Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) Deficiency, Nuclear-Type

name: Mitochondrial Complex I Deficiency
display_name: Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) Deficiency, Nuclear-Type
creation_date: "2026-09-21T00:00:00Z"
description: >-
  A group of autosomal and X-linked recessive mitochondrial disorders caused by
  defects in nuclear-encoded genes required to build or maintain complex I
  (NADH:ubiquinone oxidoreductase), the largest complex of the respiratory
  chain. Most members harbour defects in a structural subunit of the peripheral
  (N/Q) or membrane (P) arm, or in one of the assembly factors that chaperone
  the modular biogenesis of the holoenzyme; the DNAJC30 member is the exception
  and the reason this grouping is not named for assembly alone, since its lesion
  impairs the repair of an already-assembled complex rather than its
  construction. In each case the cell cannot oxidize NADH and pass electrons to
  ubiquinone, collapsing proton pumping and oxidative ATP synthesis, producing
  lactic acidosis and bioenergetic failure that preferentially injures
  high-energy tissues - basal ganglia and brainstem (Leigh syndrome), retinal
  ganglion cells and optic nerve (optic atrophy, arLHON), heart, and skeletal
  muscle.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on a shared biochemical lesion: each member conforms to the
  complex_i_deficiency module (nuclear-encoded gene defect -> complex I
  biogenesis or repair failure -> impaired NADH:ubiquinone oxidoreduction and
  ATP synthesis -> lactic acidosis and high-energy-tissue dysfunction). Members
  are kept as separate Disease entries because they differ in the specific gene
  affected, in which structural module or biogenesis sub-step it serves
  (N-module, Q-module, membrane/ND arm, iron-sulfur cluster delivery, early vs
  late assembly chaperone, subunit-exchange repair), and in the dominant organ
  phenotype. The criteria are NECESSARY_AND_SUFFICIENT: conformance to the
  complex I biogenesis-or-repair-failure node both characterizes every member
  and identifies further nuclear complex I subunit or assembly-factor defects
  as candidate members. This deliberately mirrors the sibling
  "Mitochondrial Complex IV Deficiency" grouping, which uses the same
  N&S module-conformance pattern over its own 25 members.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100223
      label: mitochondrial complex I deficiency, nuclear type
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO "mitochondrial complex I
      deficiency, nuclear type" class. Unlike its complex IV counterpart,
      complex I carries a complete three-term set upstream - MONDO:0100133
      (pan-form) over MONDO:0100223 (nuclear type) and MONDO:0100134
      (mitochondrial type) - so the nuclear-type class can be mapped
      exactMatch without absorbing pan-form cross-references.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        The numbered Mitochondrial_Complex_I_Deficiency_Nuclear_Type_* members
        are is-a descendants of MONDO:0100223. The DNAJC30 member is a
        two-step descendant, via MONDO:0030309 (Leber hereditary optic
        neuropathy, autosomal recessive), which is itself asserted under
        MONDO:0100223 - so it is in scope under the MONDO hierarchy as well as
        under the module criterion.
membership_criteria:
- description: >-
    A disorder is a nuclear-type complex I deficiency if and only if it
    conforms to the complex I deficiency module - a nuclear-encoded subunit,
    assembly-factor, or subunit-exchange-chaperone defect causing failure of
    complex I biogenesis or repair.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: complex_i_deficiency#Complex I Biogenesis or Repair Failure
    description: >-
      Conforms to the biogenesis-or-repair-failure node of the complex I
      module.
notes: >-
  Status - this grouping is a PROPOSAL against open issue #9864 ("Stub queue:
  COXPD and nuclear complex I/III deficiency - collapse, group, or keep
  per-number?"), which asks whether the MC1DN number series should be
  collapsed, covered by a grouping, or kept per-number, and where the ruling
  is explicitly reserved for a human curator. It implements option 2 of that
  issue ("Build 'Mitochondrial Complex I Deficiency' (and III) groupings now
  on the complex IV pattern"). It should not be merged ahead of that ruling
  without a maintainer signing off on the nosology.

  Note that the numbers in #9864 predate this work: it records 5 curated
  MC1DN entries and 32 remaining stubs, whereas at the time of writing there
  are 19 curated entries and 17 nuclear stubs, which is what makes the
  grouping worth building now rather than later.

  Membership is complete with respect to curated entries as of 2026-09-21: all
  19 Mitochondrial_Complex_I_Deficiency_Nuclear_Type_* entries plus the
  DNAJC30 entry are listed, and every one of them declares conforms_to against
  the module, so the N&S criterion is satisfied rather than aspirational. The
  17 remaining stubs in stubs/ are future members and are deliberately not
  listed here. Complex III (2 stubs) and complex V (3 stubs) are too small to
  group and are left undecided, per the same issue.

  Not in scope: the COXPD series, which #9864 argues should be regrouped by
  mechanism (mitochondrial gene expression) rather than by the "combined
  OXPHOS deficiency" lab signature.
members:
- member: Mitochondrial Complex I Deficiency, Nuclear Type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFS4 is an accessory subunit whose loss arrests assembly at the CI-830
      subcomplex. It is the most frequently reported nuclear cause of complex
      I-deficient Leigh syndrome and the basis of the widely used Ndufs4
      knockout mouse.
    gene:
      preferred_term: NDUFS4
      term:
        id: hgnc:7711
        label: NDUFS4
- member: Mitochondrial Complex I Deficiency, Nuclear Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFS8 is a core peripheral-arm subunit; its loss reduces both the amount
      and the intrinsic catalytic activity of complex I, with glycolytic
      compensation that can mask the bioenergetic deficit in cultured cells.
    gene:
      preferred_term: NDUFS8
      term:
        id: hgnc:7715
        label: NDUFS8
- member: Mitochondrial Complex I Deficiency Nuclear Type 3
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFS7 forms the Q-module around the N2 iron-sulfur cluster and the
      ubiquinone-binding site, so its loss strikes the electron-transfer step
      itself rather than holoenzyme stability.
    gene:
      preferred_term: NDUFS7
      term:
        id: hgnc:7714
        label: NDUFS7
- member: Mitochondrial Complex I Deficiency, Nuclear Type 6
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFS2 is the core subunit carrying the N2 iron-sulfur cluster and
      quinone-reduction site; its loss produces a Leigh syndrome spectrum
      encephalopathy with cardiomyopathy and hepatic involvement.
    gene:
      preferred_term: NDUFS2
      term:
        id: hgnc:7708
        label: NDUFS2
- member: Mitochondrial Complex I Deficiency, Nuclear Type 11
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFAF1 is a component of the MCIA complex required for early membrane-arm
      assembly; its loss leaves stalled intermediates that overproduce reactive
      oxygen species, with a cardiomyocyte-dominant presentation.
    gene:
      preferred_term: NDUFAF1
      term:
        id: hgnc:18828
        label: NDUFAF1
- member: Mitochondrial Complex I Deficiency, Nuclear Type 12
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFA1 is X-linked, the exception in an otherwise autosomal recessive
      grouping; heterozygous females can be affected through skewed
      X-inactivation.
    gene:
      preferred_term: NDUFA1
      term:
        id: hgnc:7683
        label: NDUFA1
- member: Mitochondrial Complex I Deficiency, Nuclear Type 13
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFA2 loss destabilises the NDUFA2-NDUFS1 contact and so blocks N-module
      assembly specifically, with brain and heart bioenergetic failure.
    gene:
      preferred_term: NDUFA2
      term:
        id: hgnc:7685
        label: NDUFA2
- member: Mitochondrial Complex I Deficiency, Nuclear Type 14
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFA11 loss removes a transmembrane helix and destabilises complex I
      after assembly, additionally impairing supercomplex formation and cristae
      morphology - a stability rather than a biogenesis defect.
    gene:
      preferred_term: NDUFA11
      term:
        id: hgnc:20371
        label: NDUFA11
- member: Mitochondrial Complex I Deficiency, Nuclear Type 15
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFAF4 is an assembly factor acting on Q-module intermediates; its loss
      stalls assembly with accumulated P- and N-module intermediates and can
      present with optic nerve degeneration alongside encephalopathy.
    gene:
      preferred_term: NDUFAF4
      term:
        id: hgnc:21034
        label: NDUFAF4
- member: Mitochondrial Complex I Deficiency Nuclear Type 19
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      FOXRED1 is a late-acting assembly chaperone; its loss arrests and then
      breaks down the late assembly intermediate, producing grey-matter
      degeneration.
    gene:
      preferred_term: FOXRED1
      term:
        id: hgnc:26927
        label: FOXRED1
- member: Mitochondrial Complex I Deficiency Nuclear Type 21
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NUBPL delivers iron-sulfur clusters to the complex I peripheral arm, so
      its loss is a cofactor-delivery defect. It is distinguished clinically by
      cerebellar and deep white matter degeneration rather than the usual
      basal-ganglia-dominant pattern.
    gene:
      preferred_term: NUBPL
      term:
        id: hgnc:20278
        label: NUBPL
- member: Mitochondrial Complex I Deficiency Nuclear Type 23
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFA12 loss impairs Q-module assembly and stability and is partially
      offset by compensatory NDUFAF2 association; the phenotype spans Leigh
      syndrome to isolated optic atrophy.
    gene:
      preferred_term: NDUFA12
      term:
        id: hgnc:23987
        label: NDUFA12
- member: Mitochondrial Complex I Deficiency, Nuclear Type 24
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFB9 loss disrupts the NDUFB9-acyl carrier protein module and impairs
      respirasome oligomerization, reducing complex I amount and activity.
    gene:
      preferred_term: NDUFB9
      term:
        id: hgnc:7704
        label: NDUFB9
- member: Mitochondrial Complex I Deficiency Nuclear Type 31
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TIMMDC1 disease is caused by a deep-intronic poison-exon variant rather
      than a coding lesion, which makes it the member with a demonstrated
      antisense-oligonucleotide correction strategy.
    gene:
      preferred_term: TIMMDC1
      term:
        id: hgnc:1321
        label: TIMMDC1
- member: Mitochondrial Complex I Deficiency, Nuclear Type 32
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFB8 is depleted from the distal membrane arm through exon 4 skipping
      caused by a variant-created exonic splicing silencer, with combined
      neuronal, cardiac and skeletal muscle bioenergetic failure.
    gene:
      preferred_term: NDUFB8
      term:
        id: hgnc:7703
        label: NDUFB8
- member: Mitochondrial Complex I Deficiency, Nuclear Type 33
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFA6 loss strips NDUFAB1, NDUFA7 and NDUFA12 from the assembly
      intermediate, leaving a stalled 830 kDa intermediate and a catalytically
      inactive complex I-containing supercomplex.
    gene:
      preferred_term: NDUFA6
      term:
        id: hgnc:7690
        label: NDUFA6
- member: Mitochondrial Complex I Deficiency, Nuclear Type 34
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFAF8 partners NDUFAF5 in an early assembly module; its loss stalls
      early complex I assembly and is reported with retinal ganglion cell and
      optic nerve degeneration.
    gene:
      preferred_term: NDUFAF8
      term:
        id: hgnc:33551
        label: NDUFAF8
- member: Mitochondrial Complex I Deficiency, Nuclear Type 36
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFC2 is required for ND1 and ND2 module assembly in the membrane arm;
      its loss stalls biogenesis and abolishes complex I-containing
      supercomplexes, presenting as early-onset Leigh syndrome.
    gene:
      preferred_term: NDUFC2
      term:
        id: hgnc:7706
        label: NDUFC2
- member: Mitochondrial Complex I Deficiency, Nuclear Type 39
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NDUFB7 disease arises from a biallelic intronic variant causing aberrant
      splicing and membrane-arm destabilisation, presenting with severe
      congenital lactic acidosis and hypertrophic cardiomyopathy.
    gene:
      preferred_term: NDUFB7
      term:
        id: hgnc:7702
        label: NDUFB7
- member: Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The only member whose lesion is one of repair rather than construction:
      DNAJC30 is a chaperone that exchanges oxidatively damaged complex I
      N-module subunits after the holoenzyme has been built. It is also the
      only member with a tissue-restricted adult-onset optic neuropathy as its
      usual presentation, incomplete penetrance with male predominance, and
      idebenone responsivity - although a minority of carriers of the same
      p.Tyr51Cys founder allele present instead with Leigh syndrome.
    gene:
      preferred_term: DNAJC30
      term:
        id: hgnc:16410
        label: DNAJC30