Cardiac-Specific Deletion Of Prohibitin-1 Leads To Fetal Demise, Gross Mitochondrial Abnormalities And Heart Failure In Adolescent Mice

Prohibitins (PHB1, 2) are lipid raft-associated proteins which form a multimeric, alternating ring-like structure in cellular membranes, and are particularly abundant in mitochondria and plasma membranes, but have also been found in nuclei. These pleiotropic proteins are associated with numerous signaling pathways responsible for cell differentiation, growth, and metabolism. In mitochondria, PHBs are thought to act as scaffold-like chaperone proteins responsible for stabilizing enzymes responsible for electron transport and oxidative phosphorylation (OXPHOS), minimizing reactive oxygen species (ROS), and coordinating fission/fusion. However, the extent to which PHB1 regulates mitochondria and electromechanical function of the heart, is not known. We established a cardiac-specific PHB1-deficient mouse strain by crossing floxxed phb1 mice with mice expressing Cre recombinase under control of myosin heavy chain (MHC) promoter. The vast majority of cardiac-specific PHB1-deficient mice (cPHB1ko) died in utero during pregnancy (E12-E15). Uterine sonography of the expired cPHB1ko embryos showed significantly decreased crown-rump length and increased placenta thickness with large amount of fluids, restricted uterine artery flow and detachment between amnion and chorion compared with normal embryos (P < 0.001). The few that were born develop severe dilated cardiomyopathy, resulting in mortality by 8-9 weeks of age. Heart weight/body weight ratio is ~2-fold greater in the KO mice vs. WT. Echocardiography reveals severely enlarged right atria and ventricles in cPHB1ko mice, corresponding to significantly decreased ejection faction (EF), increased end diastolic volume (EDV) and end systolic volume (ESV) compared to wild-type littermates (P < 0.05). In mitochondria, cPHB1ko mice have derangements in OXPHOS as evidenced by decreased pyruvate and palmitoylcarnitine-supported respiration and ATP production. Moreover, both the rate of calcium uptake (P = 0.05) and the total calcium retention capacity (P < 0.01) were diminished in the KO mice. These preliminary findings implicate PHB1 as a critical regulator of myocardial development and function, due in part to its role in maintaining OXPHOS and controlling metabolism.