Parkin and mitochondrial signalling.

Elizabeth M Connelly, Karling S Frankel, Gary S Shaw

Cellular signalling 2023 Jun

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Aging, toxic chemicals and changes to the cellular environment are sources of oxidative damage to mitochondria which contribute to neurodegenerative conditions including Parkinson's disease. To counteract this, cells have developed signalling mechanisms to identify and remove select proteins and unhealthy mitochondria to maintain homeostasis. Two important proteins that work in concert to control mitochondrial damage are the protein kinase PINK1 and the E3 ligase parkin. In response to oxidative stress, PINK1 phosphorylates ubiquitin present on proteins at the mitochondrial surface. This signals the translocation of parkin, accelerates further phosphorylation, and stimulates ubiquitination of outer mitochondrial membrane proteins such as Miro1/2 and Mfn1/2. The ubiquitination of these proteins is the key step needed to target them for degradation via the 26S proteasomal machinery or eliminate the entire organelle through mitophagy. This review highlights the signalling mechanisms used by PINK1 and parkin and presents several outstanding questions yet to be resolved. Copyright © 2023 Elsevier Inc. All rights reserved.