Chemotherapy Stress Induces Translocation of Mitochondrial Enzymes to the Nucleus and a Nuclear Metabolomic Shift in Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Abstract

BackgroundDoxorubicin is a highly effective chemotherapeutic agent which can induce severe cardiomyopathy and heart failure in more than 30% of the patients receiving this treatment. Human iPSC‐derived cardiomyocytes (iPSC‐CMs) can be used to model chemotherapy‐induced cardiotoxicity as well as identify adaptive stress mechanisms. We studied the metabolic responses of iPSC‐CMs to doxorubicin in order to identify mechanisms of metabolic injury as well as metabolic adaptation to stress.Methods and ResultsWe studied iPSC‐CMs following short (6 h) and prolonged (24 h) doxorubicin treatment. We observed that doxorubicin stress induces the translocation of mitochondrial TCA cycle enzymes to the nucleus during the course of treatment with ~15 % of the TCA cycle enzymes translocate to the nucleus in 6 h and 30 % in 24 h (p value <0.0001). The compartment specific metabolomic analysis of the nuclear fraction showed that the enzyme translocation induced a metabolic shift in the nuclear compartment, indicating that the translocated enzymes were metabolically active in the nucleus. Super‐resolution microscopy demonstrated that the translocation of TCA cycle enzymes was mediated by carrier vesicles originating from mitochondria. We observed that the metabolic rewiring in the nucleus alters the nuclear NAD+ levels and therefore fuels the activity of cardioprotective nuclear sirtuins by ~2 fold in 6 h of doxorubicin treatment which further increases to ~2.7 fold in 24 h (p value <0.0001).ConclusionThe recent discovery that mitochondrial TCA cycle enzymes can be found in the nuclei of cells where they generate locally acting nuclear metabolites and modulate the epigenome has raised intriguing possibilities regarding mitochondrial‐nuclear crosstalk during stress. Our findings suggest that mitochondrial enzyme translocation to the nucleus may initiate metabolic adaptation which increases the activity of sirtuin histone deacetylases. In light of the known cardioprotective function of sirtuin activation, stress‐induced mitochondrial enzyme translocation may serve as a potential novel therapeutic target to reduce chemotherapeutic cardiotoxicity.Support or Funding InformationNIH HL 126516