Mitochondria-sarcoplasmic reticulum contact sites in cardiac hypertrophy

Heart mitochondria that engage in contact sites with the sarco/endoplasmic reticulum (MSRCs) are involved in the pathophysiology of cardiac hypertrophy. The molecular landscape and the dynamical changes of MSRCs in hypertrophic hearts are still unclear. After being chronically infused with a β-adrenergic receptor agonist, isoproterenol, using Alzet osmotic minipumps, C57BL6 mice developed cardiac hypertrophy. The transmission electron microscope showed enhanced junctional SR-mitochondria proximity in heart tissues from isoproterenol-challenged mice, compared to saline controls, along with increased left ventricle wall thickness and reduced fractional shortening. In HL-1 cardiomyocytes, isoproterenol enhanced mitochondria-SR proximity and mitochondrial Ca2+ uptake. To investigate the endogenous modulators of MSRCs in cardiomyocytes upon isoproterenol treatment, we integrated a transcriptomic dataset from isoproterenol-infused mouse hearts (GSE195466) and an unbiased MSRCs proteomic catalog generated in our lab. Through combining these two datasets, we identified in hypertrophic hearts 111 differentially expressed genes encoding for MSRC proteins. Among these, a poorly characterized MERCs protein and dually localized mitochondria/peroxisome AAA ATPase, von Willebrand factor A domain-containing protein 8 (VWA8), was downregulated in hypertrophic hearts. Consistently, in isoproterenol-treated cardiomyocytes, Vwa8 expression was downregulated. As an outer mitochondrial membrane protein, Vwa8 deletion increased mitochondria-SR contacts and also enhanced hypertrophic phenotypes both in vitro and in vivo. Functionally, mitochondrial Ca2+ uptake and mitochondrial respiration were increased upon VWA8 deletion. Re-expression in VWA8 knockout AC16 cardiomyocytes of the full-length VWA8 isoform a, but not of the shorter isoform b, restored mitochondria-sarco/endoplasmic reticulum distance. Thus, Vwa8 is part of the rewired gene expression program that scaffolds the communications between mitochondria and SR, ultimately altering mitochondrial function and preventing maladaptive cardiac hypertrophy upon β-adrenergic receptor activation.