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Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I

Formosa, Luke E., Mimaki, Masakazu, Frazier, Ann E., McKenzie, Matthew, Stait, Tegan L., Thorburn, David R., Stroud, David A. and Ryan, Michael T. 2015, Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I, Human molecular genetics, vol. 24, no. 10, pp. 2952-2965, doi: 10.1093/hmg/ddv058.

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Title Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I
Author(s) Formosa, Luke E.
Mimaki, Masakazu
Frazier, Ann E.
McKenzie, MatthewORCID iD for McKenzie, Matthew orcid.org/0000-0001-7508-1800
Stait, Tegan L.
Thorburn, David R.
Stroud, David A.
Ryan, Michael T.
Journal name Human molecular genetics
Volume number 24
Issue number 10
Start page 2952
End page 2965
Total pages 14
Publisher Oxford University Press
Place of publication Oxford, Eng.
Publication date 2015-05
ISSN 1460-2083
Keyword(s) Electron Transport Complex I
HEK293 Cells
Humans
Mitochondria
Mitochondrial Proteins
Molecular Chaperones
Mutation
Protein Multimerization
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
BOVINE HEART-MITOCHONDRIA
ELECTRON-TRANSPORT CHAIN
ENCODED SUBUNITS
OXIDATIVE-PHOSPHORYLATION
MOLECULAR CHAPERONE
HIGH-THROUGHPUT
DISEASE
DEFICIENCY
MUTATIONS
MEMBRANE
Summary Human mitochondrial complex I is the largest enzyme of the respiratory chain and is composed of 44 different subunits. Complex I subunits are encoded by both nuclear and mitochondrial (mt) DNA and their assembly requires a number of additional proteins. FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1) was recently identified as a putative assembly factor and FOXRED1 mutations in patients cause complex I deficiency; however, its role in assembly is unknown. Here, we demonstrate that FOXRED1 is involved in mid-late stages of complex I assembly. In a patient with FOXRED1 mutations, the levels of mature complex I were markedly decreased, and a smaller ∼475 kDa subcomplex was detected. In the absence of FOXRED1, mtDNA-encoded complex I subunits are still translated and transiently assembled into a late stage ∼815 kDa intermediate; but instead of transitioning further to the mature complex I, the intermediate breaks down to an ∼475 kDa complex. As the patient cells contained residual assembled complex I, we disrupted the FOXRED1 gene in HEK293T cells through TALEN-mediated gene editing. Cells lacking FOXRED1 had ∼10% complex I levels, reduced complex I activity, and were unable to grow on galactose media. Interestingly, overexpression of FOXRED1 containing the patient mutations was able to rescue complex I assembly. In addition, FOXRED1 was found to co-immunoprecipitate with a number of complex I subunits. Our studies reveal that FOXRED1 is a crucial component in the productive assembly of complex I and that mutations in FOXRED1 leading to partial loss of function cause defects in complex I biogenesis.
Language eng
DOI 10.1093/hmg/ddv058
Field of Research 06 Biological Sciences
11 Medical And Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, The Author
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30112237

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.