Electron-transfer flavoprotein (ETF) system — electron sink for mitochondrial FAD dehydrogenases

The electron-transfer flavoprotein (ETF) system is the shared electron-relay that couples a large set of mitochondrial matrix FAD-dependent dehydrogenases to the respiratory chain. At least a dozen matrix flavoenzymes — the acyl-CoA dehydrogenases of fatty-acid beta-oxidation (ACADVL, ACADM, ACADS, ACAD9, etc.), the branched-chain and other acyl-CoA dehydrogenases of amino-acid catabolism (IVD, GCDH, etc.), sarcosine and dimethylglycine dehydrogenases, and others — do not pass their electrons directly to the respiratory chain. Instead they reduce a common, soluble matrix heterodimeric flavoprotein, ETF (the ETFA alpha subunit, which carries the FAD, plus the ETFB beta subunit, which carries AMP and provides the docking surface for the partner dehydrogenases). Reduced ETF then diffuses to the inner-membrane iron-sulfur flavoprotein ETF-ubiquinone oxidoreductase (ETFDH / ETF-QO), which reoxidises ETF and transfers the electrons to ubiquinone (CoQ) in the respiratory chain, linking these oxidations to oxidative phosphorylation. Because ETF/ETFDH is the common electron sink for so many dehydrogenases, its inherited deficiency (ETFA, ETFB or ETFDH) causes multiple acyl-CoA dehydrogenase deficiency (MADD / glutaric acidemia type 2), a severe fatty-acid-oxidation and amino-acid-oxidation disorder; the ETFDH form is frequently riboflavin-responsive and can present as a myopathy with secondary coenzyme-Q10 deficiency.

MODULE:electron_transfer_flavoprotein_systemDRAFTMetabolic Pathwaymodules/electron_transfer_flavoprotein_system.yaml
respiratory electron transport chainGO:0022904
GO:0045251
electron transfer flavoprotein complex
The soluble electron acceptor is grounded in the GO electron transfer flavoprotein complex (GO:0045251, the ETFA/ETFB heterodimer).
Reactome:R-HSA-169270
ETFDH oxidises ETF (reduced) to ETF, reduces CoQ to CoQH2
The relay follows the human Reactome reactions R-HSA-169260 (acyl-CoA dehydrogenases reduce ETF) and R-HSA-169270 (ETFDH reoxidises ETF and reduces ubiquinone), feeding respiratory electron transport (R-HSA-611105).
file:human/ETFA/ETFA-ai-review.yaml
ETFA gene review (human)
The ETF alpha-subunit grounding (UniProtKB:P13804, GO:0009055 electron transfer activity, FAD binding, GO:0045251 complex) matches the completed human ETFA review.
file:human/ETFB/ETFB-ai-review.yaml
ETFB gene review (human)
The ETF beta-subunit grounding (UniProtKB:P38117, GO:0009055, GO:0045251 complex) matches the completed human ETFB review.
file:human/ETFDH/ETFDH-ai-review.yaml
ETFDH gene review (human)
The ETF-ubiquinone oxidoreductase grounding (UniProtKB:Q16134, GO:0004174 electron-transferring-flavoprotein dehydrogenase activity, inner membrane) matches the completed human ETFDH review.
3Nodes
2Parts
0Variant Sets
0Variants
3Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:electron_transfer_flavoprotein_system deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (3/3 grounded genes reviewed)

3 complete review(s) · 0 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
ETFA P13804 ✓ ✓ ✗
ETFB P38117 ✓ ✓ ✗
ETFDH Q16134 ✓ ✓ ✗

Details

Context
mitochondrial matrixGO:0005759 mitochondrial inner membraneGO:0005743
Electron-transfer flavoprotein (ETF) systemMetabolic Pathwayelectron_transfer_flavoprotein_system
respiratory electron transport chainGO:0022904
Context
mitochondrial matrixGO:0005759 mitochondrial inner membraneGO:0005743

The electron-transfer flavoprotein system grounded to the human proteins ETFA (UniProtKB:P13804, GO:0009055, FAD-bearing alpha subunit) and ETFB (P38117, GO:0009055, AMP-binding beta subunit) forming the ETF heterodimer (GO:0045251), and ETFDH (Q16134, GO:0004174, EC 1.5.5.1) the inner-membrane ETF-ubiquinone oxidoreductase. GO molecular-function/cellular-component terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over paralogs and orthologs) plus a concrete human representative member; the ETF heterodimer is modelled as a PROTEIN_COMPLEX node. Upstream, the electron donors are the many matrix FAD-dependent acyl-CoA dehydrogenases (of fatty-acid beta-oxidation — see the fatty_acid_beta_oxidation and carnitine_shuttle modules — and of amino-acid catabolism, e.g. IVD in the leucine_catabolism module and GCDH); downstream, ubiquinol feeds respiratory complex III (GO:0022904). Combined deficiency of any component causes multiple acyl-CoA dehydrogenase deficiency (MADD / glutaric acidemia type 2).

Connections

etf_reduction_step -> etfdh_step Provides Input For
Reduced ETF produced when the matrix dehydrogenases transfer electrons to the ETFA/ETFB heterodimer is the substrate reoxidised by ETFDH, which then reduces ubiquinone.
Part 1: common electron acceptor for matrix FAD dehydrogenases
acyl-CoA dehydrogenases reduce the ETF (ETFA/ETFB) flavoproteinProtein Complexetf_reduction_step

Annotons

ETFA: electron transfer flavoprotein alpha (FAD-bearing)
etfa_activity
Participant: Family: Electron transfer flavoprotein alpha-subunit family (ETFA)
Family:
Electron transfer flavoprotein alpha-subunit family (ETFA)PANTHER:PTHR43153
Representative Members: ETFA (human)UniProtKB:P13804

Function

electron transfer activityGO:0009055
Substrates: reduced acyl-CoA dehydrogenase (electron donor) FAD (prosthetic group)
Products: reduced ETF (ETFH2 / ETF semiquinone)

Locations

mitochondrial matrixGO:0005759

FAD-bearing alpha subunit of the ETF heterodimer; its FAD is the redox centre reduced by the partner acyl-CoA dehydrogenases. Deficiency causes MADD / glutaric acidemia type 2 (type I).

ETFB: electron transfer flavoprotein beta (dehydrogenase docking)
etfb_activity
Participant: Family: Electron transfer flavoprotein beta-subunit family (ETFB)
Family:
Electron transfer flavoprotein beta-subunit family (ETFB)PANTHER:PTHR21294
Representative Members: ETFB (human)UniProtKB:P38117

Function

electron transfer activityGO:0009055
Substrates: reduced acyl-CoA dehydrogenase (electron donor)
Products: reduced ETF

Locations

mitochondrial matrixGO:0005759

Beta subunit of the ETF heterodimer; binds AMP and provides the recognition/docking surface for the many partner dehydrogenases. Deficiency causes MADD / glutaric acidemia type 2 (type II).

Part 2: reoxidation of ETF and electron transfer to ubiquinone
reduced ETF + ubiquinone to oxidised ETF + ubiquinolReactionetfdh_step

Annotons

ETFDH/ETF-QO: electron transfer flavoprotein-ubiquinone oxidoreductase
etfdh_activity
Participant: Family: Electron transfer flavoprotein-ubiquinone oxidoreductase family (ETFDH)
Family:
Electron transfer flavoprotein-ubiquinone oxidoreductase family (ETFDH)PANTHER:PTHR10617
Representative Members: ETFDH (human)UniProtKB:Q16134

Function

electron-transferring-flavoprotein dehydrogenase activityGO:0004174
Substrates: reduced electron-transfer flavoprotein ubiquinone (CoQ) FAD and [4Fe-4S] (prosthetic groups)
Products: oxidised electron-transfer flavoprotein ubiquinol (CoQH2)

Locations

mitochondrial inner membraneGO:0005743

Inner-membrane FAD + [4Fe-4S] flavoprotein that reoxidises reduced ETF and delivers the electrons to ubiquinone, linking the many matrix FAD dehydrogenases to the respiratory chain. Deficiency causes MADD / glutaric acidemia type 2 (type III), often riboflavin- responsive, with secondary CoQ10 deficiency.