Metabolic regulation of calcium homeostasis via SERCA succination

  • Sci Adv. 2026 Sep 11;12(37):eaeh2771. doi: 10.1126/sciadv.aeh2771.
Su Jin Ham  1  2  3 ,  Yena Kim  1  4 ,  Sehyeon Kim  1  4 ,  Sunhoe Bang  1 ,  Young Hoon Koh  1  4 ,  Soung-Hun Roh  1  2  4 ,  Hyung Seo Park  5 ,  Jongkyeong Chung  1  2  4
Affiliations
  • 1. Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea.
  • 2. Interdisciplinary Graduate Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.
  • 3. Department of Medical Science and Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
  • 4. School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 5. Department of Physiology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea.
PMID: 42715317 DOI: 10.1126/sciadv.aeh2771
Abstract

Although calcium homeostasis is disrupted in metabolic diseases, its metabolic regulation remains unclear. Here, we identify a mechanism by which fumarate suppresses sarco/endoplasmic reticulum (ER) calcium ion-adenosine triphosphatase (SERCA) activity via succination of a conserved cysteine residue, impairing ER calcium uptake and promoting metabolic dysfunction in Drosophila. In mammalian cells, high glucose or fumarate inhibits SERCA activity and increases ER calcium release and cytosolic and mitochondrial calcium levels. Mechanistically, we show that fumarate covalently modifies SERCA2b at Cys875 and that a Cys875Ser mutant resists fumarate-induced inhibition. In Drosophila, knock-in flies with the corresponding Cys875Ser mutation preserve ER calcium homeostasis and are protected from hyperglycemia, glucose intolerance, and reduced survival on a high-sugar diet. These effects are phenocopied by pharmacological fumarate reduction or allosteric SERCA activation. Collectively, these findings suggest that fumarate-mediated SERCA inhibition provides a mechanistic link between Glucose Metabolism and calcium homeostasis, with potential relevance to metabolic dysfunction.

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