARS-CoV-2 induced DMV. In this work, the morphological, biochemical, molecular, and cellular evidence that supports this hypothesis is reviewed and integrated into the current model of SARS-CoV-2 cell infection. In this scheme, some relevant questions are raised as pending topics for research that would help in the near future to test this hypothesis. The intention of this work is to provide a novel framework that could open new possibilities to tackle SARS-CoV-2 pandemic through mitochondria and DMV targeted therapies.

Multifocus microscopy with optical sectioning and high axial resolution

Multifocus microscopy enables recording of entire volumes in a single camera exposure. In dense samples, multifocus microscopy is severely hampered by background haze. Here, we introduce a scalable multifocus method that incorporates optical sectioning and offers improved axial resolution capabilities. In our method, a dithered oblique light-sheet scans the sample volume during a single exposure, while fluorescence from each illuminated plane in the sample is mapped onto a line on the camera with a multifocus optical element. A synchronized rolling shutter readout realizes optical sectioning. We describe the technique theoretically and verify its optical sectioning and resolution improvement capabilities. We demonstrate a prototype system with a multifocus beam splitter cascade and record monolayers of endothelial cells at 35 volumes per second. We furthermore image uncleared engineered human heart tissue and visualize the distribution of mitochondria at high axial resolution. Our method manages to capture sub-diffraction sized mitochondria-derived vesicles up to 30 µm deep into the tissue.

Three-dimensional structured illumination microscopy data of mitochondria and lysosomes in cardiomyoblasts under normal and galactose-adapted conditions

This three-dimensional structured illumination microscopy (3DSIM) dataset was generated to highlight the suitability of 3DSIM to investigate mitochondria-derived vesicles (MDVs) in H9c2 cardiomyoblasts in living or fixed cells. MDVs act as a mitochondria quality control mechanism. The cells were stably expressing the tandem-tag eGFP-mCherry-OMP25-TM (outer mitochondrial membrane) which can be used as a sensor for acidity. A part of the dataset is showing correlative imaging of lysosomes labeled using LysoTracker in fixed and living cells. The cells were cultivated in either normal or glucose-deprived medium containing galactose. The resulting 3DSIM data were of high quality and can be used to undertake a variety of studies. Interestingly, many dynamic tubules derived from mitochondria are visible in the 3DSIM videos under both glucose and galactose-adapted growth conditions. As the raw 3DSIM data, optical parameters, and reconstructed 3DSIM images are provided, the data is especially suitable for use in the development of SIM reconstruction algorithms, bioimage analysis methods, and for biological studies of mitochondria.

Mitochondrial dynamics and quantification of mitochondria-derived vesicles in cardiomyoblasts using structured illumination microscopy.

Mitochondria are essential energy-providing organelles of particular importance in energy-demanding tissue such as the heart. The production of mitochondria-derived vesicles (MDVs) is a cellular mechanism by which cells ensure a healthy pool of mitochondria. These vesicles are small and fast-moving objects not easily captured by imaging. In this work, we have tested the ability of the optical super-resolution technique 3DSIM to capture high-resolution images of MDVs. We optimized the imaging conditions both for high-speed video microscopy and fixed-cell imaging and analysis. From the 3DSIM videos, we observed an abundance of MDVs and many dynamic mitochondrial tubules. The density of MDVs in cells was compared for cells under normal growth conditions and cells during metabolic perturbation. Our results indicate a higher abundance of MDVs in H9c2 cells during glucose deprivation compared with cells under normal growth conditions. Furthermore, the results reveal a large untapped potential of 3DSIM in MDV research.

Evidence of mitochondria origin of SARS-CoV-2 double-membrane vesicles: a review.

Coronavirus Disease-19 (COVID-19) pandemic is caused by the coronavirus SARS-CoV-2 that has infected in a year more than 200 million people and has killed almost 4.5 million people worldwide. This infection affects mainly certain groups of people that have high susceptibility to present severe COVID-19 due to comorbidities. Moreover, the long-COVID-19 comprises a series of symptoms that may remain in some patients for months after infection that further compromises health of individuals. Therefore, this pandemic poses a serious emergency worldwide. Thus, since this pandemic is profoundly affecting economic and social life of societies, a deeper understanding of SARS-CoV-2 infection cycle could help to envisage novel therapeutic alternatives that limit or stop COVID-19. Several recent findings have unexpectedly found that mitochondria play a critical role in SARS-CoV-2 cell infection. Indeed, it has been suggested that this organelle could be the origin of its replication niches, the double membrane vesicles (DMV), as its been observed with another virus. In this regard, mitochondria derived vesicles (MDV), involved in mitochondria quality control, were discovered more than 10 years ago and interestingly there is a population characterized by a double membrane. MDV shedding is induced by mitochondrial stress and it has a fast assembly dynamic, reason that perhaps has precluded their identification in electron microscopy or tomography studies. These and other features of MDV together with recent SARS-CoV-2 protein interactome with the host and other findings linking SARS-CoV-2 to mitochondria, support that these vesicles are the precursors of SARS-CoV-2 induced DMV. In this work, the celular, molecular, phenotypical and biochemical evidence that supports this hypothesis is reviewed and integrated into the current model of SARS-CoV-2 cell infection. In this scheme, some relevant questions are raised as pending topics for research that would help in the near future to test this hypothesis. The intention (abstract truncated).

MDVs to the rescue: How autophagy-deficient cancer cells adapt to defective mitophagy.

Cancers are dependent on mitochondria, the powerhouse of the cell, and autophagy, the mechanism to preserve mitochondrial quality and function. In this issue of Developmental Cell, Towers etal. identify mitochondria-derived vesicles (MDVs) as a new adaptive mechanism enabling cancer cells to compensate for autophagy loss and to maintain mitochondrial function.

Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson’s disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.

Mitochondrial Protrusions in Neuronal Cells.

SummaryMitochondrial function relies on multiple quality control mechanisms, including the release of mitochondrial vesicles. To investigate the ultrastructure and prevalence of mitochondrial membranous protrusions (and, by extension, vesicles) in neurons, we surveyed mitochondria in rat and planarian brains using transmission electron microscopy (EM). We observed that mitochondrial protrusions mostly extend from the outer membrane. Leveraging available 3D EM datasets of the brain, we further analyzed mitochondrial protrusions in neurons of mouse and Drosophila brains, identifying high-resolution spatial views of these protrusions. To assess whether the abundance of mitochondrial protrusions and mitochondria-derived vesicles respond to cellular stress, we examined neurons expressing fluorescently tagged mitochondrial markers using confocal microscopy with Airyscan and found increased numbers of mitochondrial protrusions and vesicles with mild stress. Future studies using improved spatial resolution with added temporal information may further define the functional implications of mitochondrial protrusions and vesicles in neurons.

Mitochondrial Protein Quality Control Mechanisms.

Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.

Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond.

Parkinson's disease (PD) is a degenerative movement disorder resulting from the loss of specific neuron types in the midbrain. Early environmental and pathophysiological studies implicated mitochondrial damage and protein aggregation as the main causes of PD. These findings are now vindicated by the characterization of more than 20 genes implicated in rare familial forms of the disease. In particular, two proteins encoded by the Parkin and PINK1 genes, whose mutations cause early-onset autosomal recessive PD, function together in a mitochondrial quality control pathway. In this review, we will describe recent development in our understanding of their mechanisms of action, structure, and function. We explain how PINK1 acts as a mitochondrial damage sensor via the regulated proteolysis of its N-terminus and the phosphorylation of ubiquitin tethered to outer mitochondrial membrane proteins. In turn, phospho-ubiquitin recruits and activates Parkin via conformational changes that increase its ubiquitin ligase activity. We then describe how the formation of polyubiquitin chains on mitochondria triggers the recruitment of the autophagy machinery or the formation of mitochondria-derived vesicles. Finally, we discuss the evidence for the involvement of these mechanisms in physiological processes such as immunity and inflammation, as well as the links to other PD genes.

Mitochondria-Derived Vesicles Deliver Antimicrobial Reactive Oxygen Species to Control Phagosome-Localized Staphylococcus aureus

Pathogenic bacteria taken up into the macrophage phagosome are the target of many anti-microbial mechanisms. Although mitochondria-derived antimicrobial effectors like reactive oxygen species (mROS) aid in bacterial killing, it is unclear how these effectors reach bacteria within the phagosomal lumen. We show here that endoplasmic reticulum stress triggered upon methicillin-resistant Staphylococcus aureus (MRSA) infection induces mROS that are delivered to bacteria-containing phagosomes via mitochondria-derived vesicles (MDVs). The endoplasmic reticulum stress sensor IRE1α induces mROS, specifically hydrogen peroxide (mH2O2), upon MRSA infection. MRSA infection also stimulates the generation of MDVs, which require the mitochondrial stress response factor Parkin, and contributes to mH2O2 accumulation in bacteria-containing phagosomes. Accumulation of phagosomal H2O2 requires Toll-like receptor signaling and the mitochondrial enzyme superoxide dismutase-2 (Sod2), which is delivered to phagosomes by MDVs. Sod2 depletion compromises mH2O2 production and bacterial killing. Thus, mitochondrial redox capacity enhances macrophage antimicrobial function by delivering mitochondria-derived effector molecules into bacteria-containing phagosomes.

Beyond autophagy: a novel role for autism-linked Wdfy3 in brain mitophagy

WD repeat and FYVE domain-containing 3 (WDFY3; also known as Autophagy-Linked FYVE or Alfy) is an identified intellectual disability, developmental delay and autism risk gene. This gene encodes for a scaffolding protein that is expressed in both the developing and adult central nervous system and required for autophagy and aggrephagy with yet unexplored roles in mitophagy. Given that mitochondrial trafficking, dynamics and remodeling have key roles in synaptic plasticity, we tested the role of Wdfy3 on brain bioenergetics by using Wdfy3+/lacZ mice, the only known Wdfy3 mutant animal model with overt neurodevelopmental anomalies that survive to adulthood. We found that Wdfy3 is required for sustaining brain bioenergetics and morphology via mitophagy. Decreased mitochondrial quality control by conventional mitophagy was partly compensated for by the increased formation of mitochondria-derived vesicles (MDV) targeted to lysosomal degradation (micromitophagy). These observations, extended through proteomic analysis of mitochondria-enriched cortical fractions, showed significant enrichment for pathways associated with mitophagy, mitochondrial transport and axon guidance via semaphorin, Robo, L1cam and Eph-ephrin signaling. Collectively, our findings support a critical role for Wdfy3 in mitochondrial homeostasis with implications for neuron differentiation, neurodevelopment and age-dependent neurodegeneration.

PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease.

Parkinson's disease (PD) is one of the most frequent neurodegenerative disease caused by the preferential, progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta. PD is characterized by a multifaceted pathological process involving protein misfolding, mitochondrial dysfunction, neuroinflammation and metabolism deregulation. The molecular mechanisms governing the complex interplay between the different facets of this process are still unknown. PARK2/Parkin and PARK6/PINK1, two genes responsible for familial forms of PD, act as a ubiquitous core signaling pathway, coupling mitochondrial stress to mitochondrial surveillance, by regulating mitochondrial dynamics, the removal of damaged mitochondrial components by mitochondria-derived vesicles, mitophagy, and mitochondrial biogenesis. Over the last decade, PINK1/Parkin-dependent mitochondrial quality control emerged as a pleiotropic regulatory pathway. Loss of its function impinges on a number of physiological processes suspected to contribute to PD pathogenesis. Its role in the regulation of innate immunity and inflammatory processes stands out, providing compelling support to the contribution of non-cell-autonomous immune mechanisms in PD. In this review, we illustrate the central role of this multifunctional pathway at the crossroads between mitochondrial stress, neuroinflammation and metabolism. We discuss how its dysfunction may contribute to PD pathogenesis and pinpoint major unresolved questions in the field.