CAREER: Mitochondrial Genome Regulation By Nucleoid Proteins Involved in Redox Sensing and One Carbon-Metabolism

Hope College, Holland MI

Investigators

Abstract

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). This project focuses on biochemical mechanisms that control the function of mitochondria, specialized compartments within cells that are central to energy production and cell metabolism. Mitochondria contain their own small genome (mitochondrial DNA) that contains the genetic instructions for a small number of proteins required for cellular energy production. How cells regulate the expression of the mitochondrial genome in response to changing energetic needs is largely unknown. This work will explore if proteins known to interact with mitochondrial DNA serve as sensors of nutrient availability and in turn control mitochondrial gene expression, providing insight into fundamental mechanisms that control mammalian cell function. The project will also expand undergraduate training in biochemistry at Hope College through the training of undergraduate researchers, the implementation of a general biochemistry lab curriculum designed for short class periods, and the incorporation of the research in an upper-level biochemistry lab course. The research and educational objectives of the project promise to have broad societal impacts by providing opportunities for undergraduate research in biochemistry. These opportunities will improve the retention of students in science who will help populate the scientific workforce. American Rescue Plan funding of this project will support the investigator at a critical stage in her career. The research will focus on the intersection between one-carbon metabolism and redox metabolism with mitochondrial genome regulation. For mitochondria to function properly, these organelles rely on genetic instructions carried within their own genome, as well as those carried in the nuclear genome. Nuclear DNA carries the instructions for the majority of the 2000-member mitochondrial proteome, including a number of nucleoid proteins which are shown to associate with mitochondrial DNA. A combination of biochemical and cell biology approaches will be used to study four nucleoid proteins involved in formate and NADPH metabolism. The nature and effect of the association of these enzymes with mtDNA is unknown. As formate and NADPH levels reflect the metabolic state of the cell, the research will investigate the hypothesis that these enzymes relay signals of energetic status to control mitochondrial genome dynamics and energy production. The research promises to provide significant advances related to regulatory mechanisms within the mitochondria and mammalian cells. 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.