**Quynh-Chi L. Dang, Duong H. Phan, Abigail N. Johnson, Mukund Pasapuleti, Hind A. Alkhaldi, Fang Zhang and Steven B. Vik \***

Department of Biological Sciences, Southern Methodist University, Dallas, TX 75287, USA; quynhchid@smu.edu (Q.-C.L.D.); lisap@smu.edu (D.H.P.); abbyjohnson@smu.edu (A.N.J.); mpasapuleti@smu.edu (M.P.); halkhaldi@smu.edu (H.A.A.); fangz@smu.edu (F.Z.)

**\*** Correspondence: svik@smu.edu

Received: 30 October 2020; Accepted: 16 November 2020; Published: 20 November 2020

**Abstract:** Complex I is the largest member of the electron transport chain in human mitochondria. It comprises 45 subunits and requires at least 15 assembly factors. The subunits can be divided into 14 "core" subunits that carry out oxidation–reduction reactions and proton translocation, as well as 31 additional supernumerary (or accessory) subunits whose functions are less well known. Diminished levels of complex I activity are seen in many mitochondrial disease states. This review seeks to tabulate mutations in the supernumerary subunits of humans that appear to cause disease. Mutations in 20 of the supernumerary subunits have been identified. The mutations were analyzed in light of the tertiary and quaternary structure of human complex I (PDB id = 5xtd). Mutations were found that might disrupt the folding of that subunit or that would weaken binding to another subunit. In some cases, it appeared that no protein was made or, at least, could not be detected. A very common outcome is the lack of assembly of complex I when supernumerary subunits are mutated or missing. We suggest that poor assembly is the result of disrupting the large network of subunit interactions that the supernumerary subunits typically engage in.

**Keywords:** mitochondria; mammalian complex I; NADH dehydrogenase; complex I assembly; complex I structure; complex I deficiency; supernumerary subunits; electron transport chain; mitochondrial dysfunction; Leigh syndrome
