Selective Packaging of Mitochondrial Proteins into Extracellular Vesicles Prevents the Release of Mitochondrial DAMPs

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Mar 31

PMID 33785738

Citations 120

Authors

Kiran Todkar

Lilia Chikhi

Veronique Desjardins

Firas El-Mortada

Genevieve Pepin

Marc Germain

Affiliations

Soon will be listed here.

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.

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