Department of Neurosurgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan, 471000, China.
Department of Neurosurgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan, 471000, China.
Biochem Biophys Res Commun. 2018 Sep 26;504(1):13-18. doi: 10.1016/j.bbrc.2018.08.027. Epub 2018 Aug 29.
Mitochondrial biogenesis deficits in neuronal cells are associated with the pathological progression of neurodegenerative diseases. Resistin, a secretory adipocytokine, possesses multiple physiological functions in diverse cells and tissues. However, the effects of resistin on mitochondrial biogenesis in neuronal cells are still elusive. In the current study, we found that resistin caused a sustainable decrease in mitochondrial contents, including mitochondrial DNA/nuclear DNA ratio (mtDNA/nDNA), mitochondrial mass, cytochrome b protein expression, and cytochrome c oxidase activity, which were correlated with "loss of mitochondrial function" including reduced mitochondrial respiration rate and ATP production in human SH-SY5Y neuronal cells. Indeed, resistin treatment destroyed the expression of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, as well as its downstream target genes including nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Notably, overexpression of PGC-1α could completely rescue mitochondrial biogenesis and mitochondrial deficits induced by resistin. Mechanistically, inhibition of 5'-adenosine monophosphate-activated protein kinase (AMPK) was shown to mediate the inhibitory effects of resistin on mitochondrial biogenesis.
神经元细胞中线粒体生物发生缺陷与神经退行性疾病的病理进展有关。抵抗素是一种分泌型脂肪细胞因子，在多种细胞和组织中具有多种生理功能。然而，抵抗素对神经元细胞中线粒体生物发生的影响仍不清楚。在本研究中，我们发现抵抗素导致线粒体含量持续减少，包括线粒体 DNA/核 DNA 比值 (mtDNA/nDNA)、线粒体质量、细胞色素 b 蛋白表达和细胞色素 c 氧化酶活性，这与“线粒体功能丧失”相关，包括人 SH-SY5Y 神经元细胞中线粒体呼吸率和 ATP 产生减少。事实上，抵抗素处理破坏了过氧化物酶体增殖物激活受体 γ 共激活因子 1α (PGC-1α) 的表达，PGC-1α 是线粒体生物发生的主要调节因子，以及其下游靶基因包括核呼吸因子 1 (NRF1) 和线粒体转录因子 A (TFAM)。值得注意的是，过表达 PGC-1α 可以完全挽救抵抗素诱导的线粒体生物发生和线粒体缺陷。在机制上，5'-腺苷单磷酸激活蛋白激酶 (AMPK) 的抑制被证明介导了抵抗素对线粒体生物发生的抑制作用。
