Targeting Myocardial Mitochondria-STING-Polyamine Axis Prevents Cardiac Hypertrophy in Chronic Kidney Disease

[Display omitted] •Mitochondrial damage is early and prominent in cardiomyocytes under CKD milieu.•Mitochondrial damage stimulates myocardial STING-NFκB pathway to drive hypertrophy.•NFκB transactivates ODC1-PUT metabolic flux in cardiomyocytes.•ODC1-PUT metabolic flux is required for STING/NFκB-driven cardiac hypertrophy.•Targeting mitochondria-STING-ODC1 axis prevents cardiac hypertrophy in CKD. Chronic kidney disease (CKD) is well recognized as a distinct contributor to cardiac hypertrophy, while the underlying mechanism remains incompletely understood. Here, the authors show that myocardial mitochondrial oxidative damage is early and prominent in CKD and distinctively stimulates the STING-NFκB pathway by releasing mitochondrial DNA to drive cardiac hypertrophy. Furthermore, the authors reveal that ornithine decarboxylase (ODC1)–putrescine metabolic flux is transactivated by NFκB and is required for the STING-NFκB pathway to drive cardiac hypertrophy. Finally, genetic or pharmacologic inhibition of the myocardial mitochondria-STING-NFκB-ODC1 axis significantly prevents CKD-associated cardiac hypertrophy. Therefore, targeting the myocardial mitochoandria-STING-NFκB-ODC1 axis is a promising therapeutic strategy for cardiac hypertrophy in patients with CKD.