Can We Stop Brain Aging? Scientists Uncover Mitochondrial Key

New research identifies E-TCmito as a key link between neuronal activity and mitochondrial function, highlighting its potential to address cognitive decline in aging and diseases like Alzheimer’s.

Researchers uncovered a mechanism called excitation-mitochondrial DNA transcription coupling (E-TCmito) linking neuronal activity to mitochondrial DNA transcription, crucial for maintaining brain function. Enhancing E-TCmito in aged mice improved cognition, offering a potential therapeutic target for age-related cognitive decline and neurodegenerative diseases.

New research in mice has identified a critical mechanism that connects neuronal activity with mitochondrial function, offering insight into potential strategies to address age-related cognitive decline. Mitochondria, essential for meeting the energy needs of active neurons, generate adenosine triphosphate (ATP) primarily through oxidative phosphorylation (OXPHOS).

As mammals age, the efficiency of mitochondrial metabolism in the brain declines, significantly impacting neuronal and network function. The disruption of the OXPHOS pathway contributes to oxidative stress and mitochondrial dysfunction, exacerbating these challenges.
Challenges in Understanding Aging-Related Mitochondrial Decline

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-TCmito), 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-TCmito declines, leading to cognitive deficits. Notably, by enhancing E-TCmito 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.”

Reference: “Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice” by Wenwen Li, Jiarui Li, Jing Li, Chen Wei, Tal Laviv, Meiyi Dong, Jingran Lin, Mariah Calubag, Lesley A Colgan, Kai Jin, Bing Zhou, Ying Shen, Haohong Li, Yihui Cui, Zhihua Gao, Tao Li, Hailan Hu, Ryohei Yasuda and Huan Ma, 20 December 2024, .