# A mitochondrial phospholipid scramblase for cardiolipin biosynthesis

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $462,650

## Abstract

Mitochondria are multi-functional organelles that play crucial roles in the cell. They are widely known by
the moniker 'powerhouse of the cell' because of their role in ATP production. However, they also synthesize
metabolic intermediates, oxidize fatty acids, detoxify ammonia, regulate intracellular Ca2+, and participate
in the pathway of programmed cell death. Consequently, mitochondrial dysfunction is a common source of
inborn errors of metabolism and underlies many pathologies, including Parkinson's disease, cancer and
Barth syndrome.
The lipid composition of the mitochondrial outer and inner membranes is critical for the function of this
organelle. Cardiolipin, the signature lipid of mitochondria acts as both a lubricant and a glue in supporting
the machinery of the mitochondrial respiratory chain that produces ATP. The inability to synthesize the
mature form of cardiolipin has devastating consequences. Barth syndrome (BTHS), an X-linked disease, is
caused by defects in tafazzin an enzyme needed to synthesize mature cardiolipin. BTHS patients present
with cardioskeletal myopathy and neutropenia, with heart failure being a major cause of death.
Mitochondria import phospholipids and phospholipid precursors from the endoplasmic reticulum. Thus,
cardiolipin is synthesized in the inner membrane of mitochondria from a phosphatidic acid precursor that is
brought in from the outside. To reach internal mitochondrial compartments, phospholipids must first cross
the outer membrane by flipping from the cytoplasmic side to the internal side. As phospholipid flip-flop
across a membrane is a very slow process, occurring spontaneously at a rate of 1 flip per day, we hypothesize
that the outer membrane must have dedicated molecular machinery to promote rapid flip-flop.
Our preliminary data indicate strongly that a prominent protein of the outer membrane called VDAC is
responsible for facilitating fast flip-flop of phospholipids. We will confirm this idea in the present proposal
and also start to learn how VDAC works to achieve lipid flip-flop. We will purify VDAC protein and use
different techniques to assay its ability to flip-flop lipids after reconstitution into a synthetic membrane
environment. We will also study VDAC using computer methods to understand better how the protein
works. These studies will address a long-standing question in mitochondrial biology, namely how
mitochondria obtain the lipids they need, and specifically address the question of how precursor
phospholipids necessary for cardiolipin synthesis reach their intramitochondrial destinations.

## Key facts

- **NIH application ID:** 10107514
- **Project number:** 1R21NS119779-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** ANANT K MENON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,650
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107514

## Citation

> US National Institutes of Health, RePORTER application 10107514, A mitochondrial phospholipid scramblase for cardiolipin biosynthesis (1R21NS119779-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107514. Licensed CC0.

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