Heterozygous R403Q mutation impairs left atrial mitochondrial function in a Yucatan mini-pig model of genetic nonobstructive hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) can be caused by a R403Q gene mutation, which drives pathological cardiac remodeling and may ultimately lead to heart failure. Here, we sought to examine the effects of this mutation on cardiac mitochondrial function in a Yucatan mini-pig model of genetic HCM. Activity of key mitochondrial enzymes, citrate synthase and β-hydroxyacyl-CoA dehydrogenase, was significantly reduced in the left atrium of HCM animals compared with the control group. However, left atrial mitochondrial respiration was significantly greater in HCM pigs versus controls in the following states: basal (42%, = 0.001), state 2 (47%, = 0.02), and uncoupled ( = 0.003), potentiating a compensatory mechanism. Surprisingly, left ventricular mitochondrial respiration and mitochondrial enzymatic activity did not differ between the HCM model versus healthy control pigs. However, proteomic profiling revealed parallel mitochondrial dysfunction and impairment of energy metabolism processes in both chambers, such as inhibited fatty acid metabolism and mitogenesis in the left atrium and increased mitochondrial dysfunction and concentration of fatty acids in the left ventricle. Collectively, the R403Q mutation may contribute to HCM through chamber-specific mechanisms that promote mitochondrial dysfunction and impaired energy homeostasis. Furthermore, these findings demonstrate the utility of this preclinical large animal model for identifying novel mechanisms underlying genetic heart failure with translational impact for individuals affected with HCM. Changes in mitochondrial function have been proposed in the etiology of hypertrophic cardiomyopathy (HCM). In this report, we examine mitochondrial function and activity in response to a R403Q gene mutation that causes HCM. Our findings show chamber-dependent mitochondrial dysfunction and decreased enzymatic activity, which affect key cellular processes, such as ATP production and metabolism. These findings highlight chamber-specific metabolic dysfunction that may contribute to the development of HCM.