Structural basis for a complex I mutation that blocks pathological ROS production.
Structural basis for a complex I mutation that blocks pathological ROS production.
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DOI：
10.1038/s41467-021-20942-w
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发表时间：
2021-01-29
影响因子：
16.6
通讯作者：
Hirst J
中科院分区：
文献类型：
--
作者：
Yin Z;Burger N;Kula-Alwar D;Aksentijević D;Bridges HR;Prag HA;Grba DN;Viscomi C;James AM;Mottahedin A;Krieg T;Murphy MP;Hirst J
线粒体复合体I是病理性活性氧（ROS）产生的核心，是心脏缺血再灌注（IR）损伤的基础。ND6-P25L小鼠的致病mtDNA点突变编码复合体I的ND6亚基中的P25L替换，是同质的。ND6-P25L复合体I的低温电镜结构显示出细微的结构变化，有助于快速转化为“失活”状态，通常只有在长时间失活后才会形成。尽管其倾向于采取“失活”状态，突变体复合体对NADH氧化完全活跃，但不能通过反向电子转移（RET）产生ROS。ND6-P25L线粒体除了缺乏RET ROS产生外功能正常，ND6-P25L小鼠在体内可保护心脏免受IR损伤。因此，复合体I的单点突变不影响氧化磷酸化，但使复合体无法催化RET，证明了IR损伤期间RET产生ROS的病理作用。通过复合体I的反向电子转移（RET）产生活性氧（ROS）被认为会引起心脏病发作的组织损伤。在这里，作者将体内研究与生化和低温电镜分析相结合，以表征线粒体复合体I ND6亚基中P25L突变的影响。他们观察到该突变不影响氧化磷酸化，但使复合体I无法通过RET产生ROS: ND6-P25L小鼠免受心脏缺血再灌注损伤，从而为提出的ROS产生在心肌梗死中的作用提供了证据。
Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury. Reactive oxygen species (ROS) production by reverse electron transfer (RET) through complex I is thought to cause tissue damage from heart attacks. Here, the authors combine in vivo work with biochemical and cryo-EM analyses to characterize the effects of a P25L mutation in the ND6 subunit of mitochondrial complex I. They observe that this mutation does not affect oxidative phosphorylation but renders complex I unable to generate ROS by RET: ND6-P25L mice are protected against cardiac ischaemia–reperfusion injury, thus providing evidence for the proposed role of ROS production in myocardial infarction.
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影响因子：
48
作者：
Barad BA;Echols N;Wang RY;Cheng Y;DiMaio F;Adams PD;Fraser JS
通讯作者：
Fraser JS
影响因子：
29
作者：
Cochemé HM;Quin C;McQuaker SJ;Cabreiro F;Logan A;Prime TA;Abakumova I;Patel JV;Fearnley IM;James AM;Porteous CM;Smith RA;Saeed S;Carré JE;Singer M;Gems D;Hartley RC;Partridge L;Murphy MP
通讯作者：
Murphy MP
影响因子：
3
作者：
de la Rosa-Trevin, J. M.;Quintana, A.;Carazo, J. M.
通讯作者：
Carazo, J. M.
DOI：
10.1124/jpet.105.091702
发表时间：
2006-01-01
影响因子：
3.5
作者：
Chen, Q;Hoppel, CL;Lesnefsky, EJ
通讯作者：
Lesnefsky, EJ
影响因子：
6.6
作者：
Gorenkova, Natalia;Robinson, Emma;Galkin, Alexander
通讯作者：
Galkin, Alexander