A Novel Model of Elevated Mitochondrial Cholesterol and The Consequences for Mitochondrial Function

Abstract

Increased mitochondrial cholesterol may induce mitochondrial dysfunction and play a role in the progression of neurodegenerative disease and cancer. The voltage-dependent anion channel of the outer mitochondrial membrane has been proposed to participate in cholesterol-related mitochondrial dysfunction through altered associations with proteins involved in metabolism and apoptosis. Current models for studying the effects of mitochondrial cholesterol are disease-based models, blurring the line between true mitochondrial cholesterol effects and other disease effects. Here we present a novel model of increased mitochondrial cholesterol, MitoSTARD4, in which mitochondrial cholesterol content and import to the inner mitochondrial membrane are increased. Cells with increased mitochondrial cholesterol produce more lactate. I explored the mitochondrial associations of voltage-dependent anion channel interacting proteins in cells with elevated mitochondrial cholesterol; BCL-XL, GRP75, PINK1 and PARKIN all have increased mitochondrial presence. The MitoSTARD4 model supports previous findings in disease models that increased mitochondrial cholesterol content induces alterations to mitochondrial function.