Simultaneous Genetic Discoveries Identify a new Regulator of Cellular Energy Metabolism in Mitochondria

October 2018

Ryan Boudreau, PhD, Assistant Professor in the Division of Cardiology in the Department of Internal Medicine and a member of the FOEDRC recently discovered a new protein-coding gene in the human genome  that regulates mitochondria. These studies were simultaneously published in the Journal Cell Reports at the same time as a study from a laboratory at the University of Texas Southwestern Medical Center that made a similar discovery.

The human genome (i.e. our DNA) is an extremely vast spatial set of “letters” (A,C,G, and T – a mere four DNA bases) that are orderly-fashioned to encode vital instructions for our biological make-up and function. The sequencing of the human genome has fueled vigorous research to decipher the meaning of this complex code. The traditionally accepted role of our DNA is to produce RNA intermediates encoding the thousands of proteins that serve as our cellular building blocks and effectors; however, <5% of our genomic landscape consists of protein-coding genes, leaving us to wonder, “what is the purpose of the remaining ‘junk’ DNA?” Although many studies have demonstrated the importance of this “extra” genomic space in precisely controlling when, where, and how much of certain protein-coding RNAs are made within our cells and throughout our bodies, recent data shows that much of this DNA gives rise to thousands of uncharacterized RNAs, termed long non-coding RNAs (lncRNAs). While querying the functional significance of muscle-, heart-, and brain-enriched lncRNAs, Boudreau’s lab and others have discovered that several do actually encode for small proteins (i.e. microproteins) that have largely been overlooked due to misconceptions regarding how big proteins must be to elicit meaningful biological functions. Their team discovered a previously unknown microprotein that they named mitoregulin.  This protein localizes to mitochondria, the cellular powerhouses that make the energy needed to support virtually all biological functions.  Dr. Boudreau and his team found that mitoregulin “tunes up” mitochondria by improving the assembly and organization of mitochondrial protein complexes (i.e. the energy factory) and increases mitochondrial efficiency. In addition, they reduce the release from mitochondria of toxic byproducts known as reactive oxygen species that induce  oxidative stress. Oxidative stress plays an important role in causing many of diseases associated with aging including diabetes. Moving forward, Dr. Boudreau and his team is focusing on  better defining mitoregulin’s precise molecular function (i.e. how it works) and how alterations in mitoregulin levels in people may influence the many diseases in which mitochondria become dysfunctional (e.g. diabetes, heart failure, and Parkinson’s disease). Dr. Boudreau’s discovery and future work, lays important groundwork that could lead to new therapeutic approaches for treating disorders such as diabetes that are associated with mitochondrial dysfunction.