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Cardiolipin activates pyruvate dehydrogenase (PDH) — a potential new target for treatment of Barth syndrome

Cardiolipin activates pyruvate dehydrogenase (PDH) — a potential new target for treatment of Barth syndrome
Miriam Greenberg, PhD, Professor, Wayne State University, Detroit, MI

Award: US $50,000 over 1-year period


Barth syndrome (BTHS) is a severe X-linked genetic disorder caused by mutations in the cardiolipin (CL) remodeling enzyme, tafazzin. While the clinical presentation of BTHS, including cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis, points to mitochondrial bioenergetic defects, the mechanisms linking CL deficiency to the pathology are not understood.

To gain insight into the role of CL in energy metabolism, we analyzed metabolic flux of C13-glucose in a new BTHS model that we developed – tafazzin deficient (TAZ-KO) mouse C2C12 cells. We determined that TAZ-KO cells exhibit decreased flux of C13-glucose to acetyl-CoA and TCA cycle intermediates. These deficiencies are associated with decreased activity of pyruvate dehydrogenase (PDH). Importantly, we found that CL binds to the PDH complex and stimulates catalytic activity. Activation by CL is abrogated by phosphatase inhibitors, suggesting that enhancement of PDH activity by CL is mediated by PDH phosphatase (PDP). Based on these findings, we hypothesize that CL is required for the optimal activation of PDH, and that PDH activity is compromised in BTHS.

We propose to test the hypothesis by elucidating the mechanism whereby CL activates PDH, and determining if metabolic deficiencies in tafazzin deficient cells can be rescued by increasing PDH activity. PDH is inactivated by PDH kinases (PDK) that are components of the PDH complex. The enzyme is activated when dephosphorylated by PDH phosphatases (PDP). Potent inhibitors of the PDK, including dichloroacetate (DCA) and phenylbutyrate, increase PDH catalytic activity and are powerful tools for the proposed experiments. DCA and phenylbutyrate have been used in animal models to determine the effects of activation of PDH on cardiac contractile function. Both are used clinically to treat metabolic disorders, including PDH deficiency, lactic acidosis, urea cycle disorders, and maple syrup urine disease. The outcome of this study may reveal a new direction for BTHS treatment based on activation of PDH and/or supplementation of deficient metabolites. The study is relevant to the specific RFA to identify compounds that may improve mitochondrial performance in Barth syndrome.

Associated Publications to Date:

Li Y, Lou W, Raja V, Denis S, Yu W, Schmidtke MW, Reynolds CA, Schlame M, Houtkooper RH, Greenberg ML. Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function. J Biol Chem. 2019 Jun 11. pii: jbc.RA119.009037. doi: 10.1074/jbc.RA119.009037. [Epub ahead of print] (PubMed - Open Access)

(Last updated 6/24/2019)

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