• 2019-07
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  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • Bioenergetic stress and downstream effects caused by ischemi


    Bioenergetic stress and downstream effects caused by ischemic insult depletes NAD+ levels and compromises several metabolic pathways and mitochondrial functions [[9], [10], [11], [12], [13]]. Mitochondrial protein acetylation is dramatically reduced suggesting a deficiency in production of acetyl‑CoA (AcCoA), a substrate for acetyltransferases. Additionally, mitochondria are extensively fragmented leading to failure in oxidative phosphorylation [[14], [15], [16]]. All these events lead to bioenergetics failure and ultimately cell death. In this review we will address the metabolic links between NAD+, AcCoA, and mitochondrial dynamics that are altered by ischemia/reperfusion triggered conditions.
    Role of mitochondrial dynamics in mechanisms of pathophysiology The state of mitochondrial dynamics is determined by the balance between activities of fission and fusion processes. There are several physiological functions of mitochondrial fission. Fragmented mitochondria can move more efficiently within the cell to reach areas where there is a KRN 7000 higher demand for local ATP generation. Furthermore, by fragmentation the damaged and healthy mitochondrial proteins and DNA can be segregated into separate smaller organelles allowing the damaged, dysfunctional subpopulation to be eliminated by mitophagy [17,18]. Finally, during cell division mitochondrial fragmentation facilitates proper redistribution of mitochondrial mass into daughter KRN 7000 [19]. However, an extensive and prolonged fission due to pathologic stress can lead to transformation of the whole mitochondrial population into submicron size organelles [14]. These individual organelles are too small to harbor the required amount of all essential metabolites and proteins for proper and effective function. Thus, the cellular demand for ATP generation cannot be met and ultimately will lead to bioenergetics failure and cell death. To reverse this process, the fragmented mitochondria need to fuse back so the contents of the small organelles can combine and stabilize protein and DNA levels for normal mitochondrial function. Therefore, fusion, by combining the contents of functionally compromised small organelles into functioning mitochondria, mitigates the effects of cellular stress. For example, CA1 neurons in the hippocampus are the most vulnerable to ischemic attack and mitochondria in these neurons are extensively fragmented following ischemic insult [14,15]. This highly fragmented state lasts for several days and CA1 neurons ultimately die. On the other hand the CA3 and dentate gyrus neurons of the hippocampus are resistant to ischemic conditions [[20], [21], [22]]. Although, mitochondria in these cells are fragmented directly after the ischemic insult, later at 24 h of reperfusion the highly fragmented population is significantly reduced, and the number of longer mitochondria increases when compared to immediate post-insult state [14]. This suggests that at later recovery time, factors stimulating the fission process are diminished or the fusion activity is sufficiently increased to reverse the fission process. Interestingly, similar temporal profile of mitochondrial fragmentation is observed also in astrocytes following acute brain injury [14,23]. Mitochondrial fission and fusion is a highly controlled process by several cytosolic and mitochondrial proteins belonging to the GTPase family (for review see [[24], [25], [26], [27]]). There are a separate set of fusion proteins that control the outer and the inner membrane fusion. Mitofusin1 and mitofusin2 (Mfn1 and Mfn2) mediate the mitochondrial outer membrane fusion, while the inner membrane fusion is regulated by dynamin-like GTPase encoded by optic atrophy 1 gene (Opa1) [18,28]. Fission is facilitated by the dynamin-related protein1 (Drp1) which needs to be recruited from the cytosol to the outer mitochondrial membrane. Several proteins on the outer membrane serve as recruitment factors for Drp1, mitochondrial fission factor (MFF), Fis1 protein, and mitochondrial dynamic proteins 49/51 (MiD49/51) [29,30]. Overall modulation of the fission and fusion process is rather complex, involving several post-translational modifications [4,24,26,27]. Thus, the activity of these proteins is tightly regulated by phosphorylation, acetylation, ADP‑ribosylation, S‑nitrosylation, SUMOylation, ubiquitination, o‑linked‑N‑acetyl‑glucosamine glycosylation, and proteolytic cleavage [27,[31], [32], [33]]. Maintenance of the proper balance between mitochondrial fission and fusion by post-translational modifications is essential not only for facilitating normal mitochondrial bioenergetic function but also for dynamic cellular stress response to pathological conditions. In next paragraphs we discuss the impact of ischemia on NAD+ and AcCoA metabolism that modulates acetylation of cellular and mitochondrial proteins.