Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism

Narendra, Derek P.; Walker, John E.; Youle, Richard J.

doi:10.1101/cshperspect.a011338

Cited by 288 publications

(269 citation statements)

References 95 publications

(161 reference statements)

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“…This points to an increased elimination of mitochondria through lysosomal degradation in Pat#1 and Pat#2. This was also confirmed by the enhanced translocation of Parkin to mitochondria 33,34 in Pat#1 cells compared with the control cells (Supplementary Figure S2a).…”

Section: Resultssupporting

confidence: 63%

“…Despite no differences could be detected in the overall level of mitochondrial proteins in both resting conditions and after nutrient deprivation (Supplementary Figure S2b), MCU (in the inner mitochondrial membrane) and Tom20 (in the outer mitochondrial membrane (OMM)) show a much faster degradation in Pat#1 compared with control fibroblasts after blocking protein synthesis with cycloheximide, indicating a higher organelle turnover (Figure 2c). 33,34 Defective mitochondrial Ca 2+ homeostasis in 13514A4G fibroblasts. As previously reported, an impairment of mitochondrial Ca 2+ handling is associated with mitochondrial diseases.…”

Section: Resultsmentioning

confidence: 99%

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Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear-and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A4G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca 2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A4G cells. This is due to a specific downregulation of mitochondrial Ca 2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca 2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient. Mitochondrial disorders include a wide range of pathological conditions characterized by defects in organelle homoeostasis and energy metabolism, in particular in the electron transport chain (ETC) complexes. They are mostly caused by mutations in nuclear-or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber's hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). 1,2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms. Several studies investigated the consequences of nuclear DNA mutations on intracellular organelle physiology and Ca 2+ homeostasis. 3,4 Here we analyzed a cohort of patients with mutations in the mtDNA-encoded ND5 subunit of NADH dehydrogenase in order to correlate the clinical phenot...

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Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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“…The most thoroughly characterized pathway for mitochondrial priming is that of PINK1- PRKN/PARK2 signaling [40,52]. Upon mitochondrial depolarization, PINK1 accumulates on the outer mitochondrial membrane (OMM) to recruit the cytosolic E3 ubiquitin ligase PRKN/PARK2.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

et al. 2018

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Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in GbaL444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations.Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous GBA mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without GBA mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type

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“…It has been shown that PINK1 phosphorylates Parkin on serine 65 of its ubiquitin-like (Ubl) domain, leading to an increase of its ubiquitination activity [6]. However, PINK1 must play an additional role in Parkin activation since the non-phosphorylatable S65A mutant of Parkin is still able to translocate to mitochondria (albeit more slowly), whereas PINK1 deletion or mutation completely abolishes translocation [1]. Moreover, the phosphomimetic S65E mutant of Parkin still requires PINK1 for translocation to mitochondria.…”

mentioning

confidence: 99%

“…Since then, functional links between the two proteins have been piling up. In Drosophila, mitochondrial dysfunction caused by Parkin or PINK1 mutants can be rescued by Parkin overexpression, suggesting that PINK1 acts upstream of Parkin (reviewed in [1]). The PINK1 protein is a serine/threonine kinase that accumulates and becomes active on mitochondria in response to their depolarization, e.g., after CCCP (carbonyl cyanide m-chlorophenyl hydrazone) treatment.…”

mentioning

confidence: 99%

Phosphorylated ubiquitin: a new shade of PINK1 in Parkin activation

Sauvé

Gehring

2014

Cell Res

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Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism

Cited by 288 publications

References 95 publications

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

Phosphorylated ubiquitin: a new shade of PINK1 in Parkin activation

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