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Global ubiquitylation analysis of mitochondria in primary neurons identifies endogenous Parkin targets following activation of PINK
Published November 12, 2021
Output Details
Preprint March 31, 2021
Published November 12, 2021
Description
How activation of PINK1 and Parkin leads to elimination of damaged mitochondria by mitophagy is largely based on cell lines with few studies in neurons. Here, we have undertaken proteomic analysis of mitochondria from mouse neurons to identify ubiquitylated substrates of endogenous Parkin. Comparative analysis with human iNeuron datasets revealed a subset of 49 PINK1 activation–dependent diGLY sites in 22 proteins conserved across mouse and human systems. We use reconstitution assays to demonstrate direct ubiquitylation by Parkin in vitro. We also identified a subset of cytoplasmic proteins recruited to mitochondria that undergo PINK1 and Parkin independent ubiquitylation, indicating the presence of alternate ubiquitin E3 ligase pathways that are activated by mitochondrial depolarization in neurons. Last, we have developed an online resource to search for ubiquitin sites and enzymes in mitochondria of neurons, MitoNUb. These findings will aid future studies to understand Parkin activation in neuronal subtypes.
Article published in Science Advances on 12 November 2021. Initial preprint 10.1101/2021.04.01.438131 posted on BioRvix on 01 April 2021.
Identifier (DOI)
10.1126/sciadv.abj0722