Knockout of cardiolipin synthase disrupts postnatal cardiac development by inhibiting the maturation of mitochondrial cristae.

ABSTRACT

Background: Cardiomyocyte maturation requires a massive increase in respiratory enzymes and their assembly into long-lived complexes of oxidative phosphorylation (OXPHOS). The molecular mechanisms underlying the maturation of cardiac mitochondria have not been established. Methods: To determine whether the mitochondria-specific lipid cardiolipin is involved in cardiac maturation, we created a cardiomyocyte-restricted knockout (KO) of cardiolipin synthase ( Crls1 ) in mice and studied the postnatal development of the heart. We also measured the turnover rates of proteins and lipids in cardiolipin-deficient flight muscle from Drosophila, a tissue that has mitochondria with high OXPHOS activity like the heart. Results: Crls1KO mice survived the prenatal period but failed to accumulate OXPHOS proteins during postnatal maturation and succumbed to heart failure at the age of 2 weeks. Turnover measurements showed that the exceptionally long half-life of OXPHOS proteins is critically dependent on cardiolipin. Conclusions: Cardiolipin is essential for the postnatal maturation of cardiomyocytes because it allows mitochondrial cristae to accumulate OXPHOS proteins to a high concentration and to shield them from degradation.