Understanding the Role of Cardiolipin: Phenotyping the Tafazzin Knock-down Mouse

Mitochondria are the nexus of cellular energy metabolism. Consequently, the dysregulation of mitochondrial function has been implicated in the development of metabolic complications including the aberrant accumulation of deleterious lipids (lipotoxicity). Cardiolipin (CL) regulates many mitochondrial functions and processes due to its unique tetra-acyl structure and localization to the inner mitochondrial membrane. A mouse model of cardiolipin deficiency was recently developed by knocking-down the cardiolipin biosynthetic enzyme Tafazzin (TAZ Kd). We hypothesized that mitochondrial dysfunction as a result of TAZ-deficiency would increase susceptibility to the development of lipotoxicity. Using a whole-body physiological approach, we unexpectedly determined that TAZ Kd mice were protected against the development of diet-induced obesity. We determined that normal CL levels in the liver of TAZ Kd animals maintained hepatic mitochondrial function and supported an increase in energy expenditure. TAZ-deficiency altered CL molecular species and impaired mitochondrial function in pancreatic islets, and skeletal muscle without promoting aberrant lipid accumulation. In contrast, reductions in CL levels in the heart were accompanied by the development of a cardiomyopathy characterized by mitochondrial dysfunction and lipid accumulation. The development of the lipotoxic cardiomyopathy was accelerated with high-fat diet and prevented with resveratrol, a small cardioprotective nutraceutical. Together, our data indicates a tissue-specific relationship between TAZ-deficiency, CL levels, mitochondrial function and the development of lipotoxicity.