Novel treatment strategies for human mitochondrial disorders

A study recently published in the journal Human Molecular Genetics by Marni J. Falk and colleagues from the Mitochondrial-Genetic Disease Clinic at The Children's Hospital of Philadelphia (CHOP) holds great promise for developing new treatments for patients with mitochondrial disorders

Extra-mitochondrial mechanisms including dysregulated translation and the increased autophagy contribute to the pathophysiology of respiratory chain disorders. They showed that drugs which partially inhibit these cellular processes offer novel treatment strategies in mitochondrial disorders. 

In translation, messenger RNA (mRNA) which is produced by transcription from DNA is decoded by cellular ribosomes to produce a specific amino acid chain, or polypeptide. Autophagy is the basic cellular mechanism by which unnecessary or dysfunctional cellular components are degraded by lysosomal action. Both these processes have been shown to be dysregulated in mitochondrial disorders. 

Falk's team showed that nicotinic acid, a form of vitamin B3 (niacin), improved lifespan and metabolism in a mitochondrial disease animal model, microscopic C. elegans worms, by restoring normal activity to cellular signalling pathways. Rapamycin, an antibiotic and immunosuppressant, improved kidney disease in mice with a mitochondrial disorder caused by coenzyme Q deficiency by directly inhibiting the central translational regulator (mTORC1). Probucol (used in the past as a cholesterol-lowering drug) which also inhibits mTORC1 improved lifespan and physiological functioning in worms with mitochondrial respiratory chain complex I deficiency Partial inhibition of translation by cycloheximide an antibiotic, or of autophagy by lithium chloride, prescribed for patients with bipolar disorder, improved viability, preserved cellular respiratory function and induced mitochondrial translation. 

These findings offer novel treatment strategies in the diverse array of mitochondrial disorders involving respiratory chain dysfunction. Further research should investigate how specific subgroups of patients with mitochondrial disorders could benefit from these and similar drugs. Mitochondrial Disease Clinical Center at CHOP is planning early-stage clinical research trials to investigate these novel treatment strategies further.

Peng, M., Ostrovsky, J., Kwon, Y. J., Polyak, E., Licata, J., Tsukikawa, M., … Falk, M. J. (2015). Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease. Human Molecular Genetics, 24(17), 4829–47. doi:10.1093/hmg/ddv207