NDE1 encodes the major external type-II NADH:ubiquinone oxidoreductase (NDH-2, EC 1.6.5.9) of S. cerevisiae mitochondria. This single-subunit flavoprotein sits on the intermembrane-space face of the inner membrane and oxidises cytosolic NADH that has crossed the outer membrane, passing electrons to ubiquinone without proton pumping and thus coupling cytosolic redox balance directly to respiration without a redox shuttle. nde1 deletion reduces mitochondrial NADH oxidation about threefold and slows growth on non-fermentable carbon sources such as ethanol; NDE2 encodes a minor paralogous isoform, and the nde1 nde2 double mutant completely lacks external NADH-dependent respiration. Nde1p is part of a supramolecular assembly of intermembrane-space-facing dehydrogenases. A second Nde1 topomer spans the outer membrane and is exposed to the cytosol; this surface-exposed form is rapidly degraded by the proteasome/Cdc48 system and Yme1 and promotes cell death in response to pro-apoptotic stimuli, analogous to mammalian AIF. Nde1/Nde2 activity also kinetically regulates the other route for cytosolic NADH oxidation, the glycerol-3-phosphate shuttle: active NADH oxidation by the external dehydrogenase inhibits the mitochondrial glycerol-3-phosphate dehydrogenase Gut2, so that at saturating NADH glycerol 3-phosphate is not used as a respiratory substrate.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003954 NADH dehydrogenase activity | IDA PMID:9696750 Identification of a cytosolically directed NADH dehydrogenas... | ACCEPT | Summary: Disruption of NDE1 (called NDH1 here) gave a threefold drop in total mitochondrial NADH dehydrogenase activity and a fourfold drop in NADH-driven respiration of isolated mitochondria. Supports NADH dehydrogenase activity; the more specific ubiquinone term is also annotated. Supporting Evidence: PMID:9696750 Disruption of the gene designated NDH1 results in a threefold reduction in total mitochondrial NADH dehydrogenase activity in cells cultivated with glucose and in a fourfold reduction in the respiration of isolated mitochondria with NADH as the substrate. PMID:9696750 Thus, Ndh1p appears to be a mitochondrial dehydrogenase capable of using exogenous NADH. |
| GO:0003954 NADH dehydrogenase activity | IDA PMID:9733747 The Saccharomyces cerevisiae NDE1 and NDE2 genes encode sepa... | ACCEPT | Summary: Luttik et al. showed that mitochondrial NADH oxidation from the cytosolic side depends on Nde1p (3-fold reduction in nde1) and is abolished in nde1 nde2. Supporting Evidence: PMID:9733747 Compared with the wild type, rates of mitochondrial NADH oxidation were about 3-fold reduced in an nde1Delta mutant and unaffected in an nde2Delta mutant. PMID:9733747 NADH-dependent mitochondrial respiration was completely abolished in an nde1Delta nde2Delta double mutant. |
| GO:0003954 NADH dehydrogenase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (NDH-2 family) mapping to NADH dehydrogenase activity. Correct for Nde1p. Supporting Evidence: PMID:9696750 Disruption of the gene designated NDH1 results in a threefold reduction in total mitochondrial NADH dehydrogenase activity in cells cultivated with glucose and in a fourfold reduction in the respiration of isolated mitochondria with NADH as the substrate. |
| GO:0005739 mitochondrion | HDA PMID:14576278 The proteome of Saccharomyces cerevisiae mitochondria. | ACCEPT | Summary: Mitochondrial proteome study (Sickmann et al.) detected Nde1p; also the source of UniProt's IMS location. Supporting Evidence: file:yeast/NDE1/NDE1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: Mitochondrial proteome survey detected Nde1p. Consistent with its known location. Supporting Evidence: PMID:9696750 Under all conditions, NADH dehydrogenase activity was found to be associated with the organellar pellet. |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | ACCEPT | Summary: Quantitative mitochondrial proteomics detected Nde1p. Consistent with its known location. Supporting Evidence: PMID:9696750 Under all conditions, NADH dehydrogenase activity was found to be associated with the organellar pellet. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for mitochondrial localisation of the NDH-2 family. Correct; Nde1p is a mitochondrial inner-membrane protein facing the intermembrane space. Supporting Evidence: PMID:9733747 S. cerevisiae exhibits another mitochondrial NADH-dehydrogenase activity, which oxidizes NADH at the cytosolic side of the inner membrane. file:yeast/NDE1/NDE1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space |
| GO:0005739 mitochondrion | IDA PMID:9696750 Identification of a cytosolically directed NADH dehydrogenas... | ACCEPT | Summary: NADH dehydrogenase activity dependent on NDE1 fractionated with the organellar (mitochondrial) pellet. Supporting Evidence: PMID:9696750 Under all conditions, NADH dehydrogenase activity was found to be associated with the organellar pellet. PMID:9696750 Thus, Ndh1p appears to be a mitochondrial dehydrogenase capable of using exogenous NADH. |
| GO:0005739 mitochondrion | IDA PMID:9733747 The Saccharomyces cerevisiae NDE1 and NDE2 genes encode sepa... | ACCEPT | Summary: Mitochondria isolated from nde mutants lack NADH-dependent respiration, consistent with a mitochondrial location of Nde1p. Supporting Evidence: PMID:9733747 S. cerevisiae exhibits another mitochondrial NADH-dehydrogenase activity, which oxidizes NADH at the cytosolic side of the inner membrane. PMID:9733747 NADH-dependent mitochondrial respiration was completely abolished in an nde1Delta nde2Delta double mutant. |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of mitochondrion; correct and consistent with experimental data. Supporting Evidence: PMID:9696750 Under all conditions, NADH dehydrogenase activity was found to be associated with the organellar pellet. |
| GO:0005739 mitochondrion | IMP PMID:9696750 Identification of a cytosolically directed NADH dehydrogenas... | ACCEPT | Summary: Loss of exogenous-NADH respiration in isolated mitochondria of the disruptant places Nde1p activity in mitochondria. Supporting Evidence: PMID:9696750 Disruption of the gene designated NDH1 results in a threefold reduction in total mitochondrial NADH dehydrogenase activity in cells cultivated with glucose and in a fourfold reduction in the respiration of isolated mitochondria with NADH as the substrate. |
| GO:0005739 mitochondrion | IMP PMID:9733747 The Saccharomyces cerevisiae NDE1 and NDE2 genes encode sepa... | ACCEPT | Summary: Mutant analysis of isolated mitochondria supports Nde1p acting in mitochondria (cytosolic face of the inner membrane). Supporting Evidence: PMID:9733747 Compared with the wild type, rates of mitochondrial NADH oxidation were about 3-fold reduced in an nde1Delta mutant and unaffected in an nde2Delta mutant. |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to mitochondrial intermembrane space. Correct for the catalytic face: Nde1p oxidises NADH at the cytosolic (IMS) side of the inner membrane; the protein is associated with the inner membrane facing the IMS. Supporting Evidence: file:yeast/NDE1/NDE1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space PMID:9733747 S. cerevisiae exhibits another mitochondrial NADH-dehydrogenase activity, which oxidizes NADH at the cytosolic side of the inner membrane. PMID:31668496 forms two distinct topomers in mitochondria, one residing in the intermembrane space while the other spans the outer membrane and is exposed to the cytosol. |
| GO:0015980 energy derivation by oxidation of organic compounds | IEA GO_REF:0000117 | TOO GENERAL | Summary: ARBA prediction of the broad term 'energy derivation by oxidation of organic compounds'. Not wrong for a respiratory-chain dehydrogenase, but the specific process is mitochondrial electron transport from NADH to ubiquinone. Reason: Broad ancestor term; the core process is GO:0006120. Supporting Evidence: PMID:9733747 NADH-dependent mitochondrial respiration was completely abolished in an nde1Delta nde2Delta double mutant. |
| GO:0016491 oxidoreductase activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA giving the generic parent 'oxidoreductase activity' to the NDH-2 family. Correct but uninformative for Nde1p, whose NADH:ubiquinone oxidoreductase role is established by mutant analysis. Reason: Replace with the specific non-electrogenic NADH:ubiquinone oxidoreductase term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: GO_REF:0000033 · PAINT NDH-2 family node SUPPORTS TRANSFER Transfer of the generic oxidoreductase parent is valid; only the granularity is inadequate. Proposed replacements: NADH dehydrogenase (ubiquinone) (non-electrogenic) activity Supporting Evidence: PMID:9733747 Compared with the wild type, rates of mitochondrial NADH oxidation were about 3-fold reduced in an nde1Delta mutant and unaffected in an nde2Delta mutant. file:yeast/NDE1/NDE1-uniprot.txt Reaction=a ubiquinone + NADH + H(+) = a ubiquinol + NAD(+); |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping to generic 'oxidoreductase activity'. Correct but uninformative for Nde1p. Reason: Replace with the specific non-electrogenic NADH:ubiquinone oxidoreductase term. Proposed replacements: NADH dehydrogenase (ubiquinone) (non-electrogenic) activity Supporting Evidence: PMID:9733747 Compared with the wild type, rates of mitochondrial NADH oxidation were about 3-fold reduced in an nde1Delta mutant and unaffected in an nde2Delta mutant. |
| GO:0019655 pyruvate fermentation to ethanol | IMP PMID:9696750 Identification of a cytosolically directed NADH dehydrogenas... | MARK AS OVER ANNOTATED | Summary: This paper studies respiratory growth on non-fermentable carbon sources and NADH-linked respiration; it reports no phenotype on glucose and no measurement of ethanol fermentation. Nde1p competes with alcohol dehydrogenase for cytosolic NADH but performs no step of pyruvate-to-ethanol conversion. Reason: Nde1p re-oxidises cytosolic NADH via the respiratory chain; it is not a participant in pyruvate fermentation to ethanol. The relevant process is GO:0006120. Supporting Evidence: PMID:9696750 Thus, Ndh1p appears to be a mitochondrial dehydrogenase capable of using exogenous NADH. |
| GO:0019655 pyruvate fermentation to ethanol | IMP PMID:9733747 The Saccharomyces cerevisiae NDE1 and NDE2 genes encode sepa... | MARK AS OVER ANNOTATED | Summary: Luttik et al. found glucose metabolism of the nde1 nde2 mutant in glucose-limited chemostats was still essentially respiratory; the genes provide respiratory oxidation of cytosolic NADH. They do not catalyse any step of pyruvate fermentation to ethanol, even if loss of NDE1/NDE2 can shift NADH reoxidation towards fermentative routes. Reason: Indirect metabolic consequence, not participation in the fermentation pathway. Supporting Evidence: PMID:9733747 Glucose metabolism in aerobic, glucose-limited chemostat cultures (D = 0.10 h-1) of an nde1Delta nde2Delta mutant was essentially respiratory. |
| GO:0031966 mitochondrial membrane | IDA PMID:31668496 The NADH Dehydrogenase Nde1 Executes Cell Death after Integr... | ACCEPT | Summary: Saladi et al. found two Nde1 topomers, one in the intermembrane space (inner-membrane associated) and one spanning the outer membrane. 'Mitochondrial membrane' covers both. Supporting Evidence: PMID:31668496 forms two distinct topomers in mitochondria, one residing in the intermembrane space while the other spans the outer membrane and is exposed to the cytosol. |
| GO:0042981 regulation of apoptotic process | IMP PMID:31668496 The NADH Dehydrogenase Nde1 Executes Cell Death after Integr... | KEEP AS NON CORE | Summary: The outer-membrane-spanning, cytosol-exposed Nde1 topomer triggers cell death in response to pro-apoptotic stimuli and is controlled by proteasome/Cdc48 and Yme1 turnover. Experimentally supported, but a secondary (moonlighting) role relative to NADH oxidation. Reason: Real but non-core role of a distinct topomer. Supporting Evidence: PMID:31668496 The surface-exposed topomer triggers cell death in response to pro-apoptotic stimuli. |
| GO:0050136 NADH dehydrogenase (quinone) (non-electrogenic) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (EC 1.6.5.9) for non-electrogenic NADH:quinone oxidoreductase activity. Correct for Nde1p, an NDH-2 family enzyme whose loss abolishes (with NDE2) NADH-dependent respiration. Supporting Evidence: PMID:9733747 NADH-dependent mitochondrial respiration was completely abolished in an nde1Delta nde2Delta double mutant. file:yeast/NDE1/NDE1-uniprot.txt Reaction=a ubiquinone + NADH + H(+) = a ubiquinol + NAD(+); |
| GO:0120555 NADH dehydrogenase (ubiquinone) (non-electrogenic) activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based IEA (RHEA:23152) for ubiquinone-specific non-electrogenic NADH dehydrogenase activity. Correct; yeast respiration uses ubiquinone-6 and Nde1p delivers cytosolic NADH electrons into this pool. Supporting Evidence: file:yeast/NDE1/NDE1-uniprot.txt Reaction=a ubiquinone + NADH + H(+) = a ubiquinol + NAD(+); PMID:9733747 Compared with the wild type, rates of mitochondrial NADH oxidation were about 3-fold reduced in an nde1Delta mutant and unaffected in an nde2Delta mutant. |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IMP PMID:9733747 The Saccharomyces cerevisiae NDE1 and NDE2 genes encode sepa... | NEW | Summary: Nde1p itself transfers electrons from cytosolic NADH into the respiratory chain quinone pool: NADH-dependent respiration of isolated mitochondria falls 3-fold in nde1 and is abolished in nde1 nde2. GOA carries this process for NDI1 but not for NDE1, although the external enzyme performs the same electron-transfer step from the other face of the membrane. Reason: Nde1p catalyses the NADH-to-ubiquinone electron-transfer step (participation, not mere requirement). Supporting Evidence: PMID:9733747 Compared with the wild type, rates of mitochondrial NADH oxidation were about 3-fold reduced in an nde1Delta mutant and unaffected in an nde2Delta mutant. PMID:9733747 NADH-dependent mitochondrial respiration was completely abolished in an nde1Delta nde2Delta double mutant. |
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Download this section (compressed HTML)Q: Is the cytosol-exposed outer-membrane topomer of Nde1p catalytically active, and does its pro-death activity require NADH dehydrogenase activity?
Experiment: Purify Nde1p and Nde2p and compare kinetic parameters (NADH Km, kcat with ubiquinone-6) to determine whether the minor contribution of Nde2p reflects expression level or intrinsic activity.
Mitochondrial external NADH dehydrogenase; type II NAD(P)H:quinone oxidoreductase that catalyzes the oxidation of cytosolic NADH; Nde1p and Nde2p provide cytosolic NADH to the mitochondrial respiratory chain; NDE1 has a paralog, NDE2, that arose from the whole genome duplication
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