Ren Mindong, Xu Yang, Phoon Colin K L, Erdjument-Bromage Hediye, Neubert Thomas A, Schlame Michael
bioRxiv. 2023 Mar 10:2023.03.09.531996. doi: 10.1101/2023.03.09.531996.
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.
To determine whether the mitochondria-specific lipid cardiolipin is involved in cardiac maturation, we created a cardiomyocyte-restricted knockout (KO) of cardiolipin synthase ( ) 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.
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.
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.
心肌细胞成熟需要呼吸酶大量增加，并组装成长寿命的氧化磷酸化（OXPHOS）复合物。心脏线粒体成熟的分子机制尚未明确。
为了确定线粒体特异性脂质心磷脂是否参与心脏成熟过程，我们构建了小鼠心肌细胞特异性心磷脂合酶基因敲除（KO）模型，并研究了心脏的出生后发育情况。我们还测量了果蝇心磷脂缺陷型飞行肌中蛋白质和脂质的周转率，果蝇的飞行肌是一种像心脏一样具有高OXPHOS活性线粒体的组织。
基因敲除小鼠能度过孕期，但在出生后成熟过程中无法积累OXPHOS蛋白，并在2周龄时死于心力衰竭。周转率测量结果表明，OXPHOS蛋白异常长的半衰期严重依赖于心磷脂。
心磷脂对心肌细胞出生后成熟至关重要，因为它能使线粒体嵴积累高浓度的OXPHOS蛋白，并保护它们不被降解。
