Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health.
Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health.
复制标题
DOI：
10.1093/gbe/evu208
复制
发表时间：
2014-09-22
影响因子：
3.3
通讯作者：
Mishmar D
中科院分区：
文献类型：
--
作者：
Gershoni M;Levin L;Ovadia O;Toiw Y;Shani N;Dadon S;Barzilai N;Bergman A;Atzmon G;Wainstein J;Tsur A;Nijtmans L;Glaser B;Mishmar D
线粒体DNA(MtDNA)的突变率比核基因组高一个数量级，迫使紧密的有丝分裂核协同进化来维持线粒体的活动。这种共同进化的中断在种群间杂交崩溃、物种形成事件和疾病易感性中发挥了作用。此前，我们在核DNA编码的氧化磷酸化复合体I亚单位NDUFC2中发现了高的氨基酸替换率和正选择，这一现象对于NDUFC2与mtDNA编码的复合体I亚单位ND4的直接相互作用很重要。这一发现强调了有丝分裂核共同进化对线粒体DNA和核DNA编码因子之间的物理相互作用的重要性。然而，目前尚不清楚这种相互作用是否对复合体I的稳定性和活性重要。在这里，我们表明NDUFC2的siRNA沉默抑制了人视网膜色素上皮细胞D-407的生长，显著降低了线粒体膜电位，并干扰了复合体I的完整性。此外，NDUFC2中一个正选择的氨基酸的定点突变显著干扰了NDUFC2与其线粒体DNA编码的伙伴ND4的相互作用。最后，我们证明了包含该氨基酸(NDUFC2残基46)和mtDNA单倍组HV的基因组合可能改变了德系犹太人患2型糖尿病的易感性。因此，有丝分裂核协进化对于维持有丝分裂因子相互作用、OXPHOS和人类健康是重要的。
The mutation rate of the mitochondrial DNA (mtDNA), which is higher by an order of magnitude as compared with the nuclear genome, enforces tight mitonuclear coevolution to maintain mitochondrial activities. Interruption of such coevolution plays a role in interpopulation hybrid breakdown, speciation events, and disease susceptibility. Previously, we found an elevated amino acid replacement rate and positive selection in the nuclear DNA-encoded oxidative phosphorylation (OXPHOS) complex I subunit NDUFC2, a phenomenon important for the direct interaction of NDUFC2 with the mtDNA-encoded complex I subunit ND4. This finding underlines the importance of mitonuclear coevolution to physical interactions between mtDNA and nuclear DNA-encoded factors. Nevertheless, it remains unclear whether this interaction is important for the stability and activity of complex I. Here, we show that siRNA silencing of NDUFC2 reduced growth of human D-407 retinal pigment epithelial cells, significantly diminished mitochondrial membrane potential, and interfered with complex I integrity. Moreover, site-directed mutagenesis of a positively selected amino acid in NDUFC2 significantly interfered with the interaction of NDUFC2 with its mtDNA-encoded partner ND4. Finally, we show that a genotype combination involving this amino acid (NDUFC2 residue 46) and the mtDNA haplogroup HV likely altered susceptibility to type 2 diabetes mellitus in Ashkenazi Jews. Therefore, mitonuclear coevolution is important for maintaining mitonuclear factor interactions, OXPHOS, and for human health.
登录
查看更多内容
影响因子：
29
作者：
Balsa, Eduardo;Marco, Ricardo;Antonio Enriquez, Jose
通讯作者：
Antonio Enriquez, Jose
影响因子：
3.4
作者：
EHRENBERG, B;MONTANA, V;LOEW, LM
通讯作者：
LOEW, LM
影响因子：
4.5
作者：
Amar, Shirly;Shamir, Alon;Mishmar, Dan
通讯作者：
Mishmar, Dan
影响因子：
4
作者：
Gershoni, Moran;Templeton, Alan R.;Mishmar, Dan
通讯作者：
Mishmar, Dan
影响因子：
64.8
作者：
Efremov, Rouslan G.;Sazanov, Leonid A.
通讯作者：
Sazanov, Leonid A.