Molecular Cell
Volume 81, Issue 18, 16 September 2021, Pages 3848-3865.e19
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Article
A hydride transfer complex reprograms NAD metabolism and bypasses senescence

https://doi.org/10.1016/j.molcel.2021.08.028Get rights and content
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Highlights

  • PC, MDH1, and ME1 form a hydride transfer complex (HTC) in the cytoplasm

  • HTC transfers reducing equivalents from NADH to NADP+

  • HTC promotes tumor formation by bypassing senescence

  • HTC confers fitness to cells under hypoxia or mitochondrial dysfunction

Summary

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP+. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.

Keywords

NAD
NADPH
cellular senescence
mitochondrial dysfunction
hypoxia
MDH1
ME1
PC
metabolon
p53

Data and code availability

  • Quantification data of Immunofluorescence, quantification of SA-β-Gal, ROS analysis, NAD analysis, oxygen consumption, analyzed metabolomics data, unprocessed mitochondrial ultrastructure images, unprocessed allograft images, PLA images and unprocessed SA-β-Gal images were deposited to Mendeley Data and DOI is listed in the key resources table. Link to Mendeley http://doi.org/10.17632/xsxwjfhz8f.1. This paper analyses existing, publicly available data. These accession numbers for the datasets are listed in the key resources table. All source data not on Mendeley Data and all supporting information are either included in the figures or will be made available upon request to the lead author or the first author.

  • This paper does not report original code.

  • Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon reasonable request.

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19

These authors contributed equally

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