A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice.,Nature Communications

当前位置： X-MOL 学术 › Nat. Commun. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-16 , DOI: 10.1038/s41467-019-14201-2
Janne Purhonen _{1,

2} , Vladislav Grigorjev ₁ , Robert Ekiert ₃ , Noora Aho _{4,

5} , Jayasimman Rajendran _{1,

2} , Rafał Pietras ₃ , Katarina Truvé ₆ , Mårten Wikström ₇ , Vivek Sharma _{4,

7} , Artur Osyczka ₃ , Vineta Fellman _{1,

2,

8,

9} , Jukka Kallijärvi _{1,

2}

Affiliation

Folkhälsan Institute of Genetics, Folkhälsan Research Center, P.O. Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland.
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Molecular Biophysics, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387, Kraków, Poland.
Department of Physics, University of Helsinki, P.O. Box 64 (Gustaf Hällströmin katu 2), FI-00014, Helsinki, Finland.
Department of Chemistry, University of Jyväskylä, P.O. Box 35 (Survontie 9B), FI-40014, Jyväskylä, Finland.
Sahlgrenska Academy, University of Gothenburg, P.O. Box 413 (Medicinaregatan 3), 41390, Gothenburg, Sweden.
Institute of Biotechnology, University of Helsinki, PL 56 (Viikinkaari 9), FI-00014, Helsinki, Finland.
Department of Clinical Sciences, Pediatrics, BMC F12, Lund University, 221 84, Lund, Sweden.
Children's Hospital, Helsinki University Hospital, P.O. Box 281 (Stenbäckinkatu 11), FI-00029, Helsinki, Finland.

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.

中文翻译：

聚合在Rieske Fe-S蛋白上的自发性小核上皮加重加剧了小鼠体内III型复合物的缺乏。

我们先前观察到两个同基因背景之间呼吸链复合物III（CIII）缺陷型Bcs1lp.S78G小鼠的存活存在出乎意料的五倍（35 vs. 200天）差异。在这里，我们确定了一个自发的同质性mtDNA变异体（m.G14904A，mt-Cybp.D254N），在短生存期的背景下影响了CIII亚基细胞色素b（MT-CYB）。我们利用产妇的mtDNA遗传来确认这是致病性变异，并表明它可以将Bcs1lp.S78G组织中的低CIII活性进一步降低到35天大的存活阈值以下。分子动力学模拟预测D254N会限制MT-CYB ef环的灵活性，从而可能会影响RISP动力学。在Rhodobacter cytochrome bc1复合物中，等效取代引起动力学缺陷，RISP头结构域对喹啉氧化位点的占据时间更长。这些发现代表了自发性微核上皮转移的独特情况，并突出了mtDNA变异作为线粒体疾病表型修饰因子的作用。

更新日期：2020-01-17

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11