Impaired transport of mitochondrial transcription factor A (TFAM) and the metabolic memory phenomenon associated with the progression of diabetic retinopathy.
Impaired transport of mitochondrial transcription factor A (TFAM) and the metabolic memory phenomenon associated with the progression of diabetic retinopathy.
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DOI：
10.1002/dmrr.2384
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发表时间：
2013-03
影响因子：
8
通讯作者：
Kowluru, Renu A.
中科院分区：
文献类型：
--
作者：
Santos, Julia M.;Kowluru, Renu A.
糖尿病损害视网膜线粒体DNA（mtDNA），并损害mtDNA的转录。在线粒体DNA的转录和复制中，核编码转录因子A（TFAM）被认为是一个关键的激活因子，我们已经证明，在糖尿病中，视网膜TFAM基因表达增加，其线粒体水平下降。本研究探讨了线粒体外膜和内膜转运系统在糖尿病中TFAM转移到线粒体中的作用，以及高血糖的逆转如何影响TFAM到达线粒体的能力。对链脲佐菌素诱导的糖尿病大鼠视网膜中膜转运系统的组分Tom 70、Tom 40、Tim 23和Tim 44进行了分析，所述糖尿病大鼠保持在不良控制（PC）或良好控制（GC）8个月，或在PC 4个月后在GC 4个月（Rev）。免疫共沉淀法测定TFAM与Tom 70和Tim 44的结合，ChIP法测定TFAM与mtDNA的结合。糖尿病患者视网膜Tom 70、Tom 40和Tim 44的表达明显降低，TFAM与Tom 70、Tim 44和mtDNA的结合能力减弱。抑制高血糖对TFAM和Tom蛋白与mtDNA结合的降低没有有益的影响。因此，在糖尿病中，低于正常的膜转运系统损害TFAM向线粒体的转移，并且降低TFAM-mtDNA结合导致低于正常的线粒体转录。即使在高血糖损伤终止后，这些过程仍继续功能失调。针对线粒体膜转运蛋白的策略可能具有改善线粒体生物合成和减缓/停止糖尿病视网膜病变进展的潜力。
Diabetes damages retinal mitochondrial DNA (mtDNA), and compromises the mtDNA transcription. In the transcription and replication of mtDNA, nuclear-encoded transcription factor A (TFAM) is considered as a key activator, and we have shown that in diabetes while retinal TFAM gene expression is increased, its mitochondrial levels are decreased. This study investigates the role of mitochondrial outer and inner membrane transport systems in the transfer of TFAM into the mitochondria in diabetes, and how reversal of hyperglycemia affects the ability of TFAM to reach to the mitochondria. Components of membrane transport system, Tom70, Tom40, Tim23 and Tim44, were analyzed in the retina from streptozotocin-induced diabetic rats maintained in poor control (PC) or in good control (GC) for 8 months, or in PC for 4 months followed by in GC for 4 months (Rev). The binding of TFAM with Tom70 and Tim44 was determined by co-immunoprecipitation, and that with mtDNA by ChIP. Retinal expressions of Tom70, Tom40 and Tim44 were significantly decreased in diabetes, and the binding of TFAM with Tom70, Tim44 and mtDNA were impaired. Reversal of hyperglycemia had no beneficial effect on decreased binding of TFAM and Tom proteins and mtDNA. Thus, subnormal membrane transport system in diabetes impairs the transfer of TFAM into the mitochondria, and decreased TFAM-mtDNA binding results in subnormal mitochondria transcription. These processes continue to be dysfunctional even after the hyperglycemic insult is terminated. Strategies targeting mitochondrial membrane transport proteins could have potential in improving mitochondrial biogenesis and slowing/halting the progression of diabetic retinopathy.
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