Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.
Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.
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心肌细胞特异性删除 GCN5L1 可减少赖氨酸乙酰化，并通过改善心脏脂肪酸氧化来减轻老年小鼠的舒张功能障碍。
DOI：
10.1042/bcj20230421
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Thapa,Dharendra
中科院分区：
文献类型：
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作者：
Stewart,JacksonE;Crawford,JennaM;Mullen,WilliamE;Jacques,Angelica;Stoner,MichaelW;Scott,Iain;Thapa,Dharendra
心脏线粒体功能障碍是衰老和许多年龄相关疾病发病机制的关键因素。因此，线粒体功能的完全控制对于维持老年心脏的心脏效率至关重要。赖氨酸乙酰化是一种可逆的翻译后修饰，可调节线粒体的多种代谢和生化过程。在本研究中，我们研究了线粒体赖氨酸乙酰化如何调节脂肪酸氧化（FAO）和老年心脏的心功能。我们发现，在老年心脏线粒体蛋白乙酰化的显着增加，这与线粒体乙酰转移酶相关蛋白GCN 5L1的水平增加。我们发现，乙酰化状态的几种脂肪酸和葡萄糖氧化酶（长链酰基辅酶A脱氢酶，羟酰基辅酶A脱氢酶，丙酮酸脱氢酶）在老年心脏显着上调，这与酶活性下降。使用心脏特异性GCN 5L1敲除（KO）动物模型，我们表明老年KO动物线粒体蛋白的总体乙酰化减少，包括FAO蛋白，这导致老年心脏中观察到的FAO活性改善并减轻心脏舒张功能障碍。总之，这些研究结果表明，赖氨酸乙酰化调节老年心脏中的FAO，从而改善心脏舒张功能，这部分是由GCN 5L1调节的。
Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging and many age-related conditions. As such, complete control of mitochondrial function is critical to maintain cardiac efficiency in the aged heart. Lysine acetylation is a reversible post-translational modification shown to regulate several mitochondrial metabolic and biochemical processes. In the present study, we investigated how mitochondrial lysine acetylation regulates fatty acid oxidation (FAO) and cardiac function in the aged heart. We found a significant increase in mitochondrial protein acetylation in the aged heart which correlated with increased level of mitochondrial acetyltransferase-related protein GCN5L1. We showed that acetylation status of several fatty acid and glucose oxidation enzymes (long-chain acyl-coenzyme A dehydrogenase, hydroxyacyl-coA dehydrogenase, and pyruvate dehydrogenase) were significantly up-regulated in aged heart which correlated with decreased enzymatic activities. Using a cardiac-specific GCN5L1 knockout (KO) animal model, we showed that overall acetylation of mitochondrial proteins was decreased in aged KO animals, including FAO proteins which led to improved FAO activity and attenuated cardiac diastolic dysfunction observed in the aged heart. Together, these findings indicate that lysine acetylation regulates FAO in the aged heart which results in improved cardiac diastolic function and this is in part regulated by GCN5L1.