Neural oscillatory activity serving sensorimotor control is predicted by superoxide-sensitive mitochondrial redox environments

Significance Mitochondrial integrity and associated redox profiles have long been revered as key contributors to a host of age- and disease-related pathologies, which eventually lead to neuronal and behavioral dysfunction in the sensorimotor and other systems. However, the precise role of the mitochondrial redox environment in human sensorimotor brain systems and motor behavior remains poorly understood. Herein, we provide evidence for a strong predictive capacity of superoxide and its scavenger, superoxide dismutase, on the neural oscillatory dynamics serving motor planning and execution above and beyond the effects of mitochondrial respiratory capacities alone. Importantly, these data provide insight regarding the impact of the redox environment on the population-level neural oscillations that serve motor function in healthy humans. Motor control requires a coordinated ensemble of spatiotemporally precise neural oscillations across a distributed motor network, particularly in the beta range (15 to 30 Hz) to successfully plan and execute volitional actions. While substantial evidence implicates beta activity as critical to motor control, the molecular processes supporting these microcircuits and their inherent oscillatory dynamics remain poorly understood. Among these processes are mitochondrial integrity and the associated redox environments, although their direct impact on human neurophysiological function is unknown. Herein, 40 healthy adults completed a motor sequence paradigm during magnetoencephalography (MEG). MEG data were imaged in the time–frequency domain using a beamformer to evaluate beta oscillatory profiles during distinct phases of motor control (i.e., planning and execution) and subsequent behavior. To comprehensively quantify features of the mitochondrial redox environment, we used state-of-the-art systems biology approaches including Seahorse Analyzer to assess mitochondrial respiration and electron paramagnetic resonance spectroscopy to measure superoxide levels in whole blood as well as antioxidant activity assays. Using structural equation modeling, we tested the relationship between mitochondrial function and sensorimotor brain-behavior dynamics through alterations in the redox environment (e.g., generation of superoxide and alteration in antioxidant defenses). Our results indicated that superoxide-sensitive but not hydrogen peroxide–sensitive features of the redox environment had direct and mediating effects on the bioenergetic–neural pathways serving motor performance in healthy adults. Importantly, our results suggest that alterations in the redox environment may directly impact behavior above and beyond mitochondrial respiratory capacities alone and further may be effective targets for age- and disease-related declines in cognitive–motor function.