Spastin-mediated severing of glutamylated microtubules controls cardiomyocyte coupling

  • Nat Cardiovasc Res. 2026 Apr;5(4):366-382. doi: 10.1038/s44161-026-00800-y.
Jiayin Zhang  #  1  2  3  4 ,  Xiaozhi Huang  #  1  2  3 ,  Zhichao Wu  #  5 ,  Jinxiu Liang  1  2  3 ,  Shuo Chen  1  2  3 ,  Chen Xu  1  2  3 ,  Xinjian Wang  1  2  3 ,  Ranran Cao  1  2  3 ,  Xue Ji  1  2  3 ,  Zijian Feng  1  2  3 ,  Tao Lin  1  2  3 ,  Xuyun Li  6 ,  Xinyang Hu  2  7  8 ,  Wei Zhu  2  7  8 ,  Peidong Han  9  10  11
Affiliations
  • 1. Department of Cardiology, Center for Genetic Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 2. State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China.
  • 3. Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China.
  • 4. Experimental Teaching Center, College of Basic Medical Sciences, Naval Medical University, Shanghai, China.
  • 5. Department of Thoracic surgery, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, China.
  • 6. Basic Medicine Experimental Teaching Center, Zhejiang University, Hangzhou, China.
  • 7. Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 8. Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China.
  • 9. Department of Cardiology, Center for Genetic Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. [email protected].
  • 10. State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China. [email protected].
  • 11. Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41946976 DOI: 10.1038/s44161-026-00800-y
Abstract

Cardiac ischemia-reperfusion injury frequently induces malignant arrhythmias because of connexin 43 (Cx43) mislocalization and impaired cardiomyocyte coupling; yet, effective therapies targeting this mechanism remain scarce. Here we show that ischemic cardiomyopathy in humans and ischemia-reperfusion in mice promote the accumulation and stabilization of glutamylated microtubules, disrupting targeted Cx43 trafficking. This remodeling of the glutamylated microtubule network is mediated by the microtubule-severing enzyme spastin. Spastin overexpression in cardiomyocytes reduced microtubule density, whereas its deficiency caused accumulation of glutamylated, stabilized microtubules. Although cardiomyocyte-specific spastin knockout mice displayed normal cardiac structure and function at baseline, they were highly susceptible to stress-induced malignant arrhythmias. Mechanistically, spastin deficiency impaired microtubule plus end dynamics and Cx43 transport. Notably, genetic or pharmacological reduction of microtubule glutamylation before ischemia-reperfusion preserved Cx43 localization and mitigated oxidative stress-induced injury. Together, these findings identify microtubule glutamylation as a key regulator of cardiac electrical stability and a promising therapeutic target in ischemia-reperfusion injury.

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