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 compared patients with genetically defined mitochondrial disease to matched controls, testing whether bioenergetic stress selectively limits neural processes assessed with functional magnetic resonance imaging during rest and during tasks probing working memory, sensory perception, and affective responses (cold pain). 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 markers 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 support an energy-hierarchy model in which complex cognition fails first, while sensory processes remain largely preserved under energetic stress.