Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy.
IRCCS-Santa Lucia Foundation, 00179 Rome, Italy.
Cells. 2022 Mar 30;11(7):1169. doi: 10.3390/cells11071169.
Mitochondrial bioenergetics are progressively acquiring significant pathophysiological roles. Specifically, mitochondria in general and Electron Respiratory Chain in particular are gaining importance as unintentional targets of different drugs. The so-called PPAR ligands are a class of drugs which not only link and activate Peroxisome Proliferator-Activated Receptors but also show a myriad of extrareceptorial activities as well. In particular, they were shown to inhibit NADH coenzyme Q reductase. However, the molecular picture of this intriguing bioenergetic derangement has not yet been well defined. Using high resolution respirometry, both in permeabilized and intact HepG2 cells, and a proteomic approach, the mitochondrial bioenergetic damage induced by various PPAR ligands was evaluated. Results show a derangement of mitochondrial oxidative metabolism more complex than one related to a simple perturbation of complex I. In fact, a partial inhibition of mitochondrial NADH oxidation seems to be associated not only with hampered ATP synthesis but also with a significant reduction in respiratory control ratio, spare respiratory capacity, coupling efficiency and, last but not least, serious oxidative stress and structural damage to mitochondria.
线粒体生物能量学正逐渐获得重要的病理生理学作用。具体来说，线粒体（general mitochondria），特别是电子呼吸链（Electron Respiratory Chain），作为不同药物的非预期靶点，其重要性日益增加。所谓的过氧化物酶体增殖物激活受体配体（PPAR ligands）是一类药物，它们不仅与过氧化物酶体增殖物激活受体（Peroxisome Proliferator-Activated Receptors）结合并激活，还具有许多额外的受体外活性。特别是，它们被证明可以抑制烟酰胺腺嘌呤二核苷酸（NADH）辅酶 Q 还原酶。然而，这种引人入胜的生物能量障碍的分子图景尚未得到很好的定义。本研究采用高分辨率呼吸测量法（在通透和完整的 HepG2 细胞中）和蛋白质组学方法，评估了各种过氧化物酶体增殖物激活受体配体对线粒体生物能量的损伤作用。结果表明，线粒体氧化代谢的紊乱比单纯的复合物 I 扰动更为复杂。事实上，线粒体 NADH 氧化的部分抑制似乎不仅与 ATP 合成受阻有关，还与呼吸控制比、备用呼吸能力、偶联效率的显著降低有关，最后但并非最不重要的是，线粒体严重的氧化应激和结构损伤。
