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SLC25A51 is a mammalian mitochondrial NAD⁺ transporter.

ABSTRACT: Mitochondria require nicotinamide adenine dinucleotide (NAD⁺) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD⁺ transporters have been identified in yeast and plants^1,2, but their existence in mammals remains controversial^3-5. Here we demonstrate that mammalian mitochondria can take up intact NAD⁺, and identify SLC25A51 (also known as MCART1)-an essential^6,7 mitochondrial protein of previously unknown function-as a mammalian mitochondrial NAD⁺ transporter. Loss of SLC25A51 decreases mitochondrial-but not whole-cell-NAD⁺ content, impairs mitochondrial respiration, and blocks the uptake of NAD⁺ into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD⁺ levels and restores NAD⁺ uptake into yeast mitochondria lacking endogenous NAD⁺ transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD⁺ into mitochondria.

SUBMITTER: Luongo TS

PROVIDER: S-EPMC7718333 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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SLC25A51 is a mammalian mitochondrial NAD+ transporter.

Luongo Timothy S TS Eller Jared M JM Lu Mu-Jie MJ Niere Marc M Raith Fabio F Perry Caroline C Bornstein Marc R MR Oliphint Paul P Wang Lin L McReynolds Melanie R MR Migaud Marie E ME Rabinowitz Joshua D JD Johnson F Brad FB Johnsson Kai K Ziegler Mathias M Cambronne Xiaolu A XA Baur Joseph A JA

Nature 20200909 7836

Mitochondria require nicotinamide adenine dinucleotide (NAD+) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and plants1,2, but their existence in mammals remains controversial3-5. Here we demonstrate that mammalian mitochondria can take up intact NAD+, and identify SLC25A51 (also known as MCART1)-an essential6,7 m ...[more]

PMID: 32906142

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Project description:IntroductionNicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism and energy production. NAD+-dependent deacetylase sirtuin 3 (SIRT3) regulates the acetylation levels of mitochondrial proteins that are involved in mitochondrial homeostasis. Fasting up-regulates hepatic SIRT3 activity, which requires mitochondrial NAD+. What is the mechanism, then, to transport more NAD+ into mitochondria to sustain enhanced SIRT3 activity during fasting?ObjectiveSLC25A51 is a recently discovered mitochondrial NAD+ transporter. We tested the hypothesis that, during fasting, increased expression of SLC25A51 is needed for enhanced mitochondrial NAD+ uptake to sustain SIRT3 activity. Because the fasting-fed cycle and circadian rhythm are closely linked, we further tested the hypothesis that SLC25A51 is a circadian regulated gene.MethodsWe examined Slc25a51 expression in the liver of fasted mice, and examined its circadian rhythm in wild-type mice and those with liver-specific deletion of the clock gene BMAL1 (LKO). We suppressed Slc25a51 expression in hepatocytes and the mouse liver using shRNA-mediated knockdown, and then examined mitochondrial NAD+ levels, SIRT3 activities, and acetylation levels of SIRT3 target proteins (IDH2 and ACADL). We measured mitochondrial oxygen consumption rate using Seahorse analysis in hepatocytes with reduced Slc25a51 expression.ResultsWe found that fasting induced the hepatic expression of Slc25a51, and its expression showed a circadian rhythm-like pattern that was disrupted in LKO mice. Reduced expression of Slc25a51 in hepatocytes decreased mitochondrial NAD+ levels and SIRT3 activity, reflected by increased acetylation of SIRT3 targets. Slc25a51 knockdown reduced the oxygen consumption rate in intact hepatocytes. Mice with reduced Slc25a51 expression in the liver manifested reduced hepatic mitochondrial NAD+ levels, hepatic steatosis and hypertriglyceridemia.ConclusionsSlc25a51 is a fasting-induced gene that is needed for hepatic SIRT3 functions.

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SLC25A51 is a mammalian mitochondrial NAD⁺ transporter.

Publications

SLC25A51 is a mammalian mitochondrial NAD<sup>+</sup> transporter.

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