Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain
Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain
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DOI：
10.1016/j.bbamcr.2014.10.016
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发表时间：
2015-01-01
影响因子：
5.1
通讯作者：
Papa, Sergio
中科院分区：
文献类型：
--
作者：
De Rasmo, Domenico;Signorile, Anna;Papa, Sergio
在哺乳动物细胞中，复合物I的核编码亚基被输入线粒体，在那里它们与复合物中的mtDNA编码亚基组装，或与复合物中预先存在的拷贝交换。目前的工作表明，在成纤维细胞培养物中，KH 7通过可溶性腺苷酸环化酶（sAC）抑制线粒体基质中cAMP的产生，导致催化部分的游离非掺入核编码的NDUFS 4、NDUFV 2和NDUFA 9亚基的量减少，并抑制复合物I的活性。渗透剂8-Br-cAMP的加入防止了KH 7的这种作用。KH 7抑制在分离的大鼠肝线粒体中的积累和在“体外”产生的放射性标记的NDUFS 4和NDUFV 2亚基的复合物I中的掺入。8-Br-cAMP也阻止了KH 7的这种作用。蛋白酶抑制剂的使用表明，线粒体内cAMP通过防止线粒体蛋白酶消化核编码的亚基而对复合物I发挥这种积极作用，线粒体蛋白酶的活性由KH 7和KH 89（PICA的抑制剂）促进。(C)2014爱思唯尔有限公司版权所有。
In mammalian cells the nuclear-encoded subunits of complex I are imported into mitochondria, where they are assembled with mt-DNA encoded subunits in the complex, or exchanged with pre-existing copies in the complex. The present work shows that in fibroblast cultures inhibition by KH7 of cAMP production in the mitochondrial matrix by soluble adenylyl cyclase (sAC) results in decreased amounts of free non-incorporated nuclear-encoded NDUFS4, NDUFV2 and NDUFA9 subunits of the catalytic moiety and inhibition of the activity of complex I. Addition of permeant 8-Br-cAMP prevents this effect of KH7. KH7 inhibits accumulation in isolated rat-liver mitochondria and incorporation in complex I of "in vitro" produced, radiolabeled NDUFS4 and NDUFV2 subunits. 8-Br-cAMP prevents also this effect of KH7. Use of protease inhibitors shows that intramitochondrial cAMP exerts this positive effect on complex I by preventing digestion of nuclear-encoded subunits by mitochondrial protease(s), whose activity is promoted by KH7 and KH89, an inhibitor of PICA. (C) 2014 Elsevier B.V. All rights reserved.