Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.
Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.
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DOI：
10.1016/j.redox.2022.102258
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发表时间：
2022-05
期刊：
影响因子：
11.4
通讯作者：
Galkin A
中科院分区：
文献类型：
--
作者：
Yoval-Sánchez B;Ansari F;James J;Niatsetskaya Z;Sosunov S;Filipenko P;Tikhonova IG;Ten V;Wittig I;Rafikov R;Galkin A
在大脑和心脏等高代谢器官中，与组织缺血/再灌注（I/R）相关的病理是人类死亡和残疾的主要原因。急性I/R损伤中线粒体功能障碍的分子机制是组织特异性的，但其细节尚不完全清楚。在组织缺血中观察到代谢转移和反电子转移（RET）底物如琥珀酸盐的积累，使呼吸链线粒体复合体I （NADH：泛醌氧化还原酶）成为随后再灌注中最脆弱的酶。研究表明，在体外和体内RET条件下，脑复合体I维持在还原状态时，易于失去其黄素单核苷酸（FMN）辅因子。在这里，我们研究了脑和心脏线粒体中FMN与线粒体复合体I的氧化还原依赖解离过程。与脑酶相反，心脏复合体I在RET条件下减少时不会丢失FMN。我们提出，在RET期间FMN损失的不同动力学是由于复合物I的NDUFV3亚基的脑特异性长50kda亚型的存在，而在心脏中只发现典型的10kda短亚型而不存在。我们的模拟研究表明，NDUFV3长异构体可以到达FMN结合袋，并影响核苷酸对脱酶的亲和力。我们首次证明了复合体I的组织特异性同工型的潜在功能作用，提供了I/ r诱导的心脏和脑组织线粒体损伤的独特分子机制。通过结合完整复合物I的功能研究和分子结构模拟，我们定义了大脑和心脏酶之间的关键差异，并提出了在I/R损伤过程中复合物I氧化还原依赖性失活机制的见解。反向电子转移可引起脑内FMN复合物I的丢失，但在心脏中没有。心脏中的复合物I含量高于大脑。在两种组织中，依赖fmn的复合物I反应的动力学是不同的。NDUFV3亚基的长异构体存在于大脑中，但不存在于心脏酶中。分子模拟预测了长异构体与fmn结合位点的相互作用。
Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues. Reverse electron transfer induces loss of complex I FMN in brain but not in heart. Complex I content is higher in heart than in brain. Kinetics of complex I FMN-dependent reactions is different in both tissues. Long isoform of NDUFV3 subunit is present in the brain but not in the heart enzyme. Molecular simulation predicts interaction of long isoform with FMN-binding site.
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影响因子：
64.8
作者：
Fiedorczuk, Karol;Letts, James A.;Degliesposti, Gianluca;Kaszuba, Karol;Skehel, Mark;Sazanov, Leonid A.
通讯作者：
Sazanov, Leonid A.
影响因子：
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Sazanov, Leonid A.
影响因子：
5.8
作者：
Giese, Heiko;Ackermann, Joerg;Koch, Ina
通讯作者：
Koch, Ina
影响因子：
64.8
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.