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 PGC1? 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 PGC1? 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.

Public Health Relevance

Mitochondrial diseases are a clinically heterogeneous group of disorders caused by mutations that negatively affect mitochondrial respiratory chain function. Mitochondrial disorders affect ~1:8,500 individuals and currently, there are no effective treatment options. The proposed research aims to uncover genetic mechanisms that alleviate mitochondria dysfunction and identify therapeutic targets for the management of mitochondrial diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM125243-01A1
Application #
9469248
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2017-09-30
Project End
2020-09-29
Budget Start
2017-09-30
Budget End
2018-09-29
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215