Klimova Nina, Fearnow Adam, Kristian Tibor
Veterans Affairs Maryland Health Center System, 10 North Greene Street, Baltimore, MD 21201, USA.
Department of Anesthesiology and the Center for Shock, Trauma, and Anesthesiology Research (S.T.A.R.), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Brain Sci. 2020 Jul 14;10(7):449. doi: 10.3390/brainsci10070449.
It is commonly accepted that mitochondria represent a major source of free radicals following acute brain injury or during the progression of neurodegenerative diseases. The levels of reactive oxygen species (ROS) in cells are determined by two opposing mechanisms-the one that produces free radicals and the cellular antioxidant system that eliminates ROS. Thus, the balance between the rate of ROS production and the efficiency of the cellular detoxification process determines the levels of harmful reactive oxygen species. Consequently, increase in free radical levels can be a result of higher rates of ROS production or due to the inhibition of the enzymes that participate in the antioxidant mechanisms. The enzymes' activity can be modulated by post-translational modifications that are commonly altered under pathologic conditions. In this review we will discuss the mechanisms of mitochondrial free radical production following ischemic insult, mechanisms that protect mitochondria against free radical damage, and the impact of post-ischemic nicotinamide adenine mononucleotide (NAD) catabolism on mitochondrial protein acetylation that affects ROS generation and mitochondrial dynamics. We propose a mechanism of mitochondrial free radical generation due to a compromised mitochondrial antioxidant system caused by intra-mitochondrial NAD depletion. Finally, the interplay between different mechanisms of mitochondrial ROS generation and potential therapeutic approaches are reviewed.
人们普遍认为，线粒体是急性脑损伤后或神经退行性疾病进展过程中自由基的主要来源。细胞内活性氧（ROS）的水平由两种相反的机制决定，一种是产生自由基的机制，另一种是消除ROS的细胞抗氧化系统。因此，ROS产生速率与细胞解毒过程效率之间的平衡决定了有害活性氧的水平。因此，自由基水平的升高可能是由于ROS产生速率增加，或者是由于参与抗氧化机制的酶受到抑制。酶的活性可以通过翻译后修饰来调节，而这种修饰在病理条件下通常会发生改变。在这篇综述中，我们将讨论缺血性损伤后线粒体自由基产生的机制、保护线粒体免受自由基损伤的机制，以及缺血后烟酰胺腺嘌呤二核苷酸（NAD）分解代谢对线粒体蛋白乙酰化的影响，这种影响会影响ROS的产生和线粒体动力学。我们提出了一种由于线粒体内NAD耗竭导致线粒体抗氧化系统受损而产生线粒体自由基的机制。最后，综述了线粒体ROS产生的不同机制之间的相互作用以及潜在的治疗方法。
