Mitochondrial respiratory Complex I core (NADH:ubiquinone oxidoreductase) — catalytic N and Q modules and membrane-arm core; NDUFV1/NDUFV2/NDUFS1-3/NDUFS6-8/NDUFA9, MT-ND1/MT-ND5/MT-ND6

Respiratory Complex I (NADH:ubiquinone oxidoreductase) is the largest enzyme of the electron transport chain and its main entry point: it oxidises NADH, passes the electrons through a chain of flavin and iron-sulfur cofactors to reduce ubiquinone, and uses the energy released to pump four protons across the inner membrane. This module covers the catalytic core of the L-shaped peripheral (matrix) arm — the seven conserved "core" nuclear subunits plus the closely associated flavoprotein subunits — together with representative mtDNA-encoded core subunits of the membrane arm, organised into three functional modules. The N-module (NADH-oxidising) holds the flavin site: NDUFV1 (51 kDa) binds FMN and the NADH substrate, NDUFV2 (24 kDa) carries the first [2Fe-2S] cluster (N1a), and NDUFS1 (75 kDa) provides further Fe-S clusters, forming the flavoprotein (FP) subcomplex with the accessory NDUFS6. The Q-module (ubiquinone-reducing) forms the wire to the quinone site: NDUFS2 (49 kDa) and NDUFS3 (30 kDa) are cofactor-less core subunits shaping the ubiquinone cavity, NDUFS7 (PSST) coordinates the terminal [4Fe-4S] cluster N2 that donates electrons to ubiquinone, NDUFS8 (TYKY) carries the N6a/N6b [4Fe-4S] clusters of the electron-transfer wire, and the accessory NDUFA9 (SDR-fold, structural NADPH) stabilises the Q-module/membrane-arm junction; NDUFS4 is an accessory subunit required for assembly and stability of the whole peripheral arm. The P-module (membrane arm, proton-pumping) is represented by three of its seven mtDNA-encoded core subunits: MT-ND1 lines the quinone-channel exit and begins the E-channel, MT-ND6 forms part of the E-channel, and MT-ND5 is the distal antiporter-like subunit; each contributes to proton translocation within the assembled complex. Inherited defects in these core subunits are among the commonest causes of mitochondrial complex I deficiency — typically Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis or encephalocardiomyopathy.

MODULE:mitochondrial_complex_i_coreDRAFTProtein Complexmodules/mitochondrial_complex_i_core.yaml

mitochondrial electron transport, NADH to ubiquinoneGO:0006120 mitochondrial respiratory chain complex I assemblyGO:0032981

GO:0006120

mitochondrial electron transport, NADH to ubiquinone

The module is grounded in mitochondrial electron transport, NADH to ubiquinone (GO:0006120) — the reaction catalysed by Complex I.

GO:0032981

mitochondrial respiratory chain complex I assembly

The core subunits define the catalytic peripheral arm whose assembly is mitochondrial respiratory chain complex I assembly (GO:0032981).

Reactome:R-HSA-163217

Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2

The catalytic reaction follows the human Reactome "Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2" reaction (R-HSA-163217).

file:human/NDUFV1/NDUFV1-ai-review.yaml

NDUFV1 gene review (human)

The FMN/NADH catalytic subunit (UniProtKB:P49821, GO:0003954) matches the previously completed human NDUFV1 review (on main).

file:human/NDUFS1/NDUFS1-ai-review.yaml

NDUFS1 gene review (human)

The 75 kDa Fe-S electron-transfer subunit (UniProtKB:P28331, GO:0009055) matches the previously completed human NDUFS1 review (on main).

file:human/NDUFS2/NDUFS2-ai-review.yaml

NDUFS2 gene review (human)

The 49 kDa Q-module core subunit (UniProtKB:O75306, GO:0048039) matches the previously completed human NDUFS2 review (on main).

file:human/NDUFS4/NDUFS4-ai-review.yaml

NDUFS4 gene review (human)

The NDUFS4 accessory/assembly subunit (UniProtKB:O43181) matches the previously completed human NDUFS4 review (on main).

file:human/NDUFV2/NDUFV2-ai-review.yaml

NDUFV2 gene review (human)

The 24 kDa N1a [2Fe-2S] N-module subunit (UniProtKB:P19404, GO:0008137) matches the completed human NDUFV2 review.

file:human/NDUFS3/NDUFS3-ai-review.yaml

NDUFS3 gene review (human)

The 30 kDa Q-module core subunit (UniProtKB:O75489, GO:0005198) matches the completed human NDUFS3 review.

file:human/NDUFS6/NDUFS6-ai-review.yaml

NDUFS6 gene review (human)

The 13 kDa zinc-binding N-module accessory subunit (UniProtKB:O75380, GO:0005198) matches the completed human NDUFS6 review.

file:human/NDUFS7/NDUFS7-ai-review.yaml

NDUFS7 gene review (human)

The PSST subunit coordinating the N2 [4Fe-4S] cluster (UniProtKB:O75251, GO:0008137/GO:0051539) matches the completed human NDUFS7 review.

file:human/NDUFS8/NDUFS8-ai-review.yaml

NDUFS8 gene review (human)

The TYKY subunit coordinating the N6a/N6b [4Fe-4S] clusters (UniProtKB:O00217, GO:0051539) matches the completed human NDUFS8 review.

file:human/NDUFA9/NDUFA9-ai-review.yaml

NDUFA9 gene review (human)

The 39 kDa SDR-fold Q-module/junction accessory subunit (UniProtKB:Q16795, GO:0005198) matches the completed human NDUFA9 review.

file:human/MT-ND1/MT-ND1-ai-review.yaml

MT-ND1 gene review (human)

The mtDNA-encoded membrane-arm subunit at the quinone channel (UniProtKB:P03886, GO:0048039, contributes to GO:0008137) matches the completed human MT-ND1 review.

file:human/MT-ND5/MT-ND5-ai-review.yaml

MT-ND5 gene review (human)

The distal antiporter-like membrane-arm subunit (UniProtKB:P03915, GO:0015078, contributes to GO:0008137) matches the completed human MT-ND5 review.

file:human/MT-ND6/MT-ND6-ai-review.yaml

MT-ND6 gene review (human)

The E-channel membrane-arm subunit (UniProtKB:P03923, GO:0015078, contributes to GO:0008137) matches the completed human MT-ND6 review.

5Nodes

4Parts

0Variant Sets

0Variants

13Annotons

3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:mitochondrial_complex_i_core deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

11 gene-function check(s) reflected in core functions · 0 conflict(s) · 10 evidence or coverage gap(s) (24 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
ndufv1_activity	NDUFV1 (human) UniProtKB:P49821 Family Representative	NADH dehydrogenase activity GO:0003954	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
ndufv2_activity	NDUFV2 (human) UniProtKB:P19404 Family Representative	electron transfer activity GO:0009055	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufs1_activity	NDUFS1 (human) UniProtKB:P28331 Family Representative	electron transfer activity GO:0009055	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufs6_activity	NDUFS6 (human) UniProtKB:O75380 Family Representative	structural molecule activity GO:0005198	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufs2_activity	NDUFS2 (human) UniProtKB:O75306 Family Representative	ubiquinone binding GO:0048039	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufs3_activity	NDUFS3 (human) UniProtKB:O75489 Family Representative	structural molecule activity GO:0005198	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufs7_activity	NDUFS7 (human) UniProtKB:O75251 Family Representative	NADH dehydrogenase (ubiquinone) activity GO:0008137	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufs8_activity	NDUFS8 (human) UniProtKB:O00217 Family Representative	4 iron, 4 sulfur cluster binding GO:0051539	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufa9_activity	NDUFA9 (human) UniProtKB:Q16795 Family Representative	structural molecule activity GO:0005198	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mt_nd1_activity	MT-ND1 (human) UniProtKB:P03886 Family Representative	ubiquinone binding GO:0048039	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mt_nd6_activity	MT-ND6 (human) UniProtKB:P03923 Family Representative	proton transmembrane transporter activity GO:0015078	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mt_nd5_activity	MT-ND5 (human) UniProtKB:P03915 Family Representative	proton transmembrane transporter activity GO:0015078	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndufv1_activity	NADH dehydrogenase flavoprotein 1 family (NDUFV1) PANTHER:PTHR11780 Family	NADH dehydrogenase activity GO:0003954	Family Supported Family review supports GO:0003954 FAMILY_WIDE. The subunit's own chemistry, with the acceptor left unspecified: NADH docks on the glycine-rich loop (UniProt binding site 87-96 of P49821, GRGGAGFPTG, conserved in bacteria, plants, fungi and animals) and transfers a hydride to the bound FMN. This is true of every member, respiratory compartment and quinone identity aside, and it is the term a PAINT curator should place at the family root. PAINT currently asserts it only at the bacterial node PTN000207323, which is why human NDUFV1 - and every other eukaryotic member - receives no molecular-function IBA at all despite this being the single best-characterised function in the family.
ndufv2_activity	NADH dehydrogenase flavoprotein 2 family (NDUFV2) PANTHER:PTHR10371 Family	electron transfer activity GO:0009055	Family Supported Family review supports GO:0009055 FAMILY_WIDE. The subunit's own molecular function: redox exchange through its [2Fe-2S] cluster N1a with the reduced FMN of the 51 kDa subunit. The four cysteine ligands and the cluster domain (NCBIfam TIGR01958, PIRSF000216, PROSITE PS01099) are conserved across the reviewed members, and rapid NADH-driven reduction of N1a is measured in E. coli complex I. The cluster is on a side path rather than the main wire, so the term asserts electron exchange, not a position on the FMN-to-quinone pathway. Applies equally to the S. pombe homologue, which keeps the cluster domain even without a complex I.
ndufs1_activity	NADH-quinone oxidoreductase G/NDUFS1 family Family	electron transfer activity GO:0009055	Family Id Missing The family has no identifier linking it to a curated family review.
ndufs6_activity	NDUFS6 accessory-subunit family PANTHER:PTHR13156 Family	structural molecule activity GO:0005198	Family Review Missing No supported structured family review is available for PANTHER:PTHR13156.
ndufs2_activity	NADH-quinone oxidoreductase D/NDUFS2 family PANTHER:PTHR11993 Family	ubiquinone binding GO:0048039	Family Function Unreviewed Family review leaves GO:0048039 UNRESOLVED. Safe for the respiratory clade - human and bovine NDUFS2, plant NAD7, bacterial NuoD in ubiquinone-using lineages - and wrong for the plastid NdhH clade, whose complex reduces plastoquinone. It is recorded as UNRESOLVED rather than SUBFAMILY_ONLY because the boundary cannot be expressed on PANTHER's subfamily axis: PTHR11993:SF10 contains both the mitochondrial NDUFS2 orthologues and all 134 chloroplastic NdhH members, so naming SF10 as the applicable subfamily would grant the term to exactly the clade it must be kept from. The scoping has to be done at a clade (PTN) level. The same shape of problem was recorded for PTHR11058, where GO:0008137 on a deep node leaks into the plastid NdhC clade.
ndufs3_activity	NADH-quinone oxidoreductase C/NDUFS3 family PANTHER:PTHR10884 Family	structural molecule activity GO:0005198	Family Review Missing No supported structured family review is available for PANTHER:PTHR10884.
ndufs7_activity	NADH-quinone oxidoreductase B/NDUFS7 (PSST) family PANTHER:PTHR11995 Family	NADH dehydrogenase (ubiquinone) activity GO:0008137	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0008137.
ndufs8_activity	NADH-quinone oxidoreductase I/NDUFS8 (TYKY) family PANTHER:PTHR10849 Family	4 iron, 4 sulfur cluster binding GO:0051539	Family Supported Family review supports GO:0051539 FAMILY_WIDE. The two tandem 4Fe-4S ferredoxin-type domains (PROSITE PS51379 twice, Pfam Fer4_7) and their CxxCxxC...CP cluster-ligand motifs define the family.
ndufa9_activity	NDUFA9 / SDR-fold accessory family PANTHER:PTHR12126 Family	structural molecule activity GO:0005198	Family Review Missing No supported structured family review is available for PANTHER:PTHR12126.
mt_nd1_activity	NADH dehydrogenase subunit 1 family (ND1/NuoH) PANTHER:PTHR11432 Family	ubiquinone binding GO:0048039	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0048039.
mt_nd6_activity	NADH dehydrogenase subunit 6 family (ND6/NuoJ) PANTHER:PTHR11435 Family	proton transmembrane transporter activity GO:0015078	Family Review Missing No supported structured family review is available for PANTHER:PTHR11435.
mt_nd5_activity	NADH dehydrogenase subunit 5 family (ND5/NuoL) PANTHER:PTHR42829 Family	proton transmembrane transporter activity GO:0015078	Family Function Unreviewed Family review leaves GO:0008137 UNRESOLVED. The term holds, as contributes_to, for subunits of NADH-oxidising, ubiquinone-reducing complex I (e.g. E. coli and P. putida Nuo, mitochondrial complex I). It does not hold for members of plastid NDH (ferredoxin donor, plastoquinone acceptor), archaeal F420H2 dehydrogenase, or menaquinone-reducing actinobacterial complexes, and PANTHER subfamily boundaries in this family do not separate these lineages, so no subfamily scope is honest. Resolving it needs clade-level placement of the complex I versus NDH/Fpo lineages in the PANTHER tree (PTN nodes), which the cached files do not provide.

Gene-review completeness (13/13 grounded genes reviewed)

13 complete review(s) · 4 with deep research · 0 missing review · 9 reviewed but lacking deep research

Gene	Review	Complete	Deep research
MT-ND1 P03886	✓	✓	✗
MT-ND5 P03915	✓	✓	✗
MT-ND6 P03923	✓	✓	✗
NDUFA9 Q16795	✓	✓	✗
NDUFS1 P28331	✓	✓	✓
NDUFS2 O75306	✓	✓	✓
NDUFS3 O75489	✓	✓	✗
NDUFS4 O43181	✓	✓	✓
NDUFS6 O75380	✓	✓	✗
NDUFS7 O75251	✓	✓	✗
NDUFS8 O00217	✓	✓	✗
NDUFV1 P49821	✓	✓	✓
NDUFV2 P19404	✓	✓	✗

Tree

Mitochondrial respiratory Complex I core (N, Q and P modules)Protein Complexmitochondrial_complex_i_core

Parts
1. 1. N-module (NADH oxidation, FMN + entry Fe-S clusters)
2. N-module (flavoprotein / NADH-oxidising)Protein Complexcomplex_i_n_module
  
  Annotons
  - NDUFV1: FMN/NADH catalytic subunit (51 kDa) Family: NADH dehydrogenase flavoprotein 1 family (NDUFV1)
  - NDUFV2: N1a [2Fe-2S] subunit (24 kDa) Family: NADH dehydrogenase flavoprotein 2 family (NDUFV2)
  - NDUFS1: 75 kDa Fe-S subunit Family: NADH-quinone oxidoreductase G/NDUFS1 family
  - NDUFS6: zinc-binding N-module accessory (13 kDa) Family: NDUFS6 accessory-subunit family
3. 2. Q-module (ubiquinone reduction, terminal Fe-S wire)
4. Q-module (ubiquinone-reducing)Protein Complexcomplex_i_q_module
  
  Annotons
  - NDUFS2: 49 kDa Q-module core subunit Family: NADH-quinone oxidoreductase D/NDUFS2 family
  - NDUFS3: 30 kDa Q-module core subunit Family: NADH-quinone oxidoreductase C/NDUFS3 family
  - NDUFS7 (PSST): N2 [4Fe-4S] subunit Family: NADH-quinone oxidoreductase B/NDUFS7 (PSST) family
  - NDUFS8 (TYKY): N6a/N6b [4Fe-4S] subunit Family: NADH-quinone oxidoreductase I/NDUFS8 (TYKY) family
  - NDUFA9: SDR-fold junction accessory (39 kDa) Family: NDUFA9 / SDR-fold accessory family
5. 3. peripheral-arm assembly/stability accessory
6. NDUFS4 accessory subunit (peripheral-arm assembly)Reactioncomplex_i_ndufs4
  
  Annotons
  - NDUFS4: accessory/assembly subunit (18 kDa) Family: NDUFS4 accessory-subunit family
7. 4. membrane arm (P-module) core subunits — quinone channel exit and proton translocation (mtDNA-encoded representatives)
8. Membrane arm (P-module; mtDNA-encoded ND core subunits)Protein Complexcomplex_i_membrane_arm
  
  Annotons
  - MT-ND1: quinone-channel / E-channel membrane-arm core subunit Family: NADH dehydrogenase subunit 1 family (ND1/NuoH)
  - MT-ND6: E-channel membrane-arm core subunit Family: NADH dehydrogenase subunit 6 family (ND6/NuoJ)
  - MT-ND5: distal antiporter-like membrane-arm core subunit Family: NADH dehydrogenase subunit 5 family (ND5/NuoL)

Details

Context

mitochondrial inner membraneGO:0005743

Mitochondrial respiratory Complex I core (N, Q and P modules)Protein Complexmitochondrial_complex_i_core

mitochondrial electron transport, NADH to ubiquinoneGO:0006120 mitochondrial respiratory chain complex I assemblyGO:0032981

Context

mitochondrial inner membraneGO:0005743

Catalytic core of mitochondrial respiratory Complex I (NADH:ubiquinone oxidoreductase), grounded to the human N-module subunits NDUFV1 (UniProtKB:P49821, GO:0003954), NDUFV2 (P19404, GO:0008137), NDUFS1 (P28331, GO:0009055) and accessory NDUFS6 (O75380, GO:0005198); the Q-module subunits NDUFS2 (O75306, GO:0048039), NDUFS3 (O75489, GO:0005198), NDUFS7 (O75251, GO:0008137 + N2 [4Fe-4S]), NDUFS8 (O00217, GO:0051539) and accessory NDUFA9 (Q16795, GO:0005198); and the peripheral-arm assembly subunit NDUFS4 (O43181). GO molecular-function/BP/location terms were taken from the completed human gene reviews and verified against the local go.db; the catalytic reaction (R-HSA-163217) was verified against the local reactome cache. The complex is modelled as N-module and Q-module PROTEIN_COMPLEX nodes plus an assembly-accessory node; only the cofactor-bearing subunits carry redox/catalytic MFs (NDUFV1 FMN/NADH, NDUFV2/NDUFS7 Fe-S/NADH dehydrogenase, NDUFS8 [4Fe-4S], NDUFS1 electron transfer, NDUFS2 quinone binding), while the cofactor-less core (NDUFS3) and accessory subunits (NDUFS6, NDUFA9, NDUFS4) are structural. The membrane arm (proton-pumping P-module) is represented by three of its seven mtDNA-encoded core subunits: MT-ND1 (P03886, GO:0048039; quinone-channel exit and start of the E-channel), MT-ND6 (P03923, GO:0015078; E-channel) and MT-ND5 (P03915, GO:0015078; distal antiporter-like subunit). Each contributes to, and does not solely enable, GO:0008137. MT-ND2, MT-ND3, MT-ND4 and MT-ND4L are not yet represented because they have no gene reviews. The full holo-Complex I additionally has ~30 more accessory subunits and dedicated assembly factors (NDUFAF1-8, etc.), which are a further module. The current Complex I membership term is GO:0045271 (GO:0005747 obsolete); Complex I feeds electrons to ubiquinone shared with Complex II, then to Complex III (bc1) → cytochrome c → Complex IV. Disorders: mitochondrial complex I deficiency (the commonest OXPHOS defect) — Leigh syndrome (NDUFS4/S7/S8, NDUFV1), leukoencephalopathy, fatal infantile lactic acidosis (NDUFS6), encephalocardiomyopathy (NDUFV2) and others.

Connections

complex_i_n_module -> complex_i_q_module Provides Input For

Electrons from NADH oxidation at the FMN/N-module are relayed through the Fe-S wire to the Q-module N2 cluster, which reduces ubiquinone.

complex_i_q_module -> complex_i_membrane_arm Causes

Ubiquinone reduction at the Q site drives conformational and electrostatic changes that are transmitted into the membrane arm, where they drive proton translocation through the E-channel and the antiporter-like subunits.

complex_i_ndufs4 -> complex_i_n_module Positively Regulates

NDUFS4 is required for assembly and stability of the catalytic peripheral arm.

Part 1: N-module (NADH oxidation, FMN + entry Fe-S clusters)

mitochondrial inner membraneGO:0005743

Accessory subunit stabilising the N-module.

Part 2: Q-module (ubiquinone reduction, terminal Fe-S wire)

mitochondrial inner membraneGO:0005743

Accessory subunit stabilising the Q-module/membrane-arm junction.

Part 3: peripheral-arm assembly/stability accessory

NDUFS4 accessory subunit (peripheral-arm assembly)Reactioncomplex_i_ndufs4

Annotons

NDUFS4: accessory/assembly subunit (18 kDa)

ndufs4_activity

Participant: Family: NDUFS4 accessory-subunit family

Family:

NDUFS4 accessory-subunit familyPANTHER:PTHR12219

Representative Members: NDUFS4 (human)UniProtKB:O43181

Processes

mitochondrial respiratory chain complex I assemblyGO:0032981

Locations

mitochondrial inner membraneGO:0005743

Accessory subunit required for peripheral-arm assembly and stability.

file:human/NDUFS4/NDUFS4-ai-review.yaml

accessory subunit required for assembly/stability of the peripheral arm; deficiency = Leigh syndrome (MC1DN1)

Part 4: membrane arm (P-module) core subunits — quinone channel exit and proton translocation (mtDNA-encoded representatives)

mitochondrial inner membraneGO:0005743

Distal antiporter-like membrane-arm core subunit carrying a proton-translocation unit.