Exciting new research regarding NAD+

Reporting in a new study published today in Nature, researchers from the Department of Physiology in the Perelman School of Medicine at the University of Pennsylvania and other institutions found that the SLC25A51 gene dictates the transport of nicotinamide adenine dinucleotide (NAD+), a fundamental coenzyme in cellular metabolism, to the mitochondria, where energy from nutrients is converted into chemical energy for the cell. A low level of NAD+ is a hallmark of aging and has been associated with diseases including muscular dystrophy and heart failure.

"We have long known that NAD+ plays a critical role in the mitochondria, but the question of how it gets there had been left unanswered," said co-senior author Joseph A. Baur, Ph.D., an associate professor of Physiology and member of Penn's Institute for Diabetes, Obesity, and Metabolism. "This discovery opens up a whole new area of research where we can actually manipulate—selectively deplete or add—NAD+ at a subcellular level, now that we know how it's transported."

Xiaolu Ang Cambronne, Ph.D., an assistant professor in the department of Molecular Biosciences in The University of Texas at Austin, served as co-senior author.

The finding closes out a longstanding unknown around how NAD+ finds its way into the mitochondrial matrix. Several hypotheses had been circulating, including the idea that mammalian mitochondria were incapable of NAD+ transport, instead relying entirely on synthesis of NAD+ within the organelle, but in 2018, Baur's lab put that idea to rest when it reported in an eLife study that a transporter was in fact responsible.

From there, the team began its search for the genetic identity of the mammalian mitochondrial NAD+ transporter, homing in on several genes, including SLC25A51, that were predicted to be transporters, but for which the function remained unknown. SLC25A family members encode mitochondrially-localized proteins that carry materials across mitochondrial membranes.

"In our approach, we focused in on genes that were determined to be essential for cellular viability. NAD+ is a fundamental molecule required for maintaining the mitochondrial-mediated energy production. We predicted that loss-of mitochondrial NAD+ transport would disrupt oxidative phosphorylation and possibly reduce cell survival," said lead author Timothy S. Luongo, Ph.D., a postdoctoral fellow in the Baur lab.