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FAM3A Deficiency − Induced Mitochondrial Dysfunction Underlies Post-Infarct Mortality and Heart Failure

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Abstract

Mitochondrial protein sequence similarity 3 gene family member A (FAM3A) plays important roles in the electron transfer chain, while its functions in the heart are still unknown. This study aims to explore the roles and mechanisms of FAM3A after myocardial infarction (MI). FAM3A-deficient (Fam3a−/−) mice were implemented with MI injury and showed lower survival rates at 4 weeks as well as decreased cardiac systolic function. Isolated cardiomyocytes of Fam3a−/− mice showed reduced basal, ATP-linked respiration and respiratory reserve compared to that of wild-type mice. Transmission electron microscopy studies showed Fam3a−/− mice had a larger size and elevated density of mitochondria. FAM3A deficiency also induced elevated mitochondrial Ca2+, higher opening level of mPTP, lower mitochondrial membrane potential and elevated apoptotic rates. Further analyses demonstrated that mitochondrial dynamics protein Opa1 contributed to the effects of FAM3A in cardiomyocytes. Our study discloses the important roles of mitochondrial protein FAM3A in the heart.

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Data supporting the findings of this study are available within the article and its supplementary materials.

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Acknowledgements

We thank professor Xin Pan (State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, Beijing, China) for constructive criticism in the project design.

Funding

This work was supported by: Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences (2021RU003), National Natural Science Foundation of China (Grant No. 82270343, No. 81900315, No. U20A20345) and National Key Research and Development Program of China (No.2020YFA0803800, No. 2020YFA0803803).

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Author notes

  1. Tan Xu, Jiaxing Wang and Xiaoxiao Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China

    Tan Xu, Jiaxing Wang & Ming Xu

  2. State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China

    Xiaoxiao Liu & Shiqiang Wang

  3. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of the Ministry of Education, Center for Non-Coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China

    Rui Xiang & Jichun Yang

  4. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Houhua Li

  5. Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China

    Ming Xu

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Contributions

TX, JXW, and XXL performed the experiments and analyzed the data. TX, JXW, and XXL wrote the manuscript. RX, HHL and SQW provided experimental advice and some experimental supplies. JCY and MX designed the experiments. All authors contributed to the editing of the review and approved the final version of the manuscript for submission.

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Correspondence to Jichun Yang or Ming Xu.

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Associate Editor Yihua Bei oversaw the review of this article

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Supplementary Information

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12265_2023_10382_MOESM1_ESM.pptx

Supplementary file1 (PPTX 65865 KB) Figure S1. (A) Serum level of cardiac troponin T 6 hours post-MI (n=6). (B) Lung edema measured by wet-dry weight of sham and 28-day post-MI (n=6). (C) Heart to tibia weight ratio at 28-day post-MI (n=6). Figure S2. (A-D) representative pictures and (E) statistics analysis of protein level of Mfn1, Mfn2, DRP1, and Fis1 from cardiac infarct border tissues at 7-day post-MI or sham heart tissue. ns, non-significant. All values are presented as mean ± SEM. Data were analyzed by two-way ANOVA, followed by subsequent post hoc multiple comparison.

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Xu, T., Wang, J., Liu, X. et al. FAM3A Deficiency − Induced Mitochondrial Dysfunction Underlies Post-Infarct Mortality and Heart Failure. J. of Cardiovasc. Trans. Res. 17, 104–120 (2024). https://doi.org/10.1007/s12265-023-10382-w

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