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Cardiac‐specific deletion of prohibitin‐2 in adult mice destabilizes mitochondrial proteins, nucleoids, and cristae morphology, resulting in lethal cardiomyopathy

Evolutionally conserved prohibitins (PHBs) primarily localize in the inner mitochondrial membrane (IMM) and play a significant role in the maintenance of normal mitochondrial biogenesis, metabolism, and micro‐domain structures. In a heart failure mouse model, we found PHB was significantly decreased in the heart. Using a tamoxifen (tmx)‐inducible chimeric Cre‐lox system, the current study selectively removed PHB2 in adult cardiac myocytes in vivo. Five weeks after tmx treatment, PHB2 deletion accompanied nearly complete loss of PHB1, which is hetero‐oligomerized with PHB2, and reduced expression of oxidative phosphorylation complex I‐IV proteins. Remarkably, ~70% of the long isoforms of Opa1 in the IMM disappeared, while outer membrane GTPases Mfn1 and 2 were preserved. Serial echocardiography showed that cardiac contractility started to decline and dilated cardiomyopathy rapidly progressed after 10 weeks: all tmx‐treated mice ultimately died due to heart failure. PicoGreen staining identified disorganized mitochondrial nucleoids in PHB2‐deleted isolated cardiomyocytes. Tomographic electron microscopy found enlarged and aberrantly organized mitochondrial cristae, while outer membrane structure was not overtly affected. These results indicate that PHB is essential to the integrity of IMM micro‐domain structures and associated molecular functions in postmitotic adult mammalian cells.