Biogenesis and secretion of mitovesicles, small extracellular vesicles of mitochondrial origin at the crossroads between brain health and disease

In the brain, mitochondrial components are released into the extracellular space via several mechanisms, including a recently identified type of extracellular vesicles called mitovesicles. While vesiculation of neuronal mitochondria yields various intracellular types of vesicles, with either a single or a double membrane, mitovesicles secreted into the extracellular space are a unique subtype of these mitochondria-derived vesicles, with a double membrane and a specific set of mitochondrial DNA, RNA, proteins, and lipids. Based on the most relevant literature describing mitochondrial vesiculation and mitochondrial exocytosis, we propose a model for their secretion when the amphisomes, a hybrid endosome–autophagosome organelle, fuse with the plasma membrane, releasing mitovesicles and exosomes into the extracellular space. In aging and neurodegenerative disorders, mitochondrial dysfunction, in association with endolysosomal abnormalities, alter mitovesicle number and content, with downstream effect on brain health.