Context-specific hypermetabolism in humans with mitochondrial defects

Pathogenic mitochondrial DNA (mtDNA) defects test how impaired oxidative phosphorylation reshapes human energy expenditure. We studied adults with confirmed mtDNA defects (MitoD) and healthy controls using whole-room indirect calorimetry, doubly labeled water, quantitative magnetic resonance, actigraphy, autonomic monitoring, mood assessments, plasma inflammatory markers, and growth differentiation factor 15 (GDF15). Under behaviorally clamped conditions, fat-free mass-adjusted 24-h energy expenditure (24-h EE) was consistently higher in MitoD, with higher non-resting expenditure per unit wrist acceleration by day, and blunted sleep-related metabolic suppression at night. In contrast, free-living total daily energy expenditure (TDEE) was similar between groups despite lower physical activity in MitoD, consistent with behavioral compensation within a constrained energy budget. Plasma GDF15 was ~5-fold higher in MitoD and tracked with disease severity, systemic inflammation, fatigue, energetic burden, and lower habitual activity. These findings identify a persistent energetic burden in MitoD that is buffered in daily life and associated with elevated GDF15.