Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation
Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation
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DOI：
10.1038/s42255-021-00342-6
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发表时间：
2021-02-01
影响因子：
20.8
通讯作者：
Tsujita, Kenichi
中科院分区：
文献类型：
--
作者：
Arima, Yuichiro;Nakagawa, Yoshiko;Tsujita, Kenichi
酮体在肝脏中产生，可以在禁食和热量限制期间维持全身热量和能量稳态。先前已经证明，新生儿生酮作用的激活与饥饿无关。然而，生酮在围产期的作用仍不清楚。在这里，我们表明新生儿生酮在线粒体功能中发挥保护作用。我们通过破坏限速羟甲基戊二酰辅酶A合酶2酶基因（Hmgcs2）建立了生酮不足的小鼠模型。 Hmgcs2 敲除 (KO) 新生儿在出生后几天内就会出现微泡脂肪变性。电子显微镜分析和代谢物分析表明 Hmgcs2 KO 小鼠的能量产生能力和乙酰辅酶 A 积累受到限制。此外，Hmgcs2 KO 细胞的乙酰化分析显示线粒体蛋白的乙酰化增强。这些发现表明，新生儿生酮通过防止线粒体蛋白的过度乙酰化来保护线粒体的能量产生能力。生酮对于新生儿和围产期的生存至关重要。有马等人。确定肝生酮可防止线粒体蛋白的过度乙酰化和线粒体能量学的破坏。
Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear. Here, we show that neonatal ketogenesis plays a protective role in mitochondrial function. We generated a mouse model of insufficient ketogenesis by disrupting the rate-limiting hydroxymethylglutaryl-CoA synthase 2 enzyme gene (Hmgcs2). Hmgcs2 knockout (KO) neonates develop microvesicular steatosis within a few days of birth. Electron microscopic analysis and metabolite profiling indicate a restricted energy production capacity and accumulation of acetyl-CoA in Hmgcs2 KO mice. Furthermore, acetylome analysis of Hmgcs2 KO cells revealed enhanced acetylation of mitochondrial proteins. These findings suggest that neonatal ketogenesis protects the energy-producing capacity of mitochondria by preventing the hyperacetylation of mitochondrial proteins.Ketogenesis is critical for survival during the neonatal and perinatal periods. Arima et al. determine that hepatic ketogenesis prevents hyperacetylation of mitochondrial proteins and disruption of mitochondrial energetics.