Condition or domain being studied: Diseases and disorders; mitochondrial myopathy. Rationale for the review: Primary mitochondrial diseases (PMD) are a diverse spectrum of rare genetic disorders characterized by impaired cellular energy metabolism and multisystemic clinical manifestations1. PMD affects approximately 1 in 5,000 individuals and results from defects in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA)2. There are currently no disease modifying therapies available, and patients are often treated with vitamin supplementation (e.g. niacin, thiamine, riboflavin,) coenzymes (e.g., coenzyme Q10 [CoQ10]), amino acids (e.g. arginine, citrulline, creatinine, or L’carnitine), exercise, and diet modification) for symptom management3. Vitamin supplements, coenzymes, and amino acids in primary mitochondrial disease are designed to manage energy-dependent symptoms including fatigue, muscle weakness, and exercise intolerance as well as other organ specific symptoms. Supplementation combinations, called “mitococktails”, are often administered to patients under the theory of a potential synergistic effect among multiple therapies. As mtDNA-associated PMD is marked by substantial genetic complexity, clinical heterogeneity, and absence of uniformly effective curative therapies, a systematic literature review (SLR) is needed to integrate the evidence base, better characterize disease variability, and identify key gaps in understanding treatment. Review objectives: The primary objective of this SLR is to identify the published evidence reporting efficacy, real-world effectiveness, and safety of best supportive care (BSC) therapies in adults with mtDNA-associated PMD in the short- and long-term with respect to different symptoms of PMD. The secondary objectives include: 1.) Describe the quality of evidence available regarding the efficacy, effectiveness and safety of BSC therapies in PMD with respect to different symptoms of PMD; 2.) Identify key areas of bias, limitations, and critical research gaps present in the available literature.