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Electron transport chain (ETC) dysfunction or hypoxia causes toxic NADH accumulation. How cells regenerate NAD+ under such conditions remains elusive. Here, integrating bioinformatic analysis and experimental validation, we identify glycerol-3-phosphate (Gro3P) biosynthesis as an endogenous NAD+-regeneration pathway. Under genetic or pharmacological ETC inhibition, disrupting Gro3P synthesis inhibits yeast proliferation, shortens lifespan of C. elegans, impairs growth of cancer cells in culture and in xenografts, and causes metabolic derangements in mouse liver. Moreover, the Gro3P shuttle selectively regenerates cytosolic NAD+ under mitochondrial complex I inhibition; enhancing Gro3P synthesis promotes shuttle activity to restore proliferation of complex I-impaired cells. Mouse brain has much lower levels of Gro3P synthesis enzymes as compared with other organs. Strikingly, enhancing Gro3P synthesis suppresses neuroinflammation and extends lifespan in the Ndufs4-/- mice. Collectively, our results reveal Gro3P biosynthesis as an evolutionarily conserved coordinator of NADH/NAD+ redox homeostasis and present a therapeutic target for mitochondrial complex I diseases.
Pubmed ID: 34270929 RIS Download
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laboratory mouse with name BALB/cAnNCrl from MGI.
View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis monoclonal targets HA
View all literature mentionsThis polyclonal targets Actin
View all literature mentionsThis monoclonal targets LRP130 (F-7)
View all literature mentionsThis monoclonal targets S6 Ribosomal Protein
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsThis polyclonal targets p70 S6 Kinase
View all literature mentionsThis monoclonal targets p70 S6 Kinase, phospho (Thr389)
View all literature mentionsThis monoclonal targets NDUFS2 antibody [7A12BE5AD5 ]
View all literature mentionsThis polyclonal targets Human Glycerol 3 Phosphate Dehydrogenase
View all literature mentionsThis polyclonal targets GAPDH
View all literature mentionsThis polyclonal targets GPD1L
View all literature mentionsMus musculus with name B6J.129(Cg)-Gt(ROSA)26Sortm1.1(CAG-cas9*.-EGFP)Fezh/J from IMSR.
View all literature mentionsMus musculus with name B6.129S4-Ndufs4tm1.1Rpa/J from IMSR.
View all literature mentionsCaenorhabditis elegans with name gas-1(fc21) X. from WB.
View all literature mentionsCaenorhabditis elegans with name Caenorhabditis elegans wild isolate. from WB.
View all literature mentionsCell line MEF (C57BL/6) is a Finite cell line with a species of origin Mus musculus
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line U2OS is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line 143B is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
View all literature mentionsCell line Huh-7 is a Cancer cell line with a species of origin Homo sapiens (Human)
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