Tissue‐specific roles of cardiolipin in the control of systemic energy homeostasis

The mitochondrial inner membrane is a dynamic interface that supports bioenergetic processes, intracellular communication, and transport of metabolites, lipids, and ions. The phospholipid, cardiolipin, is one of the defining components of this membrane and is classically ascribed an indispensable role in mitochondrial structure and function. Disruption of cardiolipin biology is causally linked to numerous pathophysiologies, including diabetes, nonalcoholic fatty liver disease, Parkinson's disease, and, most notably, Barth syndrome. Yet how cardiolipin controls the metabolic functions of different tissues and how these tissues respond to loss of cardiolipin remains largely unknown. Therefore, we generated inducible gain and loss‐of‐function genetic models of cardiolipin synthesis in tissues with predominantly uncoupled (i.e. brown adipose) or coupled (i.e. skeletal muscle) mitochondria. We found that tissue‐specific loss of cardiolipin had dramatically different outcomes on respiration and whole‐body metabolic homeostasis. Cardiolipin deficiency in brown adipocytes significantly reduced organismal insulin sensitivity and glucose tolerance, whereas loss of cardiolipin in skeletal muscle unexpectedly improved glycemic control. Moreover, in contrast to the dogmatic belief that cardiolipin is ubiquitously required for mitochondrial function, we found that certain skeletal muscle fiber types fully retained respiratory capacity in the face of cardiolipin depletion through adaptive measures. Our collective findings on tissue‐specific roles of cardiolipin reshape the fundamental understanding of mitochondrial structure and function with potential therapeutic implications for phospholipid disorders.