Cardiolipin, and not monolysocardiolipin, preferentially binds to the interface of complexes III and IV.
Cardiolipin, and not monolysocardiolipin, preferentially binds to the interface of complexes III and IV.
复制标题
DOI：
10.1039/d2sc04072g
复制
发表时间：
2022-11-23
期刊：
影响因子：
8.4
通讯作者：
Duncan, Anna L. L.
中科院分区：
文献类型：
--
作者：
Corey, Robin A. A.;Harrison, Noah;Stansfeld, Philllp J. J.;Sansom, Mark S. P.;Duncan, Anna L. L.
线粒体电子传递链包括一系列嵌入线粒体内膜的蛋白质复合物，其通过氧化磷酸化产生质子动力，最终产生ATP。这些蛋白质复合物可以寡聚形成更大的结构，称为超复合物。心磷脂（CL），一种圆锥形脂质，在真核生物中独特的线粒体内膜，已被证明是维持超复合物的稳定性和功能所必需的。单溶血心磷脂（MLCL）是一种CL变体，在Barth综合征（BTHS）患者中蓄积。BTHS是由CL生物合成缺陷引起的，其特征是异常的线粒体生物能学和不稳定的超复合物。然而，MLCL导致发病的机制仍不清楚。在这里，多尺度分子动力学模拟了CL和MLCL与酵母和哺乳动物线粒体超复合物的相互作用，其中包含复合物III（CIII）和复合物IV（CIV）。粗粒度的模拟表明，CL和MLCL结合的网站之间的接口CIII和CIV的超复合物。自由能微扰计算表明，MLCL相互作用是弱于CL，并建议与CIV驱动这种差异的相互作用。原子接触分析表明，虽然与CIII的相互作用是相似的CL和MLCL，CIV使更多的接触CL比MLCL，表明CL是一个更成功的“胶水”之间的两个配合物。对人类CIII2CIV超复合物的模拟表明，这种界面位点在物种之间保持不变。我们的研究表明，MLCL在BTHS患者中的积累通过在界面脂质结合位点形成相对较弱的相互作用来破坏超复合物的稳定性。在线粒体呼吸超复合物中，心磷脂在复合物III和复合物IV的界面处比疾病相关脂质单溶血心磷脂相互作用更强。
The mitochondrial electron transport chain comprises a series of protein complexes embedded in the inner mitochondrial membrane that generate a proton motive force via oxidative phosphorylation, ultimately generating ATP. These protein complexes can oligomerize to form larger structures called supercomplexes. Cardiolipin (CL), a conical lipid, unique within eukaryotes to the inner mitochondrial membrane, has proven essential in maintaining the stability and function of supercomplexes. Monolysocardiolipin (MLCL) is a CL variant that accumulates in people with Barth syndrome (BTHS). BTHS is caused by defects in CL biosynthesis and characterised by abnormal mitochondrial bioenergetics and destabilised supercomplexes. However, the mechanisms by which MLCL causes pathogenesis remain unclear. Here, multiscale molecular dynamics characterise the interactions of CL and MLCL with yeast and mammalian mitochondrial supercomplexes containing complex III (CIII) and complex IV (CIV). Coarse-grained simulations reveal that both CL and MLCL bind to sites at the interface between CIII and CIV of the supercomplex. Free energy perturbation calculations show that MLCL interaction is weaker than that of CL and suggest that interaction with CIV drives this difference. Atomistic contact analyses show that, although interaction with CIII is similar for CL and MLCL, CIV makes more contacts with CL than MLCL, demonstrating that CL is a more successful “glue” between the two complexes. Simulations of the human CIII2CIV supercomplex show that this interface site is maintained between species. Our study suggests that MLCL accumulation in people with BTHS disrupts supercomplex stability by formation of relatively weak interactions at the interface lipid binding site. Cardiolipin interacts more strongly than a disease-related lipid, monolysocardiolipin, at the interface of Complex III and Complex IV in mitochondrial respiratory supercomplexes.
登录
查看更多内容
影响因子：
13.6
作者：
Corey RA;Song W;Duncan AL;Ansell TB;Sansom MSP;Stansfeld PJ
通讯作者：
Stansfeld PJ
影响因子：
4.6
作者：
Arnarez, C.;Marrink, S. J.;Periole, X.
通讯作者：
Periole, X.
影响因子：
30.8
作者：
Bione, S;DAdamo, P;Toniolo, D
通讯作者：
Toniolo, D
影响因子：
4.4
作者：
BARTH, PG;SCHOLTE, HR;SOBOTKAPLOJHAR, MA
通讯作者：
SOBOTKAPLOJHAR, MA
影响因子：
1.2
作者：
Dudek, Jan;Cheng, I-Fen;Guan, Kaomei
通讯作者：
Guan, Kaomei