Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.

1. Cell Metab. 2024 Oct 1;36(10):2329-2340.e4. doi: 10.1016/j.cmet.2024.07.016. Epub 2024 Aug 16.

Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.

LaMoia TE(1), Hubbard BT(1), Guerra MT(2), Nasiri A(2), Sakuma I(2), Kahn M(2), Zhang D(2), Goodman RP(3), Nathanson MH(1), Sancak Y(4), Perelis M(5), Mootha VK(6), Shulman GI(7).

Author information: (1)Departments of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA. (2)Departments of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA. (3)Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (4)Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195, USA. (5)Ionis Pharmaceuticals, Carlsbad, CA 92010, USA. (6)Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. (7)Departments of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: gerald.shulman@yale.edu.

To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.

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DOI: 10.1016/j.cmet.2024.07.016 PMCID: PMC11446666 PMID: 39153480 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of interests The authors declare no competing interests.