Mitochondrial NAD Transport

Abstract

Tissue nicotinamide adenine dinucleotide (NAD) levels correlate with healthspan, falling with age or disease, and rising with exercise or caloric restriction. Moreover, the demonstration that supplemental NAD precursors drive beneficial effects in a variety of rodent models has led to a resurgence in interest in the basic biology of this molecule. Although it is widely recognized that NAD is present in the mitochondrial matrix and critical to the function of the organelle, the source of mitochondrial NAD has been debated. We recently used an isotopic labeling approach to demonstrate that direct uptake of intact NAD is one mechanism by which mitochondria are able to obtain this nucleotide. Here, we show that this activity is sufficient to restore respiratory capacity in NAD‐deficient isolated mitochondria, and identify SLC25A51 as a carrier that can mediate the transport of NAD across mitochondrial membranes. Compartment‐specific regulation of NAD concentration may be a crucial element in the adaptation of cells and tissues to changing metabolic environment that could be targeted therapeutically once the underlying mechanisms have been revealed.Support or Funding InformationDK098656 to J.A.B., GM126897 to L.A.C.