**Accessory Subunits of the Matrix Arm of Mitochondrial Complex I with a Focus on Subunit NDUFS4 and Its Role in Complex I Function and Assembly**

**Flora Kahlhöfer 1,2,3 , Max Gansen 1,2 and Volker Zickermann 1,2, \***


**Abstract:** NADH:ubiquinone-oxidoreductase (complex I) is the largest membrane protein complex of the respiratory chain. Complex I couples electron transfer to vectorial proton translocation across the inner mitochondrial membrane. The L shaped structure of complex I is divided into a membrane arm and a matrix arm. Fourteen central subunits are conserved throughout species, while some 30 accessory subunits are typically found in eukaryotes. Complex I dysfunction is associated with mutations in the nuclear and mitochondrial genome, resulting in a broad spectrum of neuromuscular and neurodegenerative diseases. Accessory subunit NDUFS4 in the matrix arm is a hot spot for mutations causing Leigh or Leigh-like syndrome. In this review, we focus on accessory subunits of the matrix arm and discuss recent reports on the function of accessory subunit NDUFS4 and its interplay with NDUFS6, NDUFA12, and assembly factor NDUFAF2 in complex I assembly.

**Keywords:** mitochondrial disease; Leigh syndrome; NADH dehydrogenase; respiratory chain; oxidative phosphorylation; assembly factor
