NDUFS4

NDUFS4 (NADH dehydrogenase [ubiquinone] iron-sulfur protein 4) is an 18 kDa accessory (supernumerary) subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase). It is not a catalytic core subunit but plays a critical structural and regulatory role, acting as a rivet that anchors the N-module to the Q-module at the matrix-facing side of the enzyme. NDUFS4 is essential for the late-stage maturation of Complex I, where its incorporation (together with NDUFS6 and NDUFA12) displaces the assembly factor NDUFAF2 to yield the fully assembled, catalytically competent enzyme. Loss of NDUFS4 leads to destabilization and partial loss of the N-module, substantially reduced NADH:ubiquinone oxidoreductase activity, and is the most common nuclear-encoded Complex I gene cause of Leigh syndrome (MC1DN1). NDUFS4 also contains a PKA phosphorylation site at Ser-173 (Ser-131 in the mature form), through which cAMP signaling can regulate Complex I activity. The protein is a component of the iron-sulfur fragment of Complex I, localized to the mitochondrial inner membrane on the matrix side.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

• complex_i_deficiency via Mitochondrial Complex I Deficiency, Nuclear Type 1