Regulation of PRKN-independent mitophagy

Autophagy. 2022 Jan;18(1):24-39. doi: 10.1080/15548627.2021.1888244. Epub 2021 Feb 25.

Abstract

Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining cellular homeostasis. Keeping the quality of mitochondria in check is of essential importance for functioning and survival of the cells. Selective autophagic clearance of flawed mitochondria, a process termed mitophagy, is one of the most prominent mechanisms through which cells maintain a healthy mitochondrial pool. The best-studied pathway through which mitophagy is exerted is the PINK1-PRKN pathway. However, an increasing number of studies have shown an existence of alternative pathways, where different proteins and lipids are able to recruit autophagic machinery independently of PINK1 and PRKN. The significance of PRKN-independent mitophagy pathways is reflected in various physiological and pathophysiological processes, but many questions regarding the regulation and the interplay between these pathways remain open. Here we review the current knowledge and recent progress made in the field of PRKN-independent mitophagy. Particularly we focus on the regulation of various receptors that participate in targeting impaired mitochondria to autophagosomes independently of PRKN.Abbreviations: AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BH: BCL2 homology; CCCP: Carbonyl cyanide m-chlorophenylhydrazone; CL: cardiolipin; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-trifluoromethoxyphenylhydrazone; IMM: inner mitochondrial membrane; IMS: mitochondrial intermembrane space; LIR: LC3-interacting region; MDVs: mitochondrial-derived vesicles; MTORC1: mechanistic target of rapamycin kinase complex 1; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PD: Parkinson disease; PtdIns3K: phosphatidylinositol 3-kinase; RGC: retinal ganglion cell; RING: really interesting new gene; ROS: reactive oxygen species; SUMO: small ubiquitin like modifier; TBI: traumatic brain injury; TM: transmembrane.

Keywords: Autophagy receptors; mitochondria; mitochondrial dysfunction; mitophagy; selective autophagy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Autophagy* / physiology
  • Mitochondrial Membranes / metabolism
  • Mitophagy* / genetics
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Ubiquitin-Protein Ligases
  • Protein Kinases

Grants and funding

Z.E. is the incumbent of the Harold Korda Chair of Biology. We are grateful for funding from the Israel Science Foundation (Grant #215/19), the Sagol Longevity Foundation, Joint NRF - ISF Research Fund (Grant #3221/19), and the Yeda-Sela Center for Basic Research, as well as the Research Council of Norway through its Centres of Excellence funding scheme (project number 262652 to AS) and FRIPRO (project number 221831 to AS) and the Norwegian Cancer Society (project number 171318 to AS). Research in PB lab is supported by (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018-098557-B-I00 Neuroscience Projects from Fundación Tatiana Pérez de Guzmán el Bueno and 2017/BMD-3813 from Comunidad de Madrid. The first authors are supported by a Marie Skłodowska-Curie ETN grant under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement No 765912 DRIVE).