EDITORIAL Remodel mitochondria and get energized John Vissing, MD, and Corrado Angelini, MD Neurology ® 2018;90:633-634. doi:10.1212/WNL.0000000000005243 Correspondence Dr. Vissing vissing@rh.dk Patients with mitochondrial disease often present with prominent neurologic symptoms. Common features include encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Because skeletal muscle is the tissue with the highest metabolism in the body, with a staggering 50-fold increase in oxygen consumption from rest to maximal exercise, myopathic symptoms in mitochondrial disease are probably the most common presentation of the conditions. Myopathic symptoms can present as limb weakness, bulbar weakness with dysphagia, ptosis, external ophthalmoplegia, and exercise intolerance. Exercise intolerance is usually severe and, unlike most other neuromuscular conditions, typically does not relate to muscle weakness and wasting but to compromised generation of energy through oxidative phosphorylation. Thus, work capacity is often limited to a third of that in healthy persons, 1,2 which prevents patients from participating in sport activities and performing activities of daily living such as climbing stairs, grocery shopping, jogging, and playing with children. The primary cause of the low oxidative capacity relates to an impairment of the respiratory chain activity. This is caused either by specific enzyme deficiencies of the chain, due to mutations in nuclear or mitochondrial DNA genes for subunits of 1 of the 5 mitochondrial complexes, or by mutations in mitochondrial transfer RNA genes or nuclear protein assembly or DNA maintenance genes. However, these primary defects have a number of detrimental secondary effects on the respiratory chain because impaired chain function promotes the production of reactive oxygen species (ROS), which are mutagenic and denature structures within the mitochondria such as the protein components of the electron transfer chain and lipids of the mitochondrial membrane, including cardiolipin. This results in remodeling of the inner membrane structure and further lowering of respiratory chain function. The denaturing of cardiolipin has been associated with abnormal morphology of the inner mitochondrial mem- brane, subsequent impairment of respiratory chain activity, and the release of cytochrome c, which initiates apoptotic signaling. 3,4 The management of mitochondrial disease is largely supportive and includes treatment of diabetes mellitus, epilepsy, hearing impairment, and heart failure; surgically correction of ptosis; and L-arginine treatment of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Because of increased ROS production, multiple treatments with anti- oxidants such as various vitamins and other cofactors have been attempted, and although many uncontrolled case series claim positive results, no systematic larger-scale study has ever shown any effect of such treatments. 5 Aerobic exercise is an effective way of increasing mitochondrial volume and enzyme activity and of widening the metabolic bottleneck in these conditions. 6 Despite current supportive treatments of mitochondrial myopathies, there is still a substantial unmet need for more specific and curative treatments for these conditions. In this issue of Neurology ® , Karaa et al. 7 report an interesting new principle of treatment for mitochondrial myopathies using the drug elamipretide, which, in preclinical experiments, re- stored the physical and biochemical properties of the inner mitochondrial membrane via its association with cardiolipin. 8,9 In the present study, 36 patients with a variety of mitochondrial myopathies were divided into 4 groups who received either placebo or 3 different doses of elamipretide administered IV daily for just 5 days. After the 5 days, patients at the highest dose walked 40 to 50 m farther than patients on placebo, a distance that in other studies has been From the Copenhagen Neuromuscular Center (J.V.), Rigshospitalet, University of Copenhagen, Denmark; and Fondazione San Camillo Hospital IRCCS (C.A.), Lido Venice, Italy. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. RELATED ARTICLE Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy Page 641 Copyright © 2018 American Academy of Neurology 633 Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.