Complex I function and supercomplex formation are preserved in liver mitochondria despite progressive complex III deficiency.
Functional oxidative phosphorylation requires appropriately assembled mitochondrial respiratory complexes and their supercomplexes formed mainly of complexes I, III and IV. BCS1L is the chaperone needed to incorporate the catalytic subunit, Rieske iron-sulfur protein, into complex III at the final stage of its assembly. In cell culture studies, this subunit has been considered necessary for supercomplex formation and for maintaining the stability of complex I. Our aim was to assess the importance of fully assembled complex III for supercomplex formation in intact liver tissue. We used our transgenic mouse model with a homozygous c.232A>G mutation in Bcs1l leading to decreased expression of BCS1L and progressive decrease of Rieske iron-sulfur protein in complex III, resulting in hepatopathy. We studied supercomplex formation at different ages using blue native gel electrophoresis and complex activity using high-resolution respirometry. In isolated liver mitochondria of young and healthy homozygous mutant mice, we found similar supercomplexes as in wild type. In homozygotes aged 27-29 days with liver disorder, complex III was predominantly a pre-complex lacking Rieske iron-sulfur protein. However, the main supercomplex was clearly detected and contained complex III mainly in the pre-complex form. Oxygen consumption of complex IV was similar and that of complex I was twofold compared with controls. These complexes in free form were more abundant in homozygotes than in controls, and the mRNA of complex I subunits were upregulated. In conclusion, when complex III assembly is deficient, the pre-complex without Rieske iron-sulfur protein can participate with available fully assembled complex III in supercomplex formation, complex I function is preserved, and respiratory chain stability is maintained.
Department of Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
Mina
M
Davoudi
Department of Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
Heike
H
Kotarsky
Department of Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
Eva
E
Hansson
Department of Pediatrics, Clinical Sciences, Lund University, Lund, Sweden ; Folkhälsan Research Center, Helsinki, Finland ; Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Vineta
V
Fellman
D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D015153:Blotting, Western; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology
C518901:BCS1L protein, mouse; D018832:Molecular Chaperones; C037989:Rieske iron-sulfur protein; D000074183:ATPases Associated with Diverse Cellular Activities; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III