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A spontaneous miton...
A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
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- Purhonen, J. (author)
- University of Helsinki,Folkhälsan Research Center
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- Grigorjev, V. (author)
- Folkhälsan Research Center
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- Ekiert, R. (author)
- Jagiellonian University
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- Aho, N. (author)
- University of Jyväskylä,Helsinki University of Technology
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- Rajendran, J. (author)
- Folkhälsan Research Center,University of Helsinki
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- Pietras, R. (author)
- Jagiellonian University
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- Truvé, Katarina (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine,Sahlgrenska Academy
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- Wikstrom, M. (author)
- University of Helsinki
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- Sharma, V. (author)
- University of Helsinki,Helsinki University of Technology
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- Osyczka, A. (author)
- Jagiellonian University
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- Fellman, Vineta (author)
- Lund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Helsinki University Children's Hospital,University of Helsinki,Folkhälsan Research Center
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- Kallijärvi, Jukka (author)
- University of Helsinki,Folkhälsan Research Center
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(creator_code:org_t)
- 2020-01-16
- 2020
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Abstract
Subject headings
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- We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1/(p.S78G) mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cyb(p.D254N)), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1/(p.S78G) tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dynamics. In Rhodobacter cytochrome bc(1) complex the equivalent substitution causes a kinetics defect with longer occupancy of RISP head domain towards the quinol oxidation site. These findings represent a unique case of spontaneous mitonuclear epistasis and highlight the role of mtDNA variation as modifier of mitochondrial disease phenotypes.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- iron-sulfur protein
- cytochrome bc(1) complex
- gui membrane-builder
- respiratory-chain
- crystal-structure
- gracile syndrome
- mutations
- generation
- dynamics
- disease
- Science & Technology - Other Topics
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Purhonen, J.
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Grigorjev, V.
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Ekiert, R.
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Aho, N.
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Rajendran, J.
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Pietras, R.
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show more...
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Truvé, Katarina
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Wikstrom, M.
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Sharma, V.
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Osyczka, A.
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Fellman, Vineta
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Kallijärvi, Jukk ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Nature Communica ...
- By the university
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University of Gothenburg
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Lund University