Mitovesicles are a novel population of extracellular vesicles of mitochondrial origin altered in Down syndrome

TLDR

Mitochondrial dysfunction is a hallmark of aging and neurodegenerative disorders such as Down syndrome and Alzheimer’s disease, and the authors identify a new mitochondria‑derived extracellular vesicle type they call mitovesicles. The study aims to develop a selective isolation method for mitovesicles to enable in vivo characterization of mitochondria–EV interactions and support therapeutic and diagnostic advances. The authors used high‑resolution density‑gradient separation of brain‑derived EVs from Down syndrome and control mice and humans to isolate and characterize double‑membranous mitovesicles enriched in mitochondrial proteins. Brain‑derived mitovesicles carry a distinct set of mitochondrial proteins, and their abundance and cargo are altered in Down syndrome and other conditions of mitochondrial dysfunction.

Abstract

Mitochondrial dysfunction is an established hallmark of aging and neurodegenerative disorders such as Down syndrome (DS) and Alzheimer's disease (AD). Using a high-resolution density gradient separation of extracellular vesicles (EVs) isolated from murine and human DS and diploid control brains, we identify and characterize a previously unknown population of double-membraned EVs containing multiple mitochondrial proteins distinct from previously described EV subtypes, including microvesicles and exosomes. We term these newly identified mitochondria-derived EVs "mitovesicles." We demonstrate that brain-derived mitovesicles contain a specific subset of mitochondrial constituents and that their levels and cargo are altered during pathophysiological processes where mitochondrial dysfunction occurs, including in DS. The development of a method for the selective isolation of mitovesicles paves the way for the characterization in vivo of biological processes connecting EV biology and mitochondria dynamics and for innovative therapeutic and diagnostic strategies.