Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation
- 18 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Metabolism
- Vol. 3 (2), 196-210
- https://doi.org/10.1038/s42255-021-00342-6
Abstract
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.Keywords
Funding Information
- Ministry of Education, Culture, Sports, Science and Technology (19K08520, 17K16014, 18K08110)
- Japanese Circulation Society
- Sumitomo Foundation
- Takeda Medical Research Foundation
- Kanae Foundation for the Promotion of Medical Science
- Japan Foundation for Applied Enzymology
- Ono Medical Research Foundation
- Kumamoto University
- Japan Agency for Medical Research and Development (16769865)
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