Abstract
Brain function relies on energy supplied by mitochondrial energy transformation, but how cellular energetics constrains neurological function and cognition remains poorly understood. Genetic defects in mitochondrial DNA cause rare mitochondrial diseases (MitoD) that offer a unique window to examine how mitochondria affects the brain and cognition, and the possibility to identify neural processes that are most energetically constrained. In this study, we assessed functional magnetic resonance imaging (fMRI) on 29 participants with MitoD and 62 matched controls during resting state and tasks probing cognitive (N-back task), affective (cold pain), and sensory (multisensory visual and auditory perception) functions. MitoD individuals exhibited significant cognitive deficits across a range of functions, including executive function and working memory, mental and physical fatigability, low exercise tolerance, and low mood. As expected, these deficits were accompanied by markedly elevated blood levels of metabolic stress markers, including GDF15 and FGF21. Surprisingly, overall BOLD fMRI activity and connectivity were largely intact across all tasks in MitoD individuals. However, those with more severe cognitive impairment and higher GDF15 levels showed reduced working memory-related BOLD activity, which in turn mediated poorer task performance. Conversely, individuals with relatively preserved cognitive function exhibited hyperactivation in working memory regions and working memory performance compared to controls, suggesting compensatory engagement of cortical systems in high-functioning MitoD individuals. These effects were weaker in the sensory domain and absent during affective (cold pain) processing. These data suggest that when mitochondrial energy transformation is limited, the brain operates an energy hierarchy that prioritizes essential functions such as affective responses while downregulating more energy-demanding, complex cognitive processes.