Plaat1 deficiency reduces cardiac cardiolipin content and impairs exercise tolerance

Phospholipase A and acyltransferase 1 (PLAAT1) catalyzes O-transacylase, N-transacylase, and phospholipase A_1/2 reactions. We have demonstrated that PLAAT1 has O-transacylase activity in vitro using phosphatidylcholine as an acyl donor and monolysocardiolipin (MLCL) as an acyl acceptor, generating cardiolipin. However, a role for PLAAT1 in cardiolipin regulation in vivo has not yet been reported. We generated Plaat1-deficient (Plaat1^-/-) mice and studied males and females for gross morphological differences, food intakes, respiratory gas exchange, total energy expenditure, and voluntary activity. We also evaluated cardiac cardiolipin contents, levels of mitochondrial proteins, and exercise capacity. Sex-matched Plaat1^-/- mice had highly similar body weights to their wild-type (Wt) littermates, although male Plaat1^-/- mice ate less. Male and female Plaat1^-/- hearts were 14.2% and 10.6% smaller, respectively. Cardiac cardiolipin levels were ∼one-third lower in male and female Plaat1^-/- mice compared to their sex-matched Wt littermates, largely due to lower cardiolipin linoleate. Levels of the mitochondrial protein succinate dehydrogenase complex flavoprotein subunit A were 13.8% and 16.3% lower in male and female Plaat1^-/- mice, respectively. Both male and female Plaat1^-/- mice had significantly lower oxygen consumption, carbon dioxide production, and total energy expenditure, and male Plaat1^-/- mice had lower rearing activity than their sex-matched Wt littermates. While other measures of voluntary activity, including locomotion and ambulation did not differ significantly between genotypes, both males and females had reduced exercise tolerance. This work demonstrates a critical role for PLAAT1 in cardiac cardiolipin content and the regulation of energy metabolism and exercise tolerance in vivo.