A new study from the University of Bergen (UiB) reveals the critical role of mitochondria in maintaining cellular levels of nicotinamide adenine dinucleotide (NAD+), a molecule vital for energy metabolism and cellular function. The research, published in Nature Metabolism, uncovers how mitochondria act as a reservoir for NAD+, buffering cells against decline during aging and disease. These findings suggest potential therapeutic targets for age-related disorders.
NAD+ and Cellular Function
NAD+ functions like a rechargeable battery, essential for converting nutrients into energy that cells use to perform various functions. It also plays a crucial role in regulating gene expression and DNA repair within the cell nucleus. Professor Mathias Ziegler from the Department of Biomedicine, UiB, explains, "The fascinating thing about NAD is that the molecule is essential to life, as it plays critical roles in all cellular processes. Therefore, dysregulated NAD levels are involved in aging processes as well as many pathologies ranging from cancer to diabetes and neurodegenerative diseases."
Mitochondria's Role as an NAD+ Reservoir
The study highlights that mitochondria serve as a crucial NAD+ reservoir. Lena Høyaland, PhD student and first author of the study, notes, "These organelles serve as an NAD reservoir that is filled when cells function normally, and it supplies the cell with NAD when there is an increased demand." Using CRISPR-Cas9 genome editing, the researchers elucidated the molecular mechanisms by which mitochondria counteract cellular NAD+ decline.
Implications for Aging and Disease
As we age, DNA damage accumulates, increasing the demand for NAD+ and leading to a decline in cellular NAD+ levels. The researchers found that cells generally tolerate decreased NAD+ levels unless the mitochondria or their NAD+ stores are compromised over extended periods. This can have "fatal consequences since the cells may no longer have sufficient NAD 'battery capacity' to drive vital, energy-dependent processes," according to Professor Ziegler.
Research indicates that mitochondrial dysfunction and lowered cellular NAD+ levels are characteristics of aging and age-related disorders, such as dementia and neurodegenerative diseases. The team believes that excessive consumption of mitochondrial NAD+ might be a key factor leading to dysfunctional cellular powerhouses and aging-associated diseases.
Therapeutic Potential of NAD+ Supplementation
Initial clinical trials, both in Norway and internationally, using therapeutic supplementation approaches to increase NAD+ levels have shown encouraging results. These findings suggest that targeting NAD+ levels could be a promising strategy for slowing aging and treating aging-related diseases. "Our study also demonstrates the importance of basic research to identify promising targets to slow aging and to treat aging-related diseases," concludes Ziegler.
