Mitochondrial Dysfunction in Sickle Cell Trait Carriers With Exertional Collapse

Sickle cell trait (SCT) increases the risk of sudden death and exertional rhabdomyolysis (ER) in athletes and Service Members (SMs) during intense exercise. Exertional injuries in SCT carriers can result in exercise collapse associated with SCT (ECAST), an under-recognized condition characterized by variable clinical presentations ranging from ischemic muscle pain to fulminant collapse. This study presents clinical and genetic findings of two independent Black SMs with history of ECAST triggered by strenuous exercise. ECAST cases carried pathogenic heterozygous mutations POLG: p.Gly848Ser and RRM2B: p.Met282Ile associated with mitochondrial DNA depletion syndromes. Mononuclear cell mitochondria extracted from ECAST cases showed impaired mitochondrial profiles and resilience, demonstrating the potential contribution of mitochondrial dysfunction to exertional collapse in SCT carriers.