# THE ROLE OF CARDIOLIPIN IN THE TCA CYCLE: IMPLICATIONS FOR BARTH SYNDROME

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2022 · $372,017

## Abstract

Project Summary
 Cardiolipin (CL), the signature lipid of the mitochondrial membrane, is crucial for optimal
mitochondrial function. The importance of CL is underscored by the fact that perturbation of CL
metabolism due to mutation of the CL remodeling enzyme tafazzin (Taz) leads to the life-
threatening genetic disorder, Barth syndrome (BTHS). While the clinical phenotypes of dilated
cardiomyopathy and skeletal myopathy point to mitochondrial bioenergetic defects, the disorder
is also characterized by broad metabolic dysregulation, including abnormal levels of amino acids
and TCA cycle-associated metabolites. These studies suggest that CL plays an important role
not only in oxidative phosphorylation but also in intermediary metabolism. The molecular
mechanisms linking CL deficiency to these metabolic changes and to the pathologies in BTHS
are unknown.
 We are investigating the role of CL in metabolism using two powerful models. The yeast CL
mutant, crd1D, which we generated previously is a well-established model of CL deficiency. More
recently, we constructed a Taz knockout mutant, TAZ-KO, in the mouse myoblast C2C12 cell line.
TAZ-KO cells exhibit the characteristic biochemical and mitochondrial phenotypes of BTHS and
contribute a new model of the disorder. Implementing both models, we have determined that CL
regulates two pathways that converge on the TCA cycle - acetyl-CoA synthesis and Fe-S
biogenesis. Based on these findings, will use genetic, biochemical, and metabolomic approaches
to test the central hypothesis that CL is required for optimal activity of the TCA cycle as a result
of its dual role in regulating synthesis of acetyl-CoA and biogenesis of Fe-S cofactors. Aim 1 will
define the mechanism whereby CL regulates acetyl-CoA synthesis by increasing the activity of
pyruvate dehydrogenase. Aim 2 will characterize anaplerotic mechanisms that rescue TCA cycle
deficiencies. Aim 3 proposes to define the role of CL in maturation of yfh1/frataxin, an essential
component of the Fe-S machinery.
 The TCA cycle is a fundamentally important metabolic pathway of carbon metabolism. The
current study is driven by a novel hypothesis that identifies a role for CL in regulating the TCA
cycle. Elucidating the mechanisms underlying this regulatory role will establish a new paradigm
for TCA cycle control. The results may suggest potential new treatments for BTHS and other
mitochondrial cardiomyopathies.

## Key facts

- **NIH application ID:** 10322118
- **Project number:** 5R01HL117880-07
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Miriam L Greenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,017
- **Award type:** 5
- **Project period:** 2014-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322118

## Citation

> US National Institutes of Health, RePORTER application 10322118, THE ROLE OF CARDIOLIPIN IN THE TCA CYCLE: IMPLICATIONS FOR BARTH SYNDROME (5R01HL117880-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10322118. Licensed CC0.

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