Comment from Ruth McCrea

Mitochondrial Transplantation for Long COVID Restoring cellular energy by delivering healthy mitochondria to depleted tissue | For FDA repurposing / advisory review The opportunity Long COVID’s most disabling feature — fatigue and post-exertional malaise — reflects a cellular energy deficit. Mitochondrial transplantation addresses that deficit at its source, by replacing the failing energy machinery itself. The mechanism is direct Autologous mitochondrial transplantation isolates respiration-competent mitochondria from a patient’s own healthy tissue and delivers them — by injection or vascular infusion — to energy-starved cells, where uptake and functional integration restore ATP production across cell types [1,2]. The human precedent is real Pioneered by McCully and Emani at Boston Children’s Hospital and Harvard, the approach moved from large-animal ischemia-reperfusion models to first-in-human use in 2017 [3]. In pediatric cardiac ischemia, 16 children received autologous mitochondrial transplantation and 80% were weaned off ECMO, versus a 40% historical rate, with no proarrhythmia or increased oxidative stress reported [1,4]. The target fits Long COVID Mitochondrial dysfunction and energetic stress are documented in Long COVID and ME/CFS — elevated muscle and brain lactate on 7T MRS and impaired bioenergetics [5] — the very energy failure this therapy was built to reverse. Clinical delivery already exists Specialized centers such as the Mitochondrial Transplantation Institute (Mitoclinics) are already delivering mitochondrial transplantation, showing the procedure can be performed beyond a single research hospital [6]. The ask An FDA-overseen trial of autologous mitochondrial transplantation for the energy deficit in Long COVID, building on the established cardiac safety experience and a clear mechanistic match to the disease. Sources 1. McCully JD, del Nido PJ, Emani SM. Mitochondrial transplantation for organ rescue. Mitochondrion. 2022. 2. McCully JD, Cowan DB, Emani SM, del Nido PJ. Mitochondrial transplantation: from animal models to clinical use in humans. Mitochondrion. 2017. PMID 28342934. 3. Emani SM, Piekarski BL, Harrild D, del Nido PJ, McCully JD. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2017;154(1):286–289. 4. Boston Children’s Hospital: 16 pediatric patients, 80% weaned off ECMO with autologous mitochondrial transplantation. 2024. 5. Brain and muscle 7T MRS in ME/CFS and Long COVID: energetic stress, elevated lactate. 2025. 6. Mitochondrial Transplantation Institute (mitoclinics.org): clinical delivery of mitochondrial transplantation.