Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

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Electron transfer flavoprotein (ETF) is an enzyme with orthologs from bacteria to humans. Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. ETF functions as a hub taking up electrons from at least 14 flavoenzymes, feeding them into the respiratory chain. This represents a major source of reducing power for the electron transport chain from fatty acid oxidation and amino acid degradation. Transfer of electrons from the donor enzymes to ETF occurs by direct transfer between the enzyme bound flavins, a process that is tightly regulated by the polypeptide chain and by protein:protein interactions. ETF, in turn relays electrons to the iron sulfur cluster of the inner membrane protein ETF:QO, from where they travel via the FAD in ETF:QO to ubiquinone, entering the respiratory chain at the level of complex III. ETF recognizes its dehydrogenase partners via a recognition loop that anchors the protein on its partner followed by dynamic movements of the ETF flavin domain that bring redox cofactors in close proximity, thus promoting electron transfer. Genetic mutations in the ETFA or ETFB genes cause the Mendelian disorder multiple acyl-CoA dehydrogenase deficiency (MADD; OMIM #231680). We here review the knowledge on human ETF and investigations of the effects of disease-associated missense mutations in this protein that have promoted the understanding of the essential role that ETF plays in cellular metabolism and human disease.

StatusUdgivet - 15 apr. 2021

Bibliografisk note

Funding Information:
This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series - a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE.

Funding Information:
This research was supported by the Fundação para a Ciência e Tecnologia (FCT/MCTES, Portugal) through grants PTDC/BBB-BQB/5366/2014 and PTDC/BIA-BQM/29963/2017 (to B.J.H.) and centre grants UIDB/ 04046/2020 and UIDP/04046/2020 (to BioISI), the Aarhus County Research Initiative and the Danish Council of Independent Medical Research (4004-00548 to R.K.J.O.), the Department of Clinical Medicine, Aarhus University, and Department of Clinical Biochemistry Aarhus University Hospital.

Publisher Copyright:
© 2021 Elsevier B.V.

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