PL2 - Plenary lecture 2

The role of mitovesicles in brains with mitochondrial dysfunction

Prof. Levy, Efrata ^1,2

1) Departments of Psychiatry and Biochemistry & Molecular Pharmacology, Neuroscience Institute, New York University Grossman School of Medicine, USA
2) Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, USA
Contacto: Efrat.Levy@nyulangone.org

Mitochondrial dysfunction and brain hypometabolism are hallmarks of aging, neurodegenerative and neurodevelopmental disorders, including Alzheimer’s disease and Down syndrome, causing the build-up of damaged mitochondria. 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. We hypothesized that mitovesicle secretion into the brain extracellular space eliminates detrimental mitochondrial materials from the cell, especially when other mitochondrial quality control mechanisms are disrupted. We found changes in the number and content of mitovesicles in brains with dysfunctional endosomes, autophagic vesicles, lysosomes and mitochondria, including in human and a mouse model of DS and in a mouse model of β-amyloidosis and postulated that shuttling from one cell to another, dysfunctional mitovesicles can transfer this mitochondrial content from a single focal site to the rest of the brain, potentially impairing recipient distal cells. Neither mouse models had β-amyloid deposition at the age tested. We found that mitovesicles isolated from brains of the mouse models perturb long-term potentiation of otherwise normal mouse hippocampi. Microvesicles and exosomes isolated from the same brains and mitovesicles isolated from control brains do not have this electrophysiological effect. These data show that mitovesicles acquire pathogenic functions under conditions of mitochondrial dysfunction, potentially affecting memory formation and the propagation of neuropathology. In aging and neurodegenerative and neurodevelopmental disorders, mitochondrial dysfunction, in association with endosomal-autophagic-lysosomal abnormalities, alteration of mitovesicle number and content have downstream effect on brain health.