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首页> 美国卫生研究院文献>American Journal of Physiology - Cell Physiology >Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes
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Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes

机译：高血糖引起的线粒体功能和胞质钙的改变被心肌细胞中的线粒体转录因子A恢复

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Mitochondrial transcription factor A (TFAM) is essential for mitochondrial DNA transcription and replication. TFAM transcriptional activity is decreased in diabetic cardiomyopathy; however, the functional implications are unknown. We hypothesized that a reduced TFAM activity may be responsible for some of the alterations caused by hyperglycemia. Therefore, we investigated the effect of TFAM overexpression on hyperglycemia-induced cytosolic calcium handling and mitochondrial abnormalities. Neonatal rat cardiomyocytes were exposed to high glucose (30 mM) for 48 h, and we examined whether TFAM overexpression, by protecting mitochondrial DNA, could reestablish calcium fluxes and mitochondrial alterations toward normal. Our results shown that TFAM overexpression increased to more than twofold mitochondria copy number in cells treated either with normal (5.5 mM) or high glucose. ATP content was reduced by 30% and mitochondrial calcium decreased by 40% after high glucose. TFAM overexpression returned these parameters to even higher than control values. Calcium transients were prolonged by 70% after high glucose, which was associated with diminished sarco(endo)plasmic reticulum Ca2+-ATPase 2a and cytochrome-c oxidase subunit 1 expression. These parameters were returned to control values after TFAM overexpression. High glucose-induced protein oxidation was reduced by TFAM overexpression, indicating a reduction of the high glucose-induced oxidative stress. In addition, we found that TFAM activity can be modulated by O-linked β-N-acetylglucosamine glycosylation. In conclusion, TFAM overexpression protected cell function against the damage induced by high glucose in cardiomyocytes.
机译：线粒体转录因子A（TFAM）对于线粒体DNA转录和复制至关重要。在糖尿病性心肌病中，TFAM转录活性降低；但是，功能含义尚不清楚。我们假设TFAM活性降低可能是由高血糖引起的某些改变的原因。因此，我们调查了TFAM过表达对高血糖诱导的胞质钙处理和线粒体异常的影响。新生大鼠心肌细胞暴露于高葡萄糖（30 mM）下48 h，我们检查了TFAM是否通过保护线粒体DNA而过表达是否可以恢复正常的钙通量和线粒体改变。我们的结果表明，在正常（5.5 mM）或高葡萄糖处理的细胞中，TFAM过表达增加至超过两倍的线粒体拷贝数。高糖后，ATP含量降低了30％，线粒体钙降低了40％。 TFAM过表达使这些参数甚至高于控制值。高糖后钙的瞬态时间延长了70％，这与肌浆网内膜Ca 2 + -ATPase 2a和细胞色素c氧化酶亚基1的表达降低有关。在TFAM过表达之后，这些参数返回到控制值。高糖诱导的蛋白质氧化被TFAM过表达减少，表明高糖诱导的氧化应激的减少。另外，我们发现TFAM活性可以通过O-连接的β-N-乙酰氨基葡糖糖基化来调节。总之，TFAM过表达保护细胞功能免受心肌细胞中高糖诱导的损伤。

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