The Association Between Cardiolipin Deficiency and Barth Syndrome (BTHS)

Cardiolipin (CL), a vital phospholipid to mitochondrial bioenergetics, the abnormal compositions of which is associated with several human diseases, such as Alzheimer’s disease, Parkinson’s disease, diabetes, and Barth Syndrome (BTHS). Uniquely dependent on CL composition, BTHS is regarded as the only disease caused by altered CL remodeling. The characteristics of BTHS are dilated cardiomyopathy, skeletal myopathy, neurotropenia, exercise intolerance, lactic acidosis and sudden death from arrhythmia. However, the molecular basis by the lack of CL that leads to BTHS is not understood. A recent study showed that CL is required for intermediary metabolism and is closely related to the TCA cycle in yeast. Brifely, tt increases the possibility that CL is associated with BTHS pathology.

In order to clarify the effect of the CL has on energy metabolism, the research team analyzed the metabolic flux of uniformly C-13 labelled glucose in a tafazzin (TAZ), the CL-remodeling enzyme, knockout (KO) cell line by using Phosphatidic Acid and Monolysocardiolipin (MLCL). They proved for the first time that CL is required for optimal activity of the acetyl-CoA biosynthetic enzyme PDH and TCA cycle function, and PHD activity is decreased in TAZ-KO cells with the lack of CL. It results in the increase of the phosphorylatedand inactive enzyme level, and the decrease of flux of glucose to acetyl-CoA and TCA cycle intermediates. In addition, the study suggests that CL regulates PDH by decreasing the PDH phosphorylation level.

The study may have implications for BTHS. The defect in PDH activity and disturbance of TCA cycle may lead to the reduction of ATD and the lack of energy. Thus, the expression of pyruvate carboxylase (PC) may be increased to compensate for the reduction in energy caused by the decease of acetyl-CoA synthesis. Besides, the lack of PDH results in an elevated level of lactic acid which could lead to the lactic acidosis in BTHS patients. Although the BTHS patients have the same TAZ mutations, they often display different symptoms of the pathology. The study demonstrated why the BTHS patients display different symptoms.

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