Complex II deficiency

Douglas J Lanska MD FAAN MS MSPH (Dr. Lanska of the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated January 28, 2017; expires January 28, 2020

This article includes discussion of complex II deficiency, succinate cytochrome C reductase deficiency, succinate ubiquinone oxidoreductase deficiency, and succinate dehydrogenase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Historical note and terminology

The electron transport chain, located in the inner mitochondrial membrane, is the site of oxidative phosphorylation, the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy that is used to reform adenosine triphosphate (ATP).

Image: Electron transport chain
In this pathway, the NADH and succinate generated in the Krebs citric acid cycle are oxidized, releasing energy to power ATP synthase.

Within mitochondria, complex II links the 2 key cellular energy-conversion pathways: complex II serves as succinate dehydrogenase (SDH) in the Krebs cycle, and as succinate ubiquinone oxidoreductase, 1 of 5 complexes of the mitochondrial oxidative phosphorylation system. In particular, complex II couples the oxidation of succinate to fumarate in the citric acid cycle with the reduction of ubiquinone (coenzyme Q) to ubiquinol in the electron transport chain.

Complex II is a heterotetramer (ie, is protein containing 4 noncovalently bound subunits, wherein the subunits are not all identical) with 4 dissimilar subunits: SdhA, SdhB, SdhC, and SdhD.

Image: 3D schematic representation of complex II
Two of these subunits are hydrophilic (SdhA and SdhB) and 2 are hydrophobic membrane anchor subunits (SdhC and SdhD). SdhA contains a covalently attached flavin adenine dinucleotide (FAD) cofactor and the succinate binding site. Human mitochondria contain 2 distinct isoforms of SdhA (Fp subunits type I and type II). SdhB contains 3 iron-sulfur clusters: [2Fe-2S], [4Fe-4S], and [3Fe-4S].

The subunits form a membrane-bound cytochrome b complex with 6 transmembrane helices containing 1 heme b group and a ubiquinone-binding site.

Image: Schematic diagram of complex II
Image: Structural model of complex II
Two phospholipid molecules, 1 cardiolipin and 1 phosphatidylethanolamine, are also found in the SdhC and SdhD subunits in the hydrophobic space below the heme b.

Although all of the elements of the respiratory chain function in the mitochondria, many of the subunits are encoded genetically in the nucleus and imported into the mitochondria. Complex II is made of 4 subunits (A, B, C, D), all of which are autosomally encoded (ie, encoded in the nucleus) by the succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC, and SDHD). Other factors and cofactors needed for complex II activity are riboflavin, iron, cytochrome b560, and ubiquinone (coenzyme Q). Complex II activity is often measured together with complex III activity as succinate cytochrome C reductase activity.

Isolated complex II deficiency was first inferred in 2 siblings with mental retardation, seizures, myoclonus, and ataxia (Riggs et al 1984). Since that report a variety of other phenotypes have been reported, including Leigh disease (Martin et al 1988; Burgeois et al 1992), leukodystrophy (Alsto et al 2012; Ohlenbusch et al 2012), encephalomyopathy (Jackson et al 2014), Kearns-Sayre syndrome and other mitochondrial myopathies (Rivner et al 1989; Sonam et al 2014), rhabdomyolysis and hemolytic uremic syndrome (Micheletti et al 2011), cardiomyopathy with variable associated neurologic manifestations (psychiatric abnormalities, optic atrophy, oculomotor abnormalities, progressive polyneuropathy) (Angelini et al 1993; Sonam et al 2014; Alston et al 2015; Courage et al 2017), and late-onset progressive neurodegeneration (Taylor et al 1996). In persons of northern Swedish descent, a myopathic phenotype due to a combination of complex II, complex III, and aconitase deficiencies has been described (Hall et al 1993). Complex II (alone or in combination with other elements of the mitochondrial oxidative phosphorylation system) has also been reported to be abnormal in many neurodegenerative disorders, but these biochemical findings are most likely secondary events.

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