Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress.
Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress.
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DOI：
10.1038/ki.2010.532
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发表时间：
2011-06
影响因子：
19.6
通讯作者：
Borkan SC
中科院分区：
文献类型：
--
作者：
Gall JM;Wong V;Pimental DR;Havasi A;Wang Z;Pastorino JG;Bonegio RG;Schwartz JH;Borkan SC
己糖激酶(HK)是糖酵解中的限速酶，通过促进新陈代谢和/或抑制细胞凋亡来调节细胞存活。研究了线粒体靶向序列的亚型HKI和HKII在三磷酸腺苷耗竭后的肾上皮细胞中的表达。三磷酸腺苷耗竭可激活GSK3β和bax，导致线粒体膜损伤和细胞凋亡。应激可降低总ATP含量，使HKII从线粒体解离，释放线粒体凋亡诱导因子(AIF)和细胞色素c，激活caspase-3，降低细胞存活率。与对照组相比，HKI或II过表达可改善应激后的存活率，但不会阻止GSK3ATP或bax的激活，增加β的含量，或减少线粒体的碎裂。HKI或HKII的过度表达增加了线粒体相关的、异构体特异性的HK含量，减少了线粒体膜损伤和细胞凋亡。在体内，HKII定位于小鼠近端小管。缺血使近端肾小管总HKII含量减少，线粒体HKII解离，但远端肾小管未见线粒体HKII解离。在HK过度表达的细胞中，HKII和Bax在应激前后没有相互作用。然而，在应激过程中，HK的过度表达增加了细胞器相关的HK，减少了线粒体Bax的积聚，减少了外膜损伤和细胞凋亡，其方式似乎与其对肾上皮细胞ATP含量的影响无关，提示HK和Bax竞争相似的线粒体膜结合部位。
Hexokinase (HK), the rate-limiting enzyme in glycolysis, regulates cell survival either by promoting metabolism and/or inhibiting apoptosis. HKI and HKII, isoforms with mitochondrial targeting sequences, were studied in renal epithelial cells after ATP depletion, an insult that activates GSK3β and Bax, induces mitochondrial membrane injury and causes apoptosis. Stress decreased total ATP content, caused HKII to dissociate from mitochondria, released mitochondrial apoptosis inducing factor (AIF) and cytochrome c, activated caspase-3 and reduced cell survival. Compared to control, HKI or II over-expression improved survival after stress without preventing GSK3β or Bax activation, increasing ATP content, or reducing mitochondrial fragmentation. HKI or HKII over-expression increased mitochondria-associated, isoform-specific HK content and decreased mitochondrial membrane injury and apoptosis. In vivo, HKII localized to the murine proximal tubule. Ischemia reduced total HKII content and caused mitochondrial HKII dissociation in proximal but not distal tubules. In HK over-expressing cells, HKII and Bax did not interact before or after stress. However, HK over-expression increased organelle-associated HK during stress and decreased mitochondrial Bax accumulation, outer membrane injury and apoptosis in a manner that appears to be independent of its effect on renal epithelial cell ATP content, suggesting that HK and Bax compete for similar mitochondrial membrane binding sites.
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影响因子：
4.8
作者：
Havasi, Andrea;Li, Zhijian;Borkan, Steven C.
通讯作者：
Borkan, Steven C.
影响因子：
3.5
作者：
Cartron, Pierre-Francois;Bellot, Gregory;Vallette, Francois M.
通讯作者：
Vallette, Francois M.
DOI：
10.1016/s0167-4889(03)00102-2
发表时间：
2003-09-23
影响因子：
5.1
作者：
Godbole, A;Varghese, J;Mathew, MK
通讯作者：
Mathew, MK
影响因子：
12.4
作者：
Bellot, G.;Cartron, P. -F.;Vallette, F. M.
通讯作者：
Vallette, F. M.
影响因子：
4.8
作者：
Bryson, JM;Coy, PE;Robey, RB
通讯作者：
Robey, RB