title: COX7A2L/SCAFI and Pre-Complex III Modify Respiratory Chain Supercomplex Formation in Different Mouse Strains with a Bcs1l Mutation.
abstract: The COX7A2L (Supercomplex Assembly Factor I, SCAFI) protein has been proposed to be a mitochondrial supercomplex assembly factor required for respirasome (supercomplex containing complexes I, III, and IV) formation. In the C57BL/6 mouse strain a homozygous in-frame 6-base-pair deletion in the COX7a2l/SCAF1 gene resulting in unstable protein and suggesting loss of function was previously identified. The loss of SCAFI was shown to impede respirasome formation, a major concern for the use of C57BL mouse strains in mitochondrial research. In contradiction, another recent study suggested that supercomplex formation is independent of SCAFI isoforms. We investigated whether SCAFI isoform status affected the disease severity and supercomplex formation in the liver of Bcs1lc.232A>G knock-in mice with incomplete complex III assembly. In homozygotes (Bcs1lG/G) of mixed (C57BL/6:129/Sv) genetic background, the lifespan was similar in mice with wild-type SCAFI allele and in those homozygous (SCAFIshort/short) for the deleted SCAF1 variant (34±3 days; n = 6 vs. 32±2 days; n = 7, respectively). SCAFI heterozygosity (SCAFIlong/short) resulted in decreased SCAFI protein but respirasome assembly was unaffected. Congenic (C57BL/6) mice were of the genotype SCAFIshort/short and had no detectable SCAFI protein. In their liver mitochondria, respirasome composition was altered as compared to mixed background mice. Complex IV was mainly present as monomers and dimers, and only low amounts were found in combination with complex I and complex III or with precomplex III. The main supercomplex in the liver mitochondria of C57BL/6 mice comprised only complexes I and III. In conclusion, in liver mitochondria of C57BL/6 mice, supercomplexes had markedly reduced amount of, but were not completely depleted of, complex IV, supporting a role for COX7A2L/SCAFI in supercomplex assembly. However, the disease progression of the Bcs1l mutant mice was unrelated to SCAFI isoforms and supercomplex composition, suggesting that other genetic factors contribute to the different survival in the different genetic backgrounds.
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.
authors.forename: Mina
authors.initials: M
authors.lastname: Davoudi
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.
authors.forename: Heike
authors.initials: H
authors.lastname: Kotarsky
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hansson
authors.affiliation: Folkhälsan Research Center, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Kallijärvi
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.|Folkhälsan Research Center, Helsinki, Finland.|Children's Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Vineta
authors.identifier: http://orcid.org/0000-0002-1355-5633
authors.initials: V
authors.lastname: Fellman
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
chemical_list: C518901:BCS1L protein, mouse; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D003576:Electron Transport Complex IV; D000074183:ATPases Associated with Diverse Cellular Activities; D014450:Electron Transport Complex III