Faculty Collaboration Database

MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart. Proc Natl Acad Sci U S A 2024 Aug 27;121(35):e2402491121

Date

08/20/2024

Pubmed ID

39163336

Pubmed Central ID

PMC11363308

DOI

10.1073/pnas.2402491121

Scopus ID

2-s2.0-85201851900 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

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.

Author List

Hasan P, Berezhnaya E, Rodríguez-Prados M, Weaver D, Bekeova C, Cartes-Saavedra B, Birch E, Beyer AM, Santos JH, Seifert EL, Elrod JW, Hajnóczky G

Authors

Andreas M. Beyer PhD Professor in the Medicine department at Medical College of Wisconsin
Prottoy Hasan PhD Research Scientist I in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Calcium Channels
Calcium Signaling
Calcium-Binding Proteins
Cation Transport Proteins
Humans
Male
Mice
Mice, Knockout
Mitochondria, Heart
Mitochondrial Membrane Transport Proteins
Myocardium
Myocytes, Cardiac