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Chronic depletion of subcellular NAD pools reveals their interconnectivity and a buffering function of mitochondria [post]

Magali VanLinden, Lena Høyland, Jörn Dietze, Ingvill Tolås, Lars Sverkeli, Marc Niere, Camila Cimadamore-Werthein, Barbara van den Hoeven, Øyvind Strømland, Roland Sauter, Christian Dölle, Cedric Davidsen (+8 others)
2021 unpublished

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The coenzyme NAD is consumed by signaling enzymes including poly-ADP-ribose-polymerases (PARPs) and sirtuins. Understanding the mechanisms of aging-associated NAD decline and how cells cope with decreased NAD concentrations requires model systems reflecting chronic NAD deficiency. To evoke compartment-specific over-consumption of NAD, we have engineered cell lines expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum, or peroxisomes. Irrespective of the compartment
more » ... d, total cellular NAD concentrations declined by ~40%. Isotope-tracer flux measurements and mathematical modeling showed that the lowered NAD concentration limits total NAD consumption kinetically. Moreover, NAD biosynthesis rate and capacity remained unchanged, thereby also precluding an increase of total NAD turnover. The chronic NAD deficiency was surprisingly well tolerated unless the mitochondria were targeted. Oxidative phosphorylation and glycolysis were little affected by NAD over-consumption in the other compartments. Likewise, peroxisomal NAD over-consumption was balanced by mitochondrial NAD decrease to maintain beta-oxidation of very long chain fatty acids in peroxisomes. We propose that subcellular NAD pools are interconnected, with mitochondria acting as a rheostat to facilitate NAD-dependent processes in organelles with excessive consumption.
doi:10.21203/rs.3.rs-116850/v1 fatcat:n24xpqqikfgphemfs2sjmkpsy4
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Magali VanLinden, Lena Høyland, Jörn Dietze, Ingvill Tolås, Lars Sverkeli, Marc Niere, Camila Cimadamore-Werthein, Barbara van den Hoeven, Øyvind Strømland, Roland Sauter, Christian Dölle, Cedric Davidsen, Ina Pettersen, Karl Johan Tronstad, Roberto Megias Perez, Svein Mjøs, Mikhail Makarov, Marie Migaud, Ines Heiland, Mathias Ziegler. "Chronic depletion of subcellular NAD pools reveals their interconnectivity and a buffering function of mitochondria." (2021)