Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

Abstract

Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson’s disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.

The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection

“…It is still debated how mitochondria are transferred between cells, but several routes have been suggested. Apart from the direct release and uptake of mitochondria or their components, transfer via tunnelling nanotubes to adjacent cells has been suggested as well as transfer in extracellular vesicles, which is associated with a reduced release of inflammatory factors as compared to the transfer of “naked” mitochondria [ 233 ]. Importantly, the packaging of mitochondrial proteins in extracellular vesicles has recently been demonstrated to be selective, with damaged proteins being transported directly to lysosomes [ 233 ].…”

“…Apart from the direct release and uptake of mitochondria or their components, transfer via tunnelling nanotubes to adjacent cells has been suggested as well as transfer in extracellular vesicles, which is associated with a reduced release of inflammatory factors as compared to the transfer of “naked” mitochondria [ 233 ]. Importantly, the packaging of mitochondrial proteins in extracellular vesicles has recently been demonstrated to be selective, with damaged proteins being transported directly to lysosomes [ 233 ]. It is possible that mitochondrial components may also be transported by extracellular vesicles from skeletal muscle to the brain, as the release of extracellular vesicles from skeletal muscle into the systemic circulation occurs [ 120 ] particularly in response to exercise [ 118 ].…”

Mitochondrial Extracellular Vesicles – Origins and Roles

“…This suggests that cellular conditions greatly affect the nature and amount of extracellular mitochondrial material. In fact, both LPS and the Complex III inhibitor Antimycin A affect the release of mitochondrial content (Bernimoulin et al, 2009;Boudreau et al, 2014;Joshi et al, 2019;Choong et al, 2020;Crewe et al, 2021;Peruzzotti-Jametti et al, 2021;Todkar et al, 2021) although the resulting effects are not always consistent. EV type classification was normalized to reflect the MISEV2018 guidelines (Théry et al, 2018) and the centrifugation speed noted when available.…”

Mitochondrial function in development and disease

“…Another mechanistically distinct piecemeal mitophagy pathway involves the formation of MDVs ( Neuspiel et al, 2008 ). MDVs selectively transport oxidized mitochondrial components to the lysosome for degradation ( Neuspiel et al, 2008 ; Soubannier et al, 2012 ; Todkar et al, 2021 ). PINK1, Parkin and VPS35 promote MDV formation and trafficking ( Braschi et al, 2010 ; McLelland et al, 2014 ; Wang et al, 2016a ).…”