MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.

1. Nat Cell Biol. 2021 Dec;23(12):1271-1286. doi: 10.1038/s41556-021-00798-4. Epub 2021 Dec 6. MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. König T(1), Nolte H(2), Aaltonen MJ(1), Tatsuta T(2), Krols M(1), Stroh T(1), Langer T(2)(3), McBride HM(4). Author information: (1)Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. (2)Max Planck Institute for Biology of Ageing, Cologne, Germany. (3)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. (4)Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Heidi.mcbride@mcgill.ca. Comment in Nat Cell Biol. 2021 Dec;23(12):1216-1217. doi: 10.1038/s41556-021-00801-y. Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20+ MDVs. We identified 107 high-confidence MDV cargoes, which include all β-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis. © 2021. The Author(s), under exclusive licence to Springer Nature Limited. DOI: 10.1038/s41556-021-00798-4 PMID: 34873283 [Indexed for MEDLINE]