A report of a potential treatment for a mitochondrial DNA disease by researchers in the Center for Molecular Medicine and Genetics at Wayne State University and at the University of Pennsylvania is scheduled to appear in the Proceedings of the National Academy of Sciences.

The report shows that increasing the expression of a gene that functions both in the mitochondria and the nucleus is able to reverse the symptoms in a cellular model of Mitochondrial

Encephalomyopathy, Lactic Acidosis and Stroke-like episodes, or MELAS, an incurable multisystem disorder in which brain, muscle and the endocrine system are predominantly involved and that is often fatal in childhood or in young adulthood. The disease is most commonly caused by a mutation in one of the transfer RNA genes encoded by mtDNA. Because mtDNA is in a separate and less accessible compartment than most of cellular DNA, mutations in mtDNA are particularly refractory to gene manipulation approaches.

The gene that was targeted for enhanced expression, MNRR1 -- also called CHCHD2 -- produces a protein that works in mitochondria to increase respiration and works in the nucleus as a transcription enhancer that helps the cell respond to stress and to produce more mitochondria. When expression of the gene is reduced, cells behave in many ways like cells that carry the MELAS mutation, leading the investigators to try increasing MNRR1 expression in MELAS mutation-containing cells to counteract their deficiencies. They were able to do so, and found that they were also able to stimulate quality control pathways that normally recycle defective mitochondria. This work presents a new paradigm for mitochondrial DNA diseases for which no standard therapeutic regimen exists.

The work at Wayne State University was carried out by Siddhesh Aras, M.B.B.S., Ph.D., assistant professor of Molecular Medicine and Genetics; Kezhong Zhang, Ph.D., professor of Molecular Medicine and Genetics and of Biochemistry, Microbiology and Immunology; Lawrence Grossman, Ph.D., the Henry L. Brasza Professor of Molecular Medicine and Genetics and professor of Internal Medicine; postdoctoral researchers Drs. Neeraja Purandare, Ph.D., and Mallika Somayajulu-Nitu, Ph.D., and graduate student Stephanie Gladyck. The work at CHOP was carried out by Dr. Douglas Wallace, Ph.D., the Michael and Charles Barrett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Disease, director of the Center for Mitochondrial and Epigenomic Medicine, and professor of Pediatrics.