2. Academic Validation
  3. Cardiomyocyte βII spectrin plays a critical role in maintaining cardiac function by regulating mitochondrial respiratory function

Cardiomyocyte βII spectrin plays a critical role in maintaining cardiac function by regulating mitochondrial respiratory function

  • Cardiovasc Res. 2024 Jun 4:cvae116. doi: 10.1093/cvr/cvae116.
Rongjin Yang 1 2,  Banjun Ruan 1,  Rutao Wang 1,  Xiaomeng Zhang 1,  Pingping Xing 1,  Congye Li 1,  Yunyun Zhang 3,  Xiaoqian Chang 1 4,  Haifeng Song 1,  Shun Zhang 1,  Huishou Zhao 1,  Feiyu Zhang 1,  Tao Yin 1,  Tingting Qi 1,  Wenjun Yan 1,  Fuyang Zhang 1,  Guangyu Hu 1,  Shan Wang 1,  Ling Tao 1
Affiliations

Affiliations

  • 1 Department of Cardiology, Xijing Hospital, Air Force Medical University, 169 Changle West Road, Xi'an 710032, China.
  • 2 Department of Cardiology, The 989th Hospital of the People's Liberation Army Joint Logistic Support Force, 2 Huaxia West Road, Luoyang 471000, China.
  • 3 Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Air Force Medical University, 169 Changle West Road, Xi'an 710032, China.
  • 4 Department of Cardiology, Yan'an University Affiliated Hospital, 43 Bei Dajie, Yan'an 716000, China.
PMID: 38832923 DOI: 10.1093/cvr/cvae116
Abstract

Aims: βII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of βII spectrin in cardiac contractile function and pathological post-myocardial infarction remodeling remain unclear. Here, we investigated whether and how βII spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischemia/reperfusion (I/R) injury.

Methods and results: We observed that the levels of serum βII spectrin breakdown products (βII SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, βII spectrin was degraded into βII SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific βII spectrin knockout mice, we found that deletion of βII spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific βII spectrin knockout mice had not developed, deletion of βII spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of βII spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that βII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, βII spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability.

Conclusion: βII spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in βII spectrin exacerbate cardiac I/R injury.

Keywords

Cardiac function; Cytoskeleton; Mitochondria; Mitochondrial complex I; βII spectrin.

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