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Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration

ABSTRACT: Supplemental NAD+ precursors show metabolic and functional benefits in rodent models of disease and are being explored as potential therapeutics in human studies. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down mechanisms of action. Here we provide evidence that for a well-established benefit of NAD+ precursors in mice, faster liver regeneration, nearly the entire effect can be attributed to the concentration of NAD+ in hepatocyte mitochondria. We find that mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1), as has previously been shown in cultured cells. Heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, while hepatocyte-specific overexpression is sufficient to enhance regeneration comparably to the effect of systemic supplements, despite increasing NAD+ only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Kevin A Janssen

LAB HEAD: Douglas Wallace

PROVIDER: PXD067549 | Pride | 2025-11-06

REPOSITORIES: Pride

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			Action	DRS
	Liver_Post_GFP_1.raw	Raw
	Liver_Post_GFP_2.raw	Raw
	Liver_Post_GFP_3.raw	Raw
	Liver_Post_GFP_5.raw	Raw
	Liver_Post_OE_1.raw	Raw

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Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration

Project description:Supplemental NAD+ precursors show metabolic and functional benefits in rodent models of disease and are being explored as potential therapeutics in human studies. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down mechanisms of action. Here we provide evidence that for a well-established benefit of NAD+ precursors in mice, faster liver regeneration, nearly the entire effect can be attributed to the concentration of NAD+ in hepatocyte mitochondria. We find that mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1), as has previously been shown in cultured cells. Heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, while hepatocyte-specific overexpression is sufficient to enhance regeneration comparably to the effect of systemic supplements, despite increasing NAD+ only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.

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