Background <p>Exercise has been demonstrated to be effective in the general population and in a small number of Primary Mitochondrial Disease (PMD) human studies, raising the potential of exercise as standard of care in PMD. However, standardized exercise prescriptions have not been established in this heterogeneous patient population. This study aimed to identify effective and feasible exercise training protocols, to inform the design of rigorous exercise studies in adults and/or children with PMD. This was achieved through integration of a structured feasibility evaluation preceded by a quantitative review of published PMD studies, with specific focus on subgroup analyses by exercise type (aerobic, resistance, interval, and combination exercise).</p> Methods <p>A systematic literature review was conducted to identify published exercise studies in PMD cohorts. Due to the limited number of PMD exercise studies, the search was expanded to include disorders with secondary mitochondrial dysfunction (SMD), with similar symptoms of muscle weakness, muscle fatigue and exercise intolerance, as occurs in PMD. In total, 77 studies comprising 109 exercise training protocols were identified. Of those, a quantitative analysis was performed on 37 PMD and SMD studies reporting key outcome measures to assess the effects of aerobic, resistance, combination or interval exercise training. All 109 exercise training protocols were then systematically evaluated for feasibility, as defined by the likelihood of successful implementation in future exercise studies of PMD, using a standardized scoring system.</p> Results <p>Results of our quantitative analysis demonstrate the significant effect of distinct exercise types including aerobic exercise training on relative peak oxygen consumption (VO₂), peak work, and Short-Form 36 (SF-36) physical summary score; and combination (interval/resistance/inspiratory muscle training) exercise training on relative peak VO₂ and SF-36 across PMD studies. Feasibility evaluation across PMD and SMD studies involving expert group consensus review identified high-intensity circuit training (HICT), low-intensity steady-state (LISS) aerobic exercise, low-intensity resistance training, and blood flow restriction resistance training (BFR-RT) as being potentially feasible and effective in PMD.</p> Conclusions <p>Results of this study highlight specific exercise training protocols that merit assessment in future rigorously designed exercise studies to determine their feasibility and therapeutic efficacy in adults and/or children with PMD.</p>