The PINK1 repertoire: Not just a one trick pony

Pollock, Liam; Jardine, Jane; Urbé, Sylvie; Clague, Michael J.

doi:10.1002/bies.202100168

Cited by 11 publications

(7 citation statements)

References 136 publications

(163 reference statements)

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“…5,6,7 Mitophagy-independent functions of PINK1 and parkin have also been described. 13,14 PARK7 mutations are the rarest known cause of autosomal recessive Parkinson's disease. 15,16 Clinically, Parkinson's disease caused by PARK7 mutations is indistinguishable from disease resulting from PRKN or PINK1 mutations.…”

Section: Accepted Manuscript Introductionmentioning

confidence: 99%

DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy

Imberechts

Kinnart

Wauters

et al. 2022

Brain

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Loss-of-function mutations in the PRKN, PINK1 and PARK7 genes (encoding parkin, PINK1 and DJ-1, respectively) cause autosomal recessive forms of Parkinson’s disease. PINK1 and parkin jointly mediate selective autophagy of damaged mitochondria (mitophagy), but the mechanisms by which loss of DJ-1 induces Parkinson’s disease, are not well understood. Here, we investigated PINK1/parkin-mediated mitophagy in cultured human fibroblasts and iPSC-derived neurons with homozygous PARK7 mutations. We found that DJ-1 is essential for PINK1/parkin-mediated mitophagy. Loss of DJ-1 did not interfere with PINK1 or parkin activation after mitochondrial depolarization, but blocked mitophagy further downstream by inhibiting recruitment of the selective autophagy receptor optineurin to depolarized mitochondria. By contrast, starvation-induced, non-selective autophagy was not affected by loss of DJ-1. In wild-type fibroblasts and iPSC-derived dopaminergic neurons, endogenous DJ-1 translocated to depolarized mitochondria in close proximity with optineurin. DJ-1 translocation to depolarized mitochondria was dependent on PINK1 and parkin and did not require oxidation of cysteine residue 106 of DJ-1. Overexpression of DJ-1 did not rescue the mitophagy defect of PINK1- or parkin-deficient cells. These findings position DJ-1 downstream of PINK1 and parkin in the same pathway and suggest that disruption of PINK1/parkin/DJ-1-mediated mitophagy is a common pathogenic mechanism in autosomal recessive Parkinson’s disease.

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Section: Accepted Manuscript Introductionmentioning

confidence: 99%

DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy

Imberechts

Kinnart

Wauters

et al. 2022

Brain

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“…Given the diverse nature of Parkinson’s disease genes, as well as environmental factors linked to sporadic forms of the disease, it is likely that there are multiple pathways and mechanisms leading to mitochondrial impairment. It is important to note that non-mitophagy functions have also been ascribed to PINK1 and parkin, 9 and it is possible that these are key for Parkinson’s disease.…”

mentioning

confidence: 99%

Strengthening the link between mitophagy and Parkinson’s disease

Ganley

2022

Brain

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“…And mitophagy, a speci c type of autophagy that selectively degrades defective mitochondria, has received extra attention in energy maintenance for damaged axons. PINK1 dependent pathway is one of the beststudied mitophagy mechanisms [52][53][54][55]. PINK1 is a serine/threonine kinase with an N-terminal mitochondrial targeting sequence.…”

Section: Discussionmentioning

confidence: 99%

Mitophagy Eliminates the Accumulation of SARM1 on the Mitochondria, Alleviating Programmed Axon Death in Acrylamide Neuropathy

Wang

Yong

Zhang

et al. 2022

Preprint

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Sterile-α and toll/interleukin 1 receptor motif containing protein 1 (SARM1) is the central executioner of programmed axon death (Wallerian degeneration). Although it has been confirmed to have a mitochondrial targeting sequence and can bind to and stabilize PINK1 on mitochondria, the biological significance for mitochondrial localization of SARM1 is still unclear. The relationship between mitochondrial quality control mechanisms and programmed axon death also needs to be clarified. Chronic acrylamide (ACR) intoxication cause typical pathology of axon degeneration involving early axon loss. Here, we demonstrated that the SARM1 dependent Wallerian axon self-destruction pathway was activated following ACR intoxication. Moreover, increased SARM1 was observed on the mitochondria, which interfered with the mitochondrial quality control mechanisms. As a protective response to stress, mitochondrial components enriched in SARM1 were isolated from the mitochondrial network through an increased fission process and were degraded in an autophagy-dependent manner. Importantly, rapamycin (RAPA) administration eliminated mitochondrial accumulated SARM1 and inhibited axon loss. Thus, mitochondrial localization of SARM1 may be complement to the coordinated activity of NMNAT2 and SARM1, and may be part of the self-limiting molecular mechanisms of programmed axon death. In the early latent period, the mitochondrial localization of SARM1 will help it to be isolated by the mitochondrial network and to be degraded through mitophagy to maintain local axon homeostasis. When the mitochondrial quality control mechanisms are broken down, SARM1 will cause irreversible damage for axon death.

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The PINK1 repertoire: Not just a one trick pony

Cited by 11 publications

References 136 publications

DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy

DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy

Strengthening the link between mitophagy and Parkinson’s disease

Mitophagy Eliminates the Accumulation of SARM1 on the Mitochondria, Alleviating Programmed Axon Death in Acrylamide Neuropathy

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