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

By characterizing the composition of mitochondrial-derived vesicles (MDVs), Konig et al. define a MIRO1/2- and DRP1-dependent MDV biogenesis pathway and propose that MDVs maintain the mitochondrial proteome by shuttling assembled protein complexes to lysosomes. 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 beta-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.

Automated summary

The study characterizes a MIRO1/2- and DRP1-dependent MDV biogenesis pathway and reveals how MDVs shuttle fully assembled protein complexes to lysosomes, maintaining mitochondrial proteome quality. This provides insights into a selective quality control mechanism for multi-subunit complexes within mitochondria.