Mitochondrial medicine therapies: rationale, evidence, and dosing guidelines

Primary mitochondrial disease is a highly heterogeneous but collectively common inherited metabolic disorder, affecting at least one in 4300 individuals. Therapeutic management of mitochondrial disease typically involves empiric prescription of enzymatic cofactors, antioxidants, and amino acid and other nutrient supplements, based on biochemical reasoning, historical experience, and consensus expert opinion. As the field continues to rapidly advance, we review here the preclinical and clinical evidence, and specific dosing guidelines, for common mitochondrial medicine therapies to guide practitioners in their prescribing practices.

Since publication of Mitochondrial Medicine Society guidelines for mitochondrial medicine therapies management in 2009, data has emerged to support consideration for using additional therapeutic agents and discontinuation of several previously used agents. Preclinical animal modeling data have indicated a lack of efficacy for vitamin C as an antioxidant for primary mitochondrial disease, but provided strong evidence for vitamin E and N-acetylcysteine. Clinical data have suggested L-carnitine may accelerate atherosclerotic disease. Long-term follow up on L-arginine use as prophylaxis against or acute treatment for metabolic strokes has provided more data supporting its clinical use in individuals with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and Leigh syndrome. Further, several precision therapies have been developed for specific molecular causes and/or shared clinical phenotypes of primary mitochondrial disease.

We provide a comprehensive update on mitochondrial medicine therapies based on current evidence and our single-center clinical experience to support or refute their use, and provide detailed dosing guidelines, for the clinical management of mitochondrial disease. The overarching goal of empiric mitochondrial medicines is to utilize therapies with favorable benefit-to-risk profiles that may stabilize and enhance residual metabolic function to improve cellular resiliency and slow clinical disease progression and/or prevent acute decompensation.