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. 2022 Jun 3;11:32. doi: 10.1186/s40035-022-00305-1

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — Ubiquitin-dependent mitophagy. PINK1 binds to the TOM complex and, under physiological conditions, is transported to the inner mitochondrial membrane and interacts with the TIM complex. PARL truncates the transmembrane segment of PINK1, releasing the 52-kDa ΔN-PINK1 into the cytoplasm. ΔN-PINK1 is then ubiquitylated and degraded by proteasomes. However, when mitochondria are damaged, PINK1 aggregates on the mitochondrial outer membrane and activates parkin. Parkin-dependent ubiquitin chains are then assembled on the outer membrane. Parkin ubiquitinates several mitochondrial outer membrane proteins, such as VDAC, Mfn2, and DRP1, which are then recognized by the ubiquitin-binding proteins, including OPTN, p62, NDP52, and NBR. These proteins recognize phosphorylated polyubiquitin chains and initiate autophagosome formation by binding to LC3. Finally, the damaged mitochondria recruit the autophagy pathway and fuse with the lysosome, leading to mitochondrial degradation