Optimizing Cardiac Energetics in Barth Syndrome
John Ussher, PhD, University of Alberta
Overview of the Health Issue: Barth Syndrome (BTHS) is a rare X-linked genetic disease with high infant mortality due to mutations in the gene TAFAZZIN (mouse gene Tafazzin), which encodes for tafazzin, a phospholipid acyltransferase that plays a key role in the remodeling of the mitochondrial lipid cardiolipin (CL). There are currently <500 patients in the BTHS Registry from around the world, the majority of whom exhibit some form of cardiomyopathy and/or heart failure (HF), with other clinical presentations including neutropenia, reduced exercise tolerance and chronic fatigue. Mortality is highest in the first 4 years of life for a child born with BTHS, though BTHS patients now have greater chances at surviving past infancy. Despite clear improvements in the management of BTHS, the cardiovascular abnormalities remain frequent concerns for these individuals, who require ongoing surveillance as their risk for cardiovascular decline can develop/worsen at any given time.
People with BTHS have impaired maturation of CL remodeling due to the mutation in TAFAZZIN, which leads to destabilization of the electron transport chain (ETC) and subsequent respiratory dysfunction. We recently profiled energy metabolism in hearts from the Tafazzin knockdown (TazKD) mouse model of BTHS, and observed several disturbances, with the most notable defect being a marked reduction in glucose oxidation. When coupled together with recent data in BTHS adolescents showing abnormal cardiac energetics, it suggests that optimizing cardiac energy metabolism may be a viable strategy to attenuate BTHS-related HF, potentially improving the quality of life for individuals with BTHS. However, we demonstrated that stimulating glucose oxidation with the agent, dichloroacetate (DCA), failed to alleviate the cardiac abnormalities present in TazKD mice, indicating that other metabolic strategies may be necessary to improve cardiovascular outcomes in BTHS.
Rationale & Hypothesis: We speculate that the reason promoting myocardial glucose oxidation failed to alleviate the cardiac abnormalities in TazKD mice, is that the enzymes of glucose oxidation tightly interact with CL, or that the defects in ETC respiratory function would likely still persist due to impaired CL remodeling. In either scenario, increases in glucose oxidation would not couple properly to ATP production. We hypothesize that promoting ketone oxidation may be the better metabolic intervention in BTHS, since the enzymes of ketone oxidation do not tightly interact with CL, and we observed increases in the expression of ketone oxidation enzymes in TazKD mouse hearts. This is consistent with data in humans with HF having an increased reliance on ketones as a fuel source. We also hypothesize that stabilizing CL to improve ETC respiratory function will augment the ability of metabolic interventions to improve cardiovascular outcomes in BTHS.
