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  • It is acknowledged that mitochondrial outer membrane


    It is acknowledged that mitochondrial outer membrane permeabilisation is a pivotal signal for apoptosis, which leads to the liberation of pro-apoptotic molecule such as cytochrome c and post-caspase activation [37]. As a consequence of the protection of mitochondrial integrity, AIV improved mitochondrial oxidation by increasing OCR and reduced the release of pro-apoptotic molecules by preventing the opening of mPTP, resultantly protecting neurons from caspase-dependent cell death. Glutamate neurotoxicity increases ROS production due to mitochondrial dysfunction [2], [32] and oxidative stress leads to DNA damage, which is a trigger of parthanatos pathway [38]. AIV reduced ROS production and attenuated oxidative DNA damage, contributing to preventing PAR formation via PARP-1 inactivation [38]. PAR polymer is a death signal to mitochondria and induces the mitochondrial AIF translocation to nucleus, leading to DNA fragmentation, nuclear condensation and final cell death [39]. AIV protected the structural and functional integrity of mitochondria, and these benefic effects contributed to preventing AIF release from mitochondria. 2-DG mimics glucose-6-phosphate accumulation to impair mitochondrial HK-II, while insulin increases HK-II binding to mitochondria via Akt activation. 2-DG and insulin increased and reduced AIF release from mitochondria, respectively, implying the special role of mitochondrial HK-II in the protection of neuron survival from DNA damage. PAR synthesis consumes NAD+ as a substrate and requires ATP [17]. AIV restored glutamate-induced loss of cellar NAD+ and ATP, further indicating the inhibitory effect of AIV on parthanatos. In addition, the improved mitochondrial oxidation by AIV was also a source for increased NAD+ and ATP contents, contributing to improving cellular energy homeostasis. The activation of NMDA receptor arouses PARP-1 hyper-activation [40] and DNA-alkylating agent MNNG is certified to induce PARP activation [18]. AIV protected neuronal survival and reduce AIF release from mitochondria when FAK Inhibitor 14 were exposed to NMDA or MNNG, further confirming its role to protect neurons from PARP-1activation-mediated cell death. In summary, our work showed that apoptosis and parthanatos simultaneously occurred in glutamate-mediated neuronal damage due to mitochondrial dysfunction. AIV activated Akt to promote HK-II binding to mitochondria, and the structural and functional integrity of mitochondria was essential for AIV to protect neuronal survival from apoptosis and DNA damage (Fig. 8). These findings not only show the association of apoptosis with regulated parthanatos, but also address the important role of mitochondrial HK-II in neuronal protection.
    Introduction The co-occurrence of environmental hyperoxia and high temperatures is well-recognized, particularly in tropical and sub-tropical freshwaters. In these areas with substantial aquatic photosynthetic biomass, waters with low flow can exceed 200% air saturation (DO2) (35°C in a tropical pond; (MacCormack et al., 2003), or even higher (c.a. 375% DO2 at 28°C in a subtropical pond) (Jiménez et al., 2003) depending on water depth and level of solar irradiation. Temperate waters such as the Miramichi system in New Brunswick, Canada, can already reach well over 30°C in the summer months (Caissie et al., 2012). Although oxygen measurements in the Miramichi are not available, they are likely comparable to those of subtropical waters reaching 28°C and c.a. 160% oxygen saturation daily in the summer (e.g., Xu and Xu, 2015). Climate change threatens to further raise water temperatures in temperate regions (Caissie et al., 2014), which may increase the system's biomass even more (Feuchtmayr et al., 2009), increasing the likelihood of combined hyperthermic and hyperoxic stress. Cardiomyocytes (CMs) from fish, such as the rainbow trout (Oncorhynchus mykiss), have long been a topic of interest due to their unique physiology. They are relatively tolerant of hypoxia much like fetal or neonatal mammalian CMs (Patterson and Zhang, 2010) due to both a relatively low metabolic rate and high glycogen content. Salmonid CMs have a narrow and elongated morphology with well-organized sarcomeric structure (Karro et al., 2017), in contrast with the rounded shape and disorganized contractile machinery of young mammalian CMs. These cells are metabolically specialized, as piscine CMs are highly dependent on oxidative metabolism but their mitochondria are well-separated from the sarcolemma (Karro et al., 2017). Since they largely lack transverse tubules, there is a considerable cytosolic gap between extracellular nutrients and the mitochondria they must reach to maintain cellular metabolic activity. This gap is functionally analogous to the cytosolic gap in rat and human CMs, which is shorter due to the presence of transverse tubules but rendered considerably more tortuous by a denser, more extensive cytoskeleton and sarcoplasmic reticulum (Karro et al., 2017). The recycling of ADP to the mitochondria can also be subject to a bottleneck at the outer mitochondrial membrane specifically in fish CMs, but this is mitigated by the close coupling of the highly-conserved glycolytic enzyme hexokinase (HK) to mitochondrial respiration (Karro et al., 2017). Hexokinase binds to the outer mitochondrial membrane at the voltage-dependent anion channel (VDAC), driven at least partially via pro-survival signaling through the Akt pathway. Increased mitochondrial HK (mtHK) density is accomplished in part by increasing total hexokinase expression to passively increase the bound fraction (Vander Heiden et al., 2001). In addition, a higher relative fraction of HK can be induced to bind to the outer mitochondrial membrane through post-translational modifications. The more mobile hexokinase II (HKII) isoform is directly phosphorylated by Akt and therefore its translocation patterns have been extensively elucidated; however, hexokinase I (HKI) does not share the Akt target consensus sequence (see review by Roberts and Miyamoto, 2015). The precise mechanisms underlying the mitochondrial binding of HKI are still unclear (Regenold et al., 2012), however both isoforms are sensitive to allosteric inhibition and removal from the mitochondria by their product glucose-6-phosphate (Sui and Wilson, 1997).