EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat

Mitochondria are fundamental in energy homeostasis and undergo dynamic changes in brown and beige fat. Mitochondrial dysfunctions impair thermogenic capacity and cause obesity-associated metabolic diseases. The phospholipid composition is crucial for maintaining mitochondrial function and fission-fusion processes. Here, we described EBF2, a transcription factor pivotal for brown fat development and function that regulates the integrity of mitochondrial membrane composition, function and dynamics in brown adipocytes. Strikingly, Myf5Cre-driven targeted deletion of Ebf2 in brown adipose tissue (BAT) drastically reduces cardiolipin and phosphatidylethanolamine abundance and alters acyl chain remodeling of major phospholipids. BAT mitochondria of Ebf2-KO neonates exhibit a severe reduction of DRP1 and OPA1, key regulators of mitochondrial fission-fusion dynamics; further, Ebf2 deletion impairs fragmentation-fusion events in brown adipose tissue. Mechanistically, EBF2 directly binds to key genes, including Srebf1, which are involved in membrane lipid metabolism and differentially regulate their expression. Also, the deletion of Ebf2 downregulates CL and PE-synthesizing genes and accumulates phosphatidylserine and sphingomyelin levels in mitochondria. Thus, the deletion of Ebf2 perturbs the acyl chain remodeling of mitochondrial lipids and affects the fission-fusion cycle in neonatal brown adipocytes. To conclude, Ebf2 is crucial for regulating the levels and remodeling of bilayer and non-bilayer-forming lipids to conserve mitochondrial metabolism.