Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism

• Published in: Nature communications 2023-07, Vol.14 (1), p.4360-4360, Article 4360
• Main Authors: Srivastava, Shubhi, Gajwani, Priyanka, Jousma, Jordan, Miyamoto, Hiroe, Kwon, Youjeong, Jana, Arundhati, Toth, Peter T., Yan, Gege, Ong, Sang-Ging, Rehman, Jalees
• Format: Article
• Language: English
• Subjects: 14; 14/19; 631/80/642/333/1465; 631/80/86/2366; 64/60; 692/4019/592; 692/4028/67/1059/99; 96/100; 96/106; 96/2; Anthracycline; Anthracyclines - pharmacology; Antibiotics, Antineoplastic - pharmacology; Cardiomyocytes; Cardiotoxicity; Cardiotoxicity - metabolism; Cellular stress response; Chemotherapy; Chromatin; Damage; Dehydrogenases; Doxorubicin - pharmacology; Heart; Heart Diseases - metabolism; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Injuries; Kinases; Metabolites; Mitochondria; multidisciplinary; Myocytes, Cardiac - metabolism; Nuclear transport; Nuclei (cytology); Oxidoreductases - metabolism; Pluripotency; Science; Science (multidisciplinary); Stem cells; Topoisomerase II Inhibitors - pharmacology; Translocation; Tricarboxylic acid cycle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40084-5

Chemotherapy-induced cardiac damage remains a leading cause of death amongst cancer survivors. Anthracycline-induced cardiotoxicity is mediated by severe mitochondrial injury, but little is known about the mechanisms by which cardiomyocytes adaptively respond to the injury. We observed the translocation of selected mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases to the nucleus as an adaptive stress response to anthracycline-cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes and in vivo. The expression of nuclear-targeted mitochondrial dehydrogenases shifts the nuclear metabolic milieu to maintain their function both in vitro and in vivo. This protective effect is mediated by two parallel pathways: metabolite-induced chromatin accessibility and AMP-kinase (AMPK) signaling. The extent of chemotherapy-induced cardiac damage thus reflects a balance between mitochondrial injury and the protective response initiated by the nuclear pool of mitochondrial dehydrogenases. Our study identifies nuclear translocation of mitochondrial dehydrogenases as an endogenous adaptive mechanism that can be leveraged to attenuate cardiomyocyte injury. Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.