Mitochondrial Dysfunction in Congenital Heart Disease

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  Figure 1. Substrate utilization of the myocardium. The heart utilizes various sources of fuel to drive adenosine triphosphate (ATP) production in the mitochondria. Fatty acid oxidation (FAO) is the main source of fuel. Once fatty acids are transported into the cytosol, carnitine palmitoyl transferase 1 (CPT1) adds a carnitine group on them, allowing for transport into the IMM. CPT2 then removes the carnitine group as it transports the fatty acids into the mitochondrial matrix (MM), where FAO takes place, yielding Acetyl-CoA. Glucose oxidation is still present in the mature cardiomyocytes, except at a lower rate. Glucose transporters introduce glucose and lactate into the cytosol, where they undergo glycolysis. The end product, pyruvate, gets transported into the MM by mitochondria pyruvate carrier (MPC), where pyruvate dehydrogenase (PDH) converts it into Acetyl-CoA. Ketones, such as 3-hydroxybutyrate, often play a small role in energy production in the mitochondria. As it is a small-carbon-chain molecule, it is easily defused though the OMM and then transported into the matrix by SLC16a7 transporter, where it undergoes ketolysis. B-hydroxybutyrate dehydrogenase 1 (BDH1) converts it into…

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  Figure 2. Mitochondrial dysfunction associated with gestational diabetes, heterotaxy syndrome and single-ventricle disease. Gestational diabetes mellitus (GDM) has been associated with heterotaxy syndrome and single-ventricle heart disease. GDM and the high-fat diet (HFD) rat model lead to a mitochondrial dysfunction characterized by an increase in lipid peroxidation, increase in mtDNA copy number and a pro-fission pattern by increasing expression of mitofusin 1/2 (MFN) and optic atrophy 1 (OPA1). The electron transport chain (ETC) is disrupted, and an increase in reactive oxygen species ROS occurred during GDM and single-ventricle heart disease. An overexpression of superoxide dismutase 1 (SOD1) in rat repressed GDM-regulated miRNAs and blunted the increase in ROS induced by GDM. Inhibition of rapamycin complex 1 (TORC1) in zebrafish induces a heterotaxy phenotype and modulates mitochondrial biogenesis by decreasing mtDNA content. In addition, blood from heterotaxy patients presents a lower mtDNA content. Myocardium and peripheral blood mononuclear cells (PBMCs) from single-ventricle patients show a decrease in mitochondrial respiratory function and cardiolipin (CL) content, which is…

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  Figure 3. Mitochondrial targeted therapies for the failing heart. Sodium-glucose transport protein 2 inhibitor (SGLT2i) has been shown to increase endogenous production of ketone bodies in the liver. This likely results in an increase in circulating ketones bodies, which provides the heart with an additional source of fuel to support the impaired mitochondrial metabolism. Elamipretide (SS-31) is a peptide that can mediate the cardiolipin remodeling, known to play a role in the mitochondrial dysfunction present in pediatric heart failure. It can defuse into the outer mitochondrial membrane (OMM) and anchors the cardiolipin in the inner mitochondrial membrane (IMM) to stabilize the electron transport chain (ETC) complexes. Antioxidants such as MitoQ and Idebenone can interact with superoxides by donating electrons and detoxifying them. MitoQ is composed of quinone conjugated to a lipophilic triphenylphonium cation (TTP+) that allows it to travel into the mitochondrial matrix via membrane potential. There, it interacts with complex II, turning it into quinol molecules that can donate electrons to reactive oxygen species (ROS), reducing them. This donation results in quinone molecules that can…