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The genetic basis of isolated mitochondrial complex II deficiency

Lookup NU author(s): Millie Fullerton, Professor Bobby McFarlandORCiD, Professor Robert Taylor, Dr Charlotte Alston



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020 The AuthorsMitochondrial complex II (succinate:ubiquinone oxidoreductase) is the smallest complex of the oxidative phosphorylation system, a tetramer of just 140 kDa. Despite its diminutive size, it is a key complex in two coupled metabolic pathways - it oxidises succinate to fumarate in the tricarboxylic acid cycle and the electrons are used to reduce FAD to FADH2, ultimately reducing ubiquinone to ubiquinol in the respiratory chain. The biogenesis and assembly of complex II is facilitated by four ancillary proteins, all of which are autosomally-encoded. Numerous pathogenic defects have been reported which describe two broad clinical manifestations, either susceptibility to cancer in the case of single, heterozygous germline variants, or a mitochondrial disease presentation, almost exclusively due to bi-allelic recessive variants and associated with an isolated complex II deficiency. Here we present a compendium of pathogenic gene variants that have been documented in the literature in patients with an isolated mitochondrial complex II deficiency. To date, 61 patients are described, harbouring 32 different pathogenic variants in four distinct complex II genes: three structural subunit genes (SDHA, SDHB and SDHD) and one assembly factor gene (SDHAF1). Many pathogenic variants result in a null allele due to nonsense, frameshift or splicing defects however, the missense variants that do occur tend to induce substitutions at highly conserved residues in regions of the proteins that are critical for binding to other subunits or substrates. There is phenotypic heterogeneity associated with defects in each complex II gene, similar to other mitochondrial diseases.

Publication metadata

Author(s): Fullerton M, McFarland R, Taylor RW, Alston CL

Publication type: Review

Publication status: Published

Journal: Molecular Genetics and Metabolism

Year: 2020

Volume: 131

Issue: 1-2

Pages: 53-65

Print publication date: 01/09/2020

Online publication date: 03/10/2020

Acceptance date: 30/09/2020

ISSN (print): 1096-7192

ISSN (electronic): 1096-7206

Publisher: Academic Press Inc.


DOI: 10.1016/j.ymgme.2020.09.009

PubMed id: 33162331