A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
Purhonen, J., Grigorjev, V., Ekiert, R., Aho, N., Rajendran, J., Pietras, R., Truvé, K., Wikström, M., Sharma, V., Osyczka, A., Fellman, V., & Kallijärvi, J. (2020). A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. Nature Communications, 11, Article 322. https://doi.org/10.1038/s41467-019-14201-2
Published in
Nature CommunicationsAuthors
Date
2020Copyright
© 2020 the Author(s)
We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1lp.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cybp.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 Bcs1lp.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 bc1 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.
...
![showless](/themes/JYX2//images/showless.png)
![showmore](/themes/JYX2//images/showmore.png)
Publisher
Nature Publishing GroupISSN Search the Publication Forum
2041-1723Keywords
Publication in research information system
https://converis.jyu.fi/converis/portal/detail/Publication/34183360
Metadata
Show full item recordCollections
Related funder(s)
Research Council of FinlandFunding program(s)
Academy Project, AoFAdditional information about funding
This study was supported by grants from Academy of Finland (grant 259296 to V.F., grant 294652 to V.S., grant 311031 to N.A.), Swedish Research Council (grant 521-2011-3877 to V.F.), Finnish Physicians’ Society (to V.F.), Foundation for Pediatric Research in Finland (to V.F.), Folkhälsan Research Center (to V.F. and J.K.), Magnus Ehrnrooth Foundation (to V.F. and V.S.), University of Helsinki (to V.S.), Sigrid Jusélius Foundation (to V.S.), and National Science Centre, Poland (Maestro grant 2015/18/A/NZ1/00046 to A.O.).![showless](/themes/JYX2//images/showless.png)
![showmore](/themes/JYX2//images/showmore.png)
License
Related items
Showing items with similar title or keywords.
-
Rats with elevated genetic risk for metabolic syndrome exhibit cognitive deficiencies when young
Wikgren, Jan; Nokia, Miriam S.; Mäkinen, Elina; Koch, Lauren G.; Britton, Steven L.; Kainulainen, Heikki; Lensu, Sanna (Elsevier, 2021)Metabolic syndrome (MetS) is a known risk factor for cognitive decline. Using polygenic rat models selectively bred for high and low intrinsic exercise capacity and simultaneously modelling as low and high innate risk ... -
Interactive effects of aging and aerobic capacity on energy metabolism–related metabolites of serum, skeletal muscle, and white adipose tissue
Zhuang, Haihui; Karvinen, Sira; Törmäkangas, Timo; Zhang, Xiaobo; Ojanen, Xiaowei; Velagapudi, Vidya; Alen, Markku; Britton, Steven L.; Koch, Lauren G.; Kainulainen, Heikki; Cheng, Sulin; Wiklund, Petri (Springer, 2021)Aerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, ... -
Exercise and Metformin Intervention Prevents Lipotoxicity-Induced Hepatocyte Apoptosis by Alleviating Oxidative and ER Stress and Activating the AMPK/Nrf2/HO-1 Signaling Pathway in db/db Mice
Zhang, Yuan; Liu, Yuting; Liu, Xiaowei; Yuan, Xinmeng; Xiang, Mengqi; Liu, Jingjing; Zhang, Liumei; Zhu, Shouqian; Lu, Jiao; Tang, Qiang; Cheng, Sulin (Hindawi Limited, 2022)Objective. Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise ... -
Deviance detection in sound frequency in simple and complex sounds in urethane-anesthetized rats
Yang, Tiantian; Hämäläinen, Jarmo; Lohvansuu, Kaisa; Lipponen, Arto; Penttonen, Markku; Astikainen, Piia (Elsevier, 2021)Mismatch negativity (MMN), which is an electrophysiological response demonstrated in humans and animals, reflects memory-based deviance detection in a series of sounds. However, only a few studies on rodents have used ... -
Body composition and molecular reflections of obesity-related cardio-metabolic disorders : a cross-sectional and longitudinal study in women
Wiklund, Petri (University of Jyväskylä, 2016)