Abstract
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.
Highlights
Mitochondria are essential organelles in determining continuous cell survival and cell death.Conditions of many diseases are linked to mitochondrial dysfunction and mitochondrial abnormalities.by improving mitochondrial functions and physiology one can significantly mitigate the disease pathology
During oxidative phosphorylation (OXPHOS) the energy stored in the reduced compounds is used by the electron transport chain to pump hydrogen ions across the inner membrane, generating the electrochemical gradient (Figure 1)
Since mitochondria provide the majority of intracellular adenosine triphosphate (ATP) via oxidative phosphorylation, Since mitochondria provide the majority of intracellular ATP via oxidative phosphorylation, the the cellular ATP levels rapidly fall after onset of global cerebral ischemia [35,37,38]
Summary
Mitochondria are essential organelles in determining continuous cell survival and cell death. Mitochondria are critical for several essential cellular processes, including intracellular metabolic activities, and signal transduction of several cellular pathways. They are involved in cellular ion homeostasis, oxidative stress, and both apoptotic and necrotic cell death. One of the generally accepted adverse effects of mitochondrial activity under disease conditions is the increased mitochondrial free radical production. For normal cellular and mitochondrial functions the level of free radicals is fine-tuned by the two opposite processes, the rate of ROS generation, and the effectiveness of their enzymatic elimination. There are several mechanisms by which mitochondria can generate an excess of free radicals, and the individual mechanisms can have different contributions to the increase in ROS production under different disease conditions. We will outline the potential therapeutic implications and new targets that can mitigate the adverse effects caused by free radicals due to changes in NAD+ metabolism
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