Mitochondrial Energy Transformation Capacity Influences Brain Activation During Sensory, Affective, and Cognitive Tasks

Abstract

Mitochondria supply the energy required for brain function, but how energetic capacity constrains human brain activity remains unclear. We used genetically defined mitochondrial disease as a human model of impaired bioenergetics to test whether energetic limitations produce global disruption of brain function or selective vulnerability across certain functional domains. Participants completed resting-state fMRI and tasks probing working memory, sensory perception, and affective responses to cold pain, together with behavioral, clinical, and circulating biomarker assessments. We report impairment in working memory performance and reduced activation of associated brain networks in a subset of patients with the largest clinical and cognitive impairments. A resilient subgroup showed higher working-memory-related BOLD responses, which were associated with preserved task performance. Neural and behavioral effects scaled with the circulating marker of energetic stress growth differentiation factor 15 (GDF15). Brain activity related to sensory and affective responses and resting-state connectivity were comparable for patients and controls. These findings are consistent with an energy-hierarchy model and link clinical disease severity to working-memory brain responses and performance, while suggesting relative preservation of sensory and pain-related brain processes under energetic stress.