2. Academic Validation
  3. Redox switch C674 in SERCA2 triggers Ca2+-calcineurin-MCU-Drp1 cascade and pulmonary vascular remodeling

Redox switch C674 in SERCA2 triggers Ca2+-calcineurin-MCU-Drp1 cascade and pulmonary vascular remodeling

  • Free Radic Biol Med. 2025 Dec 16:244:380-394. doi: 10.1016/j.freeradbiomed.2025.12.023.
Hui Chen 1,  Yi-Xiang Qiu 2,  Yu-Fei Xie 3,  Xun Chen 4,  Ying-Ying Xiang 5,  Hai-Long Zhang 6,  Wei-Min Yu 7,  Ping-Ping Hu 8,  Lang-Tao Wang 9,  Fu-Hua Wu 10,  Xiao-Yong Tong 11
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China. Electronic address: [email protected].
  • 2 School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China. Electronic address: [email protected].
  • 3 School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China. Electronic address: [email protected].
  • 4 School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China. Electronic address: [email protected].
  • 5 School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China. Electronic address: [email protected].
  • 6 School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China. Electronic address: [email protected].
  • 7 Chongqing Key Laboratory for Pharmaceutical Metabolism Research, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. Electronic address: [email protected].
  • 8 Chongqing Key Laboratory for Pharmaceutical Metabolism Research, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. Electronic address: [email protected].
  • 9 School of Biosciences and Technology, Chengdu Medical College, Chengdu, 610500, China. Electronic address: [email protected].
  • 10 Genetic Diseases Key Laboratory of Sichuan Province and the Center for Medical Genetics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China. Electronic address: [email protected].
  • 11 School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
PMID: 41412527 DOI: 10.1016/j.freeradbiomed.2025.12.023
Abstract

Pulmonary arterial smooth muscle cell (PASMC) phenotypic switching from a contractile to a proliferative state is a central driver of pulmonary vascular remodeling in pulmonary hypertension (PH). Mitochondrial fragmentation is a key metabolic hallmark of this switch, yet the molecular trigger initiating fragmentation remains undefined. We hypothesized that oxidative dysfunction of sarcoplasmic/endoplasmic-reticulum CA2+-ATPase 2 (SERCA2) at its redox-sensitive C674 residue governs mitochondrial dynamics in PASMCs. Primary PASMCs were isolated from wild-type (WT) mice and from SERCA2 C674S mutant knock-in (SKI) mice that phenocopy irreversible oxidation of SERCA2 under PH-relevant oxidative stress. Mitochondrial morphology, CA2+ levels, and membrane potential (ΔΨm) were assessed using Mito-Tracker Red CMXRos, Rhod-2 AM, and Rhodamine 123, respectively. Protein expression was analyzed by Western blot. In vivo experiments employed SKI mice treated with either the dynamin-related protein 1 (Drp1) inhibitor Mdivi-1 or AAV6-mediated SERCA2b gene transfer. SKI PASMCs exhibited extensive mitochondrial fragmentation and upregulated pro-fission proteins, accompanied by downregulated fusion proteins. SERCA2 dysfunction causes mitochondrial CA2+ overload and ΔΨm loss by upregulating the mitochondrial calcium uniporter (MCU). Chelation of intracellular CA2+, inhibition of Calcineurin, MCU, or Drp1 restored mitochondrial integrity and inhibited PASMC phenotypic switch. In SKI mice, Drp1 inhibition or SERCA2b overexpression attenuated pulmonary vascular remodeling. In conclusion, oxidative disruption of SERCA2-C674 initiates a CA2+/calcineurin-MCU-Drp1 cascade resulting in mitochondrial fragmentation and PASMC phenotypic switch. Targeting SERCA2b restoration, balancing MCU and mitochondrial CA2+, or Drp1 blockade offers complementary therapeutic strategies for PH by disrupting this pathogenic axis.

Keywords

Dynamin-related protein 1; Mitochondrial calcium uniporter; Pulmonary arterial smooth muscle cell; Pulmonary vascular remodeling; SERCA2.

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