# Barth syndrome: Evaluating cardiolipin mediated tissue specific oxidative phosphorylation dysfunction

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2020 · $45,520

## Abstract

Project Summary
Barth Syndrome (BTHS), is an X-linked inborn error of mitochondrial phospholipid metabolism, caused by
variants in the gene tafazzin (TAZ). TAZ encodes for a transacylase involved in the final remodeling step of
cardiolipin (CL), a phospholipid localized to the inner mitochondrial membrane with key roles in cristae
formation, organization of the mitochondrial respiratory chain, and in the apoptotic cascade. Both TAZ and CL
are ubiquitously expressed in all tissues, however the CL content is tissue specific; brain CL is characterized
by a diversified array of acyl chains including polyunsaturated chains, whereas in the cardiac and skeletal
muscle CL is predominantly characterized by the tetralinoleoyl form. As is typical of most primary mitochondrial
diseases, BTHS is a multisystem disorder, characterized by cardiomyopathy, skeletal myopathy, and
neutropenia among other features. However, in sharp contrast to many mitochondrial diseases, BTHS has
minimal neurological burden. Thus, understanding the mechanisms of tissue specificity in BTHS has the
potential to provide great insight into the role of specific CL content on mitochondrial function, as well as to
offer novel treatment targets for BTHS. In my preliminary work with a novel TAZ deficient cellular model, I
found that complex I of the respiratory chain is dysregulated at the protein and metabolic level. Based on this,
I hypothesize that complex I is a major site of oxidative phosphorylation (OXPHOS) dysfunction in
tissues affected in BTHS. Dysregulation of complex I in BTHS is a particularly interesting finding, because
other complex I disorders, including Leigh Disease, have a significant neurological impact. Therefore, I further
hypothesize that the tissue specific CL content of neurologic tissue spares it from this dysfunction. To
address this hypothesis, I propose two specific aims. Aim 1: To determine the impact of TAZ deficiency, and
therefore abnormal CL content, on complex I function. I will first investigate the effect of the reduced
expression of Complex I proteins on enzyme stability and function. Then I will determine whether the assembly
factor NDUFAF1 plays a prominent role in the reduced expression of complex I proteins, and if the reduced
NDUFAF1 expression is due to dysregulation at the transcriptional level. Aim 2: To understand the role of
tissue specificity of CL content on the pathophysiology of BTHS. I will first differentiate TAZ deficient iPSCs,
iPSC TAZ∆50, into cardiomyocytes and neurons in order to characterize and compare complex I dysregulation
by assessing NDUFAF1 protein expression, NADH/NAD+ ratio, and complex I enzyme stability/function. Then,
I will determine if TAZ deficient neurons display altered CL as compared to WT neurons, and if the lack of
altered CL content in TAZ deficient neurons reflects a smaller role for TAZ in neuronal CL remodeling. This
project proposal combines basic science and translational approaches to unravel cellular p...

## Key facts

- **NIH application ID:** 9972745
- **Project number:** 5F31HL147454-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Arianna Lee Franca Anzmann
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972745

## Citation

> US National Institutes of Health, RePORTER application 9972745, Barth syndrome: Evaluating cardiolipin mediated tissue specific oxidative phosphorylation dysfunction (5F31HL147454-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972745. Licensed CC0.

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