RUI: Mechanisms of regulation of mitochondrial DNA transcription

Hope College, Holland MI

Investigators

Abstract

The goal of this research is to determine how the expression of mitochondrial DNA is regulated to meet the varying energetic demands of a cell. Mitochondria are the metabolic centers of cells and have a small genome that contains instructions to make machinery essential for energy production. This project is expected to provide important advances related to fundamental genetic mechanisms of mammalian cell function. Additionally, the research will provide undergraduate research opportunities to students at Hope College, in order to improve student retention in science and technology. Undergraduate students, with a particular emphasis for selection on women and first year students, will be engaged in all aspects of the project, gaining experience in interdisciplinary research and science communication. Students will be prepared to populate the scientific workforce and become the next generation of scientists capable of addressing complex societal issues. Mitochondrial DNA encodes 13 essential subunits of electron transport chain complexes. The remaining 1500 member mitochondrial proteome, including additional components necessary for energy production and the enzymatic machinery required for mitochondrial DNA expression, is encoded by the nuclear genome. To respond to metabolic changes, mitochondrial gene expression must be coordinated with nuclear gene expression. While the control of nuclear DNA transcription is widely studied, there is a need to understand the mechanisms that control the transcription of mitochondrial DNA. The objective of the project is to determine whether reversible protein post-translational modification regulates mitochondrial DNA transcription. Post-translational modifications, specifically lysine acetylation and serine/threonine phosphorylation, are widely found in the mitochondrial proteome, including on the proteins required for mitochondrial DNA transcription. The research will investigate how these chemical tags provide a means to regulate transcription in response to changes in cellular metabolism. To address this question, a combination of cell biology and protein biochemistry will be used to map the regulatory post-translational modification sites on protein components required for mitochondrial DNA transcription. The biochemical mechanisms by which these sites control transcription will be determined using transcriptional profiling and DNA binding assays. The research is expected to contribute a mechanism explaining the role of post-translational modifications in regulating mitochondrial DNA transcription in response to changing cellular energetic demands. This fundamental knowledge will help advance the understanding of the dynamics and coordination of nuclear and mitochondrial gene transcription. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.