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FB2026_01
,
released March 12, 2026
This report describes :mitochondrial complex II deficiency, nuclear type 1 (MC2DN1); MC2DN1 exhibits autosomal recessive inheritance. The human gene implicated in this disease is SDHA, a subunit of mitochondrial complex II. Mitochondrial complex II, also known as succinate:ubiquinone oxidoreductase or succinate dehydrogenase, participates in both the citric acid cycle and the electron transport chain. It is formed from four subunits: catalytic subunits SDHA and SDHB, and anchoring subunits SDHC and SDHD. Multiple patients with SDHA mutations have been identified and diagnosed with mitochondrial complex II deficiency.
The fly orthologs of both SDH catalytic subunits have been studied in the context of disease: Dmel\SdhA, which is ortholgous to SDHA (this report) and Dmel\SdhB, which is orthologous to SDHB (see FBhh0001364). For SdhA, loss-of-function alleles and RNAi targeting constructs have been generated.
The human SDHA gene has not been introduced into flies.
Dmel\SdhA mutants die as first instar larvae. Treatment with rapamycin, which generally increases SDH enzymatic activity and decreases the production of reactive oxygen species (ROS), doubles the lifespan of larvae but does affect hydrogen peroxide production in third instar larvae.
[updated Jun. 2021 by FlyBase; FBrf0222196]
Mitochondrial complex II deficiency is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, and muscle with onset in infancy, whereas others have only isolated cardiac or muscle involvement. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013; pubmed:23322652). [from MIM:252011; 2021.06.15]
[MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1; MC2DN1](https://omim.org/entry/252011)
[SUCCINATE DEHYDROGENASE COMPLEX, FLAVOPROTEIN SUBUNIT A; SDHA](https://omim.org/entry/600857)
SDH is composed of four subunits (A, B, C and D), which, in contrast with other respiratory chain complexes, are nucleus-encoded and inherited in an autosomal fashion. (Fan et al. 2019, FBrf0241558.)
Mitochondrial complex II deficiency nuclear type 1 (MC2DN1) is caused by homozygous or compound heterozygous mutation in the SDHA gene. [from MIM:252011; 2021.06.15]
BN-PAGE analysis using enriched skeletal muscle mitochondria from a patient carrying a novel homozygous mutation c.143A>T (p.Asp48Val) in SDHB showed a relative lower amount of fully assembled complex II compared with complex I. SDS-PAGE analysis demonstrated an almost complete absence of the SDHB subunit compared to both control samples and mitochondrial loading controls. In addition, expression of the SDHA subunit of complex II also appeared to be decreased, suggesting instability of the assembled complex. (Alston et al. 2012, pubmed:22972948.)
The SDH genes encode subunits of the heterotetrameric succinate dehydrogenase complex, a component of both the mitochondrial-respiratory chain (complex II) and the Krebs cycle. SDHA and SDHB encode the two catalytic subunits, the flavoprotein and the iron-sulfur protein respectively; SDHC and SDHD encode transmembrane proteins that anchor complex II in the inner mitochondrial membrane, and contain a ubiquinone binding site. (Bayley et al. 2005, pubmed:16288654.)
The striking differences observed among phenotypes associated with SDH deficiency might originate from SDH's position at the intersection of key pathways in energy production: the citric acid cycle and the electron transport chain. SDH performs this dual role located in the inner mitochondrial membrane where it oxidizes succinate into fumarate in the citric acid cycle and it reduces ubiquinone in the process of oxidative phosphorylation as complex II of the electron transport chain. Therefore, defects in its operation will affect the homeostatic nature of metabolic networks and a complex organelle-systemic response. (Fan et al. 2019 and references therein, FBrf0241558.)
1 to 1: one human gene to one Drosophila gene.
One to one: human gene to one Drosophila gene.
High-scoring ortholog of human SDHA. There is another moderately-scoring ortholog in flies, SdhAL, but it is expressed exclusively in testis.