Neuronal, Mitochondrial Disconnect in Aged Mice Found

New findings in mice have uncovered a crucial mechanism linking neuronal activity to mitochondrial function, researchers report, revealing a potential pathway to combat age-related cognitive decline. Mitochondria play a pivotal role in meeting the dynamic energy demands of neuronal activity, producing adenosine triphosphate (ATP) primarily via oxidative phosphorylation (OXPHOS). However, in the aging mammalian brain, mitochondrial metabolism deteriorates, leading to profound effects on neuronal and circuit functionality. The breakdown of the OXPHOS pathway contributes to oxidative stress and mitochondrial dysfunction. However, the mechanisms underlying the decline in OXPHOS activity and its impact on mitochondrial efficiency in aging neurons remain poorly understood, which, by extension, has limited the development of targeted interventions for age-related cognitive decline. To address this, Wenwen Li and colleagues investigated the role of mitochondrial transcription in cognition in the hippocampus of young and aged mice. Li et al. identified a novel coupling mechanism, which they dubbed excitation-mitochondrial DNA transcription coupling (E-TC_mito), that connects neuronal excitation with mitochondrial DNA transcription. This coupling, distinct from the traditional excitation-transcription coupling in the nucleus, is essential for maintaining synaptic and mitochondrial health. In aging brains, the effectiveness of E-TC_mito declines, leading to cognitive deficits. Notably, by enhancing E-TC_mito in aged mice, the authors observed improved cognitive function, highlighting its potential as a therapeutic target for counteracting cognitive decline associated with aging. "Through an impressive combination of innovative tools, innovative physiology, and behavior experiments, Li et al. provide key insights into mitochondrial biology in the aging mammalian brain," write Deniz Bingul and Scott Owen in a related Perspective. "The findings raise the possibility of identifying targets for age-related neurocognitive disorders associated with mitochondrial dysfunction, including Alzheimer's and Parkinson's diseases."