MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart

• 成果类型: Article
• 署名作者: Hasan, Prottoy; Berezhnaya, Elena; Rodriguez-Prados, Macarena; Weaver, David; Bekeova, Carmen; Cartes-Saavedra, Benjamin; Birch, Erin; Beyer, Andreas M.; Santos, Janine H.; Seifert, Erin L.; Elrod, John W.; Hajnoczky, Gyorgy
• 署名单位: Thomas Jefferson University; Medical College of Wisconsin; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10444
• DOI: 10.1073/pnas.2402491121
• 发表日期: 2024-08-27
• 关键词: to-beat oscillations; ca2+ uptake; uniporter; mcu; lacking; stress; homeostasis; integration; gatekeeper; responses

摘要

Activating Ca2+- sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.