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Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.

ABSTRACT: Altered mitochondrial quality control and dynamics may contribute to neurodegenerative diseases, including Parkinson's disease, but we understand little about these processes in neurons. We combined time-lapse microscopy and correlative light and electron microscopy to track individual mitochondria in neurons lacking the fission-promoting protein dynamin-related protein 1 (Drp1) and delineate the kinetics of PINK1-dependent pathways of mitochondrial quality control. Depolarized mitochondria recruit Parkin to the outer mitochondrial membrane, triggering autophagosome formation, rapid lysosomal fusion, and Parkin redistribution. Unexpectedly, these mitolysosomes are dynamic and persist for hours. Some are engulfed by healthy mitochondria, and others are deacidified before bursting. In other cases, Parkin is directly recruited to the matrix of polarized mitochondria. Loss of PINK1 blocks Parkin recruitment, causes LC3 accumulation within mitochondria, and exacerbates Drp1KO toxicity to dopamine neurons. These results define a distinct neuronal mitochondrial life cycle, revealing potential mechanisms of mitochondrial recycling and signaling relevant to neurodegeneration.

SUBMITTER: Li H

PROVIDER: S-EPMC8346224 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin.

Project description:To minimize oxidative damage to the cell, malfunctioning mitochondria need to be removed by mitophagy. In neuronal axons, mitochondrial damage may occur in distal regions, far from the soma where most lysosomal degradation is thought to occur. In this paper, we report that PINK1 and Parkin, two Parkinson's disease-associated proteins, mediate local mitophagy of dysfunctional mitochondria in neuronal axons. To reduce cytotoxicity and mimic physiological levels of mitochondrial damage, we selectively damaged a subset of mitochondria in hippocampal axons. Parkin was rapidly recruited to damaged mitochondria in axons followed by formation of LC3-positive autophagosomes and LAMP1-positive lysosomes. In PINK1(-/-) axons, damaged mitochondria did not accumulate Parkin and failed to be engulfed in autophagosomes. Similarly, initiation of mitophagy was blocked in Parkin(-/-) axons. Our findings demonstrate that the PINK1-Parkin-mediated pathway is required for local mitophagy in distal axons in response to focal damage. Local mitophagy likely provides rapid neuroprotection against oxidative stress without a requirement for retrograde transport to the soma.

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PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.

Project description:Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss of mitochondrial membrane potential (DeltaPsi(m)) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of DeltaPsi(m) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal DeltaPsi(m). We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.

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PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix.

Project description:Loss-of-function mutations in PINK1, which encodes a mitochondrially targeted serine/threonine kinase, result in an early-onset heritable form of Parkinson's disease. Previous work has shown that PINK1 is constitutively degraded in healthy cells, but selectively accumulates on the surface of depolarized mitochondria, thereby initiating their autophagic degradation. Although PINK1 is known to be a cleavage target of several mitochondrial proteases, whether these proteases account for the constitutive degradation of PINK1 in healthy mitochondria remains unclear. To explore the mechanism by which PINK1 is degraded, we performed a screen for mitochondrial proteases that influence PINK1 abundance in the fruit fly Drosophila melanogaster. We found that genetic perturbations targeting the matrix-localized protease Lon caused dramatic accumulation of processed PINK1 species in several mitochondrial compartments, including the matrix. Knockdown of Lon did not decrease mitochondrial membrane potential or trigger activation of the mitochondrial unfolded protein stress response (UPRmt), indicating that PINK1 accumulation in Lon-deficient animals is not a secondary consequence of mitochondrial depolarization or the UPRmt. Moreover, the influence of Lon on PINK1 abundance was highly specific, as Lon inactivation had little or no effect on the abundance of other mitochondrial proteins. Further studies indicated that the processed forms of PINK1 that accumulate upon Lon inactivation are capable of activating the PINK1-Parkin pathway in vivo. Our findings thus suggest that Lon plays an essential role in regulating the PINK1-Parkin pathway by promoting the degradation of PINK1 in the matrix of healthy mitochondria.

| S-EPMC4038460 | biostudies-literature

Cytosolic cleaved PINK1 represses Parkin translocation to mitochondria and mitophagy.

Project description:PINK1 is a mitochondrial kinase proposed to have a role in the pathogenesis of Parkinson's disease through the regulation of mitophagy. Here, we show that the PINK1 main cleavage product, PINK152, after being generated inside mitochondria, can exit these organelles and localize to the cytosol, where it is not only destined for degradation by the proteasome but binds to Parkin. The interaction of cytosolic PINK1 with Parkin represses Parkin translocation to the mitochondria and subsequent mitophagy. Our work therefore highlights the existence of two cellular pools of PINK1 that have different effects on Parkin translocation and mitophagy.

| S-EPMC4303452 | biostudies-other

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Project description:Senescent and damaged mitochondria undergo selective mitophagic elimination through mechanisms requiring two Parkinson's disease factors, the mitochondrial kinase PINK1 (PTEN-induced putative kinase protein 1; PTEN is phosphatase and tensin homolog) and the cytosolic ubiquitin ligase Parkin. The nature of the PINK-Parkin interaction and the identity of key factors directing Parkin to damaged mitochondria are unknown. We show that the mitochondrial outer membrane guanosine triphosphatase mitofusin (Mfn) 2 mediates Parkin recruitment to damaged mitochondria. Parkin bound to Mfn2 in a PINK1-dependent manner; PINK1 phosphorylated Mfn2 and promoted its Parkin-mediated ubiqitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of Parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in Parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria.

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Project description:Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson's disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1α expression and dopaminergic neuronal survival.

| S-EPMC5312976 | biostudies-literature

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Project description:Endoplasmic reticulum (ER)-mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson's disease, are two of the best characterized mitophagy players. They accumulate at ER-mitochondria contact sites and modulate organelles crosstalk. Alterations in ER-mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson's disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER-mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

| S-EPMC7084677 | biostudies-literature

Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment.

Project description:Dysfunction of PTEN-induced putative kinase 1 (PINK1), a Ser/Thr kinase with an N-terminal mitochondrial-targeting sequence (MTS), causes familial recessive parkinsonism. Reduction of the mitochondrial membrane potential limits MTS-mediated matrix import and promotes PINK1 accumulation on the outer mitochondrial membrane (OMM) of depolarized mitochondria. PINK1 then undergoes autophosphorylation and phosphorylates ubiquitin and Parkin, a cytosolic ubiquitin ligase, for clearance of damaged mitochondria. The molecular basis for PINK1 localization on the OMM of depolarized mitochondria rather than release to the cytosol is poorly understood. Here, we disentangle the PINK1 localization mechanism using deletion mutants and a newly established constitutively active PINK1 mutant. Disruption of the MTS through N-terminal insertion of aspartic acid residues results in OMM localization of PINK1 in energized mitochondria. Unexpectedly, the MTS and putative transmembrane domain (TMD) are dispensable for OMM localization, whereas mitochondrial translocase Tom40 (also known as TOMM40) and an alternative mitochondrial localization signal that resides between the MTS and TMD are required. PINK1 utilizes a mitochondrial localization mechanism that is distinct from that of conventional MTS proteins and that presumably functions in conjunction with the Tom complex in OMM localization when the conventional N-terminal MTS is inhibited.

| S-EPMC4342580 | biostudies-literature

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