Research Spotlight: Cardiolipin-Induced Activation of Pyruvate Dehydrogenase Links Mitochondrial Lipid Biosynthesis to TCA Cycle Function

Posted on June 10, 2021


“Cardiolipin-Induced Activation of Pyruvate Dehydrogenase Links Mitochondrial Lipid Biosynthesis to TCA Cycle Function”

Cardiolipin (CL) is a phospholipid that is integral to mitochondrial bioenergetics. Several human disorders are associated with abnormal CL composition including Alzheimer’s disease, Parkinson’s disease, diabetes, and Barth Syndrome (BTHS). BTHS is uniquely dependent on CL composition and is the only known disorder that is caused by altered CL remodeling. BTHS is characterized by dilated cardiomyopathy, skeletal myopathy, neurotropenia, exercise intolerance, lactic acidosis, and sudden death from arrhythmia. The molecular basis whereby CL deficiency leads to BTHS is not understood. Recently, it has been shown that CL is required for intermediary metabolism and is closely linked to the TCA cycle in yeast. This increases the likelihood that CL is associated with BTHS pathology.

To elucidate the role of CL in energy metabolism, Dr. Greenberg’s team analyzed the metabolic flux of uniformly C-13 labelled glucose in a tafazzin (TAZ), the CL-remodeling enzyme, knockout (KO) cell line. To do so, they utilized Phosphatidic Acid and Monolysocardiolipin (MLCL) from Avanti! They were able to prove for the first time that CL is required for optimal activity of the acetyl-CoA biosynthetic enzyme PDH and TCA cycle function. PDH activity was decreased in TAZ-KO cells with CL-deficeincy. This also resulted in an increase in levels of the phosphorylated, inactive enzyme and a decrease in flux of glucose to acetyl-CoA and TCA cycle intermediates. The research also suggests that CL regulates PDH by decreasing the level of PDH phosphorylation.

This study may have implications for BTHS. Defects in PDH activity and perturbation of the TCA cycle are expected to lead to reduced ATP and thus an energy deficit. This may lead to an increase in expression of pyruvate carboxylase (PC) to compensate for a reduction in energy from decreased acetyl-CoA synthesis. PDH deficiency also results in an elevated level of lactic acid which could lead to the observed lactic acidosis in patients suffering from BTHS. Patients suffering from BTHS often display different symptoms of the pathology even with identical TAZ mutations. This work could explain why these patients exhibit different symptoms.

Dr. Greenberg has been highly involved with the investigation of CL and its roles in BTHS. We can’t wait to see what else her team uncovers! And, we thank Dr. Greenberg and her team for always counting on Avanti when they need the highest quality lipids for their research.

Click HERE to read the full research article and don’t forget to read our Interview with Dr. Greenberg!