Mitochondrial dysfunction and oxidative stress in metabolic heart disease
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Patients with obesity develop a metabolic heart disease (MHD) of unclear mechanisms and limited therapeutic options. MHD is characterized by left-ventricular hypertrophy and impaired ventricular relaxation and is associated with cardiac lipid accumulation, oxidative stress and impaired energetics. Mitochondria play a critical role in cardiac metabolism and mitochondrial dysfunction results in a pathologic decrease in ATP production and increase in reactive oxygen species (ROS) generation. I hypothesized that nutrient excess and cardiac lipid accumulation impair mitochondrial function and cause cardiac remodeling through mitochondrial oxidative stress. Mice overexpressing fatty acid transport protein 1 (FATP1) in cardiomyocytes have increased uptake and use of cardiac lipids and develop MHD. I observed that FATP1 mice have increased cardiac diacylglycerols and PKC activation and decreased mitochondrial biogenesis, size, and oxygen consumption with unchanged ATP synthesis and ROS production. Overexpression of the antioxidant enzyme catalase in mitochondria (mCAT) does not attenuate MHD in FATP1 mice. This suggests that FATP1-driven cardiac lipid accumulation leads to compensated downregulation of mitochondrial function without oxidant overproduction. Mice fed a high fat, high sucrose (HFHS) diet have myocardial oxidative stress and develop MHD. I observed that cardiac mitochondria of HFHS-fed mice have increased ROS production and decreased ATP synthesis and oxygen consumption. HFHS-fed mCAT mice do not develop mitochondrial dysfunction or cardiac remodeling, suggesting that mitochondrial ROS may mediate HFHS-driven mitochondrial dysfunction and MHD. Mice with partial loss of the mitochondrial transporter ABCB10 exhibit cardiac oxidative stress leading to impaired recovery from ischemic injury. I generated mice with cardiomyocyte-specific ABCB10 deletion and observed that ABCB10 loss decreases mitochondrial oxygen consumption and increases ROS production without altering ATP synthesis or affecting cardiac structure and function. After HFHS feeding, mice with heterozygous loss of cardiomyocyte ABCB10 have exaggerated MHD and increased mortality, suggesting a protective role of ABCB10 in MHD induced by HFHS diet. In summary, cardiac lipid accumulation leads to transcriptional downregulation of mitochondrial respiration, while dietary fat and sugar excess leads to mitochondrial dysfunction and cardiac remodeling driven by mitochondrial oxidative stress and exacerbated by loss of ABCB10. This study suggests that oxidant-driven mitochondrial dysfunction plays a key role in MHD.