Department of Biochemistry, University of Kerala, Kariavattom, Thiruvananthapuram, Kerala, 695581, India.
Department of Biochemistry, Government College, Kariavattom, Thiruvananthapuram, Kerala, 695581, India.
Mol Cell Biochem. 2023 Oct;478(10):2257-2270. doi: 10.1007/s11010-022-04656-1. Epub 2023 Feb 13.
Cardiac function depends mainly on mitochondrial metabolism. Cold conditions increase the risk of cardiovascular diseases by increasing blood pressure. Adaptive thermogenesis leads to increased mitochondrial biogenesis and function in skeletal muscles and adipocytes. Here, we studied the effect of acute cold exposure on cardiac mitochondrial function and its regulation by sirtuins. Significant increase in mitochondrial DNA copy number as measured by the ratio between mitochondrial-coded COX-II and nuclear-coded cyclophilin A gene expression by qRT-PCR and increase in the expression of PGC-1α, a mitochondriogenic factor and its downstream target NRF-1 were observed on cold exposure. This was associated with an increase in the activity of SIRT-1, which is known to activate PGC-1α. Mitochondrial SIRT-3 was also upregulated. Increase in sirtuin activity was reflected in total protein acetylome, which decreased in cold-exposed cardiac tissue. An increase in mitochondrial MnSOD further indicated enhanced mitochondrial function. Further evidence for this was obtained from ex vivo studies of cardiac tissue treated with norepinephrine, which caused a significant increase in mitochondrial MnSOD and SIRT-3. SIRT-3 appears to mediate the regulation of MnSOD, as treatment with AGK-7, a SIRT-3 inhibitor reversed the norepinephrine-induced upregulation of MnSOD. It, therefore, appears that SIRT-3 activation in response to SIRT-1-PGC-1α activation contributes to the regulation of cardiac mitochondrial activity during acute cold exposure.
心脏功能主要依赖于线粒体代谢。寒冷条件通过增加血压增加了心血管疾病的风险。适应性生热导致骨骼肌和脂肪细胞中线粒体生物发生和功能的增加。在这里，我们研究了急性冷暴露对心脏线粒体功能的影响及其受沉默调节蛋白的调节。冷暴露时，通过 qRT-PCR 测量线粒体编码的 COX-II 和核编码的环孢素 A 基因表达之间的比率，观察到线粒体 DNA 拷贝数显著增加，以及线粒体生成因子 PGC-1α及其下游靶标 NRF-1 的表达增加。这与 SIRT-1 的活性增加有关，SIRT-1 已知可激活 PGC-1α。线粒体 SIRT-3 也被上调。沉默调节蛋白活性的增加反映在总蛋白乙酰组中，冷暴露的心脏组织中的总蛋白乙酰组减少。线粒体 MnSOD 的增加进一步表明线粒体功能增强。从用去甲肾上腺素处理的心脏组织的离体研究中获得了进一步的证据，去甲肾上腺素导致线粒体 MnSOD 和 SIRT-3 显著增加。SIRT-3 似乎介导了 MnSOD 的调节，因为 SIRT-3 抑制剂 AGK-7 的治疗逆转了去甲肾上腺素诱导的 MnSOD 上调。因此，SIRT-1-PGC-1α 激活后 SIRT-3 的激活似乎有助于急性冷暴露期间心脏线粒体活性的调节。
