# Lipid metabolism disruption as a consequence of mitochondrial dysfunction in Friedreich's ataxia

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $485,625

## Abstract

ABSTRACT: Lipid metabolism disruption as a consequence of mitochondrial dysfunction in
Friedreich’s ataxia
 Friedreich’s Ataxia (FA) is an untreatable autosomal recessive disorder with a typical onset in children
and young adults, 10 ± 7.4 years. Currently there is no approved therapy for FA. FA is characterized by
progressive mobility loss, impairment of speech, and eventual loss of vision and hearing. Individuals with FA
exhibit neurodegeneration and hypertrophic cardiomyopathy. FA pathology is attributed entirely to a guanine-
adenine-adenine (GAA) repeat expansion in intron 1 of the gene for frataxin, a mitochondrial protein involved in
the iron-sulfur cluster biogenesis. In platelets from FA patients, decreased conversion of glucose to the central
metabolic intermediate acetyl-CoA has been observed and is consistent with diminished pyruvate oxidation in
FA fibroblasts. Murine models of FA have shown lipid accumulation in different organs and increased
sphingolipid levels and PDK1 activity in the hearts of FA patients. Reduced frataxin also reduces the level of
Nrf2. The resultant chronic elevation of oxidative stress in FA patients and animal models may be a
contributing factor in the activation of cytokines responsible for COX-2 overexpression. The COX-2 lipid
products derived from arachidonic acid are important bioactive lipids and their increase has been noted in FA
mouse models and likely contribute to FA pathophysiology. We hypothesize that dysregulation in mitochondrial
metabolic pathways will lead to dysregulated metabolomic and lipidomic profiles and could provide a rich set of
biomarkers of the disease that could be complementary to the RNA data currently available and that fibroblasts
provide a surrogate tissue to study the pathology of the disease and to discover new biomarkers of FA. Since
fibroblast cells are not directly involved in disease pathogenesis, we will validate our fibroblast findings with
whole blood from FA patients. This will be accomplished by the following specific aims. In Aim1: We will
Quantify the differences between the central carbon metabolites in the fibroblasts from FA patients
and healthy controls; In Aim 2: We will quantify the differences between the lipids from the
sphingolipid/PDK1/Mef2 and COX-2 pathways in the fibroblasts from FA patients and healthy controls;
In Aim 3: We will validate the fibroblast findings by measuring whole blood metabolomics and
lipidomics in FA patients and healthy controls.

## Key facts

- **NIH application ID:** 9957427
- **Project number:** 1R21NS116315-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** A. Clementina Mesaros
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,625
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957427

## Citation

> US National Institutes of Health, RePORTER application 9957427, Lipid metabolism disruption as a consequence of mitochondrial dysfunction in Friedreich's ataxia (1R21NS116315-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9957427. Licensed CC0.

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