# Aberrant Cardiolipin Dynamics in Barth Syndrome

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $5,544

## Abstract

Project Summary/Abstract
Mitochondria are membrane-rich organelles that are essential to eukaryotic life. Detailed insight has emerged
into the assembly and the dynamics of mitochondrial membrane proteins, but a fundamental gap has remained
in understanding mitochondrial lipids. Barth syndrome (BS) is a disorder of the mitochondrial lipid metabolism,
in particular the metabolism of the mitochondria-specific phospholipid cardiolipin (CL), and thus provides a
unique opportunity to address this gap in a context relevant to human health. BS is caused by mutations in
tafazzin, an enzyme that catalyzes CL remodeling, i.e. the fatty acid exchange reaction by which the
characteristic molecular composition of CL is created. The objective of this application is to identify
mechanism and function of CL remodeling. This objective fits into our broad goals to understand the function of
CL in mitochondria and to unravel the molecular pathophysiology of BS. We discovered that the global
assembly of the system of oxidative phosphorylation (OXPHOS) is driving CL remodeling. We hypothesize
that CL remodeling reduces the packing stress imposed on mitochondrial lipids by the extremely high protein
concentration, which arises in mitochondrial membranes due to the OXPHOS system and other proteins. Thus,
the function of CL remodeling is to stabilize lipid-protein interactions in order to allow the assembly of protein-
crowded membranes. To test this hypothesis, we will (i) identify the mechanism by which OXPHOS expression
controls CL remodeling and (ii) establish the function of CL remodeling in membrane assembly. First, in order
to identify the mechanism by which OXPHOS expression controls CL remodeling, we will determine the effect
of OXPHOS assembly on the CL remodeling reaction, then identify the OXPHOS assembly step that is critical
for CL remodeling, and finally determine whether protein crowding affects CL remodeling. Second, in order to
establish the function of CL remodeling, we will determine the effect of CL remodeling on the density of
OXPHOS complexes, on the stability of cristae membranes, and on the development of germ cell
mitochondria. Germ cell mitochondria will be studied because our preliminary data suggest a specific role of
CL remodeling and OXPHOS assembly in spermatogenesis. Experiments will be carried out in genetically
modified yeast, Drosophila, and mice. Our application relies on cutting-edge techniques, such as lipidome-
wide flux analysis with stable isotopes, cryo-electron microscopic tomography, and quantitative proteomics.
The proposed study is significant because it will identify the mechanism and the function of CL remodeling, a
widely conserved reaction of uncertain significance, and because it will establish the pathologic mechanism of
BS.

## Key facts

- **NIH application ID:** 10385350
- **Project number:** 3R01GM115593-06S1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Michael Schlame
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $5,544
- **Award type:** 3
- **Project period:** 2015-09-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385350

## Citation

> US National Institutes of Health, RePORTER application 10385350, Aberrant Cardiolipin Dynamics in Barth Syndrome (3R01GM115593-06S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10385350. Licensed CC0.

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