Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+

Published 2024

Publication details

Journal : Nature Metabolism , vol. 6 , p. 2319–2337 , 2024

International Standard Numbers :
Electronic : 2522-5812

Publication type : Academic article

Contributors : Ashrafi, Hanan; Bifulco, Ersilia; Cimadamore-Werthein, Camila; Davidsen, Cedric; Dietze, Jörn Lukas Franz; Dölle, Christian; Haukanes, Kjellfrid Fosso; Hayat, Faisal; Heiland, Ines; Høyland, Lena Elise; Lucena, Eva; Makarov, Mikhail V.; Migaud, Marie E.; Mjøs, Svein Are; Niere, Marc; Pettersen, Ina Katrine Nitschke; Sharma, Suraj; Strømland, Øyvind; Sverkeli, Lars Jansen; Tolås, Ingvill; Tronstad, Karl Johan; Van Linden, Magali R; Ziegler, Mathias; van der Hoeven, Barbara

Issue : 12

Links :
ARKIV : hdl.handle.net/10037/36063
DOI : doi.org/10.1038/s42255-024-011...

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Summary

The coenzyme NAD+ is consumed by signaling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Aging is associated with a decrease in cellular NAD+ levels but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific over-consumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum, or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modeling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51, and reversibly cleave NAD+ to NMN and ATP, when NMNAT3 is present. Thereby, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated aging-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.