Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism

Shubhi Srivastava, Priyanka Gajwani, Jordan Jousma, Hiroe Miyamoto, Youjeong Kwon, Arundhati Jana, Peter T. Toth, Gege Yan, Sang-Ging Ong () and Jalees Rehman ()
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Shubhi Srivastava: The University of Illinois College of Medicine
Priyanka Gajwani: The University of Illinois College of Medicine
Jordan Jousma: The University of Illinois College of Medicine
Hiroe Miyamoto: The University of Illinois College of Medicine
Youjeong Kwon: The University of Illinois College of Medicine
Arundhati Jana: The University of Illinois College of Medicine
Peter T. Toth: The University of Illinois College of Medicine
Gege Yan: The University of Illinois College of Medicine
Sang-Ging Ong: The University of Illinois College of Medicine
Jalees Rehman: The University of Illinois College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40084-5

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