# Characterization of genetic modifiers of bioenergetic rescue in mitochondrial disease cell lines

> **NIH NIH F32** · DANA-FARBER CANCER INST · 2020 · $11,241

## Abstract

PROJECT SUMMARY
There is a growing appreciation of mitochondrial dysfunction contributing to several diseases such as cancer,
diabetes, neurodegenerative disease, and mitochondrial diseases. Mitochondrial diseases result from
mutations in mitochondrial genes that cause bioenergetic defects in high-energy tissues leading to tissue
damage. Currently, there are no effective treatment options for individuals afflicted with mitochondrial diseases
and few promising targets for drug development. In this research proposal, we aim to elucidate genetic
mechanisms that rescue the bioenergetics deficits associated with mitochondrial mutations in human cells. I
propose to 1) mechanistically dissect how inhibition of BRD4 (a bromodomain-containing protein identified in
our recent unbiased screens) rescues mitochondrial bioenergetics, 2) determine cellular effectors (factors or
metabolic pathways) downstream of BRD4 inhibition, and 3) identify additional genes that rescue mitochondrial
respiratory chain deficiencies through CRISPR gene-editing technology. I will first determine the PGC1α
transcription factor that upregulates expression of mitochondrial respiratory genes in the context of BRD4
inhibition through gene knockdown studies. This will allow me to further test our model that mitochondrial gene
promoter access by at least one PGC1α transcription factor is inhibited by BRD4 promoter occupancy using
ChIP analyses. For my second aim, I will perform paired mitochondrial proteomics and metabolomics to
uncover the effectors downstream of BRD4 inhibition and for my third aim, I will expand our CRISPR-based
platform to identify gene mutations that rescue the bioenergetics defects associated with respiratory chain
complex IV deficiency. These studies with utilize resources at Dana-Farber Cancer Institute, Harvard Medical
School, and the Broad Institute to provide insights into how cells cope with mitochondrial deficiencies and
identify potential therapeutic targets for mitochondrial diseases.

## Key facts

- **NIH application ID:** 10228359
- **Project number:** 3F32GM125243-03S1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Christopher F. Bennett
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $11,241
- **Award type:** 3
- **Project period:** 2017-09-30 → 2020-11-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228359

## Citation

> US National Institutes of Health, RePORTER application 10228359, Characterization of genetic modifiers of bioenergetic rescue in mitochondrial disease cell lines (3F32GM125243-03S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10228359. Licensed CC0.

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