Proteomics

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Parkin-dependent mitophagy occurs via proteasome-dependent stepwise inwardly directed mitochondrial sub-compartment targeting to lysosomes


ABSTRACT: PINK1/parkin-dependent mitophagy initially involves (phospho) ubiquitin-proteasome-dependent degradation of certain outer mitochondrial membrane (OMM) proteins (e.g. mitofusins) and then the recruitment of autophagy effectors to more stable ubiquitinated OMM proteins. It is widely assumed that such ubiquitinated mitochondria are ultimately degraded via wholesale mitophagy. However, we demonstrate that mitochondrial degradation occurs via step-wise delivery of separate mitochondrial sub-compartments to lysosomes. OMM and inner mitochondrial material appears to become separately isolated for autophagolysosomal degradation, not only in parkin-overexpressing HeLa cells but also in cells that express endogenous parkin (human embryonic kidney cells and neural progenitor cells) with slower mitophagy kinetics. The remaining inner mitochondrial material becomes degraded only after much prolonged membrane depolarization, involving another proteasome-sensitive step. These combined microscopy and proteomics analyses lend support to the idea that cell stress-induced parkin-dependent mitophagy is a complex regulated multi-step process with distinct sub-compartments separately targeted to autophagic degradation.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Parkinson's Disease

SUBMITTER: Katharina Zittlau  

LAB HEAD: Boris Macek

PROVIDER: PXD034136 | Pride | 2025-05-26

REPOSITORIES: Pride

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Parkin-dependent mitophagy occurs via proteasome-dependent steps sequentially targeting separate mitochondrial sub-compartments for autophagy.

Lechado-Terradas Anna A   Schepers Sandra S   Zittlau Katharina I KI   Sharma Karan K   Ok Orkun O   Fitzgerald Julia C JC   Geimer Stefan S   Westermann Benedikt B   Macek Boris B   Kahle Philipp J PJ  

Autophagy reports 20221219 1


PINK1/parkin-dependent mitophagy initially involves (phospho)ubiquitin-directed proteasome-dependent degradation of certain outer mitochondrial membrane (OMM) proteins (e.g. mitofusins) and the recruitment of autophagy adaptors to a group of ubiquitinated OMM proteins, eventually leading to autophagic removal of damaged mitochondria in stressed cells. Here we provide evidence that mitochondrial degradation occurs via stepwise delivery of separate mitochondrial sub-compartments for autophagic deg  ...[more]

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