GNPS - Cocaine perturbs mitovesicle biology in the brain

Cocaine is one of the most abused psychostimulants in the United States. In addition to its established roles in the regulation of dopaminergic circuitries, cocaine has a broader mechanism of action, including global alterations in brain metabolism and mitochondrial homeostasis. Our group recently identified a subpopulation of non-microvesicular, non-exosomal extracellular vesicles of mitochondrial origin, mitovesicles (mtVs), and provided a method to isolate mtVs from brain parenchyma. Given their origin, we hypothesized that mtVs could be affected by mitochondrial abnormalities induced by chronic cocaine exposure. Therefore, we analyzed mtVs from hemibrains of 3-month-old mice that received for two weeks intraperitoneal injections of cocaine or saline as control. MtVs from the brain extracellular space of cocaine-intoxicated mice were enlarged and more numerous when compared to controls. Moreover, cocaine stimulated higher intracellular mitochondrial fission and higher levels of upstream (but not downstream) mitophagy pathways, suggesting increased mitochondrial fragmentation and a block in mitophagy flux. Lastly, cocaine impaired brain mtV cargo loading as revealed by Mass Spec analysis, causing an alteration in mtV ATP production capacity. These data suggest that mtVs are a previously unidentified player in the biology of cocaine addiction and that target therapies to fine tune brain mtV functionality may be beneficial to mitigate chronic cocaine pathology.