Alteration of Isocitrate Dehydrogenase Following Acute Ischemic Injury as a Means to Improve Cellular Energetic Status in Neuroadaptation

Abstract

The isocitrate dehydrogenase (IDH) enzymes were initially identified as essential components of the Krebs cycle. IDH mutations were thought to be incompatible with cell survival. However, 90% of glioblastomas were recently shown to be associated with somatic mutations in these enzymes, indicating a possible role for IDH in promoting cellular survival in hypoxic environments. Our proteomic analysis of rats given 10 minutes of middle cerebral artery occlusion to induce transient ischemia demonstrates a significant decrease in IDH expression. We have recapitulated this decrease in an in vitro model using primary cortical neurons exposed to acute oxygen and glucose deprivation. Given the role of IDHs in energy metabolism and antioxidant production, we hypothesize that the IDHs may serve as first-line, rapid-response enzymes that regulate survival in environments of energetic or oxidative stress. In order to identify the specific events that regulate IDH enzymes, HT-22 neural cells were subjected to either a selective energetic challenge or a pure oxidative stress. In response to the non-lethal energetic challenge induced by substituting galactose for glucose, we observed increased IDH1, 2, and 3 expression and cessation of cellular proliferation. No change in expression of any IDH isoform was observed when neural cells were subjected to subtoxic oxidative stress via glutathione depletion. Taken together, these data imply that IDH expression rapidly responds to changes in energetic status, but not to oxidative stress. These data also suggest that IDH enzymes respond not only to allosteric modulation, but can also change patterns of expression in response to moderate stress in an effort to maximize ATP production and survival.

Isocitrate dehydrogenase‐mutant glioma: Evolving clinical and therapeutic implications

“…The observation of less contrast enhancement in IDH ‐mutant tumors is believed to be driven primarily by the integrity of the blood‐brain barrier, which is more intact than in patients with IDH wild‐type gliomas. This is supported by report of hypoperfusion in IDH ‐mutant gliomas . Decreased permeability of the blood‐brain barrier may be related to the inhibition of angiogenesis in IDH ‐mutant glioma …”

“…This is supported by report of hypoperfusion in IDHmutant gliomas. 49 Decreased permeability of the bloodbrain barrier may be related to the inhibition of angiogenesis in IDH-mutant glioma. 50,51 The most striking clinical correlation that reinforced the theory that IDH-mutant gliomas behave differently is the finding that patients with an IDH-mutant glioma live longer than patients with IDH wild-type glioma.…”

Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network

“…Moreover, in the model, we observed an increased flux in antioxidant enzymes and key enzymes in glycolysis (Table 4 ). In this aspect, many studies have shown that these enzymes can be part of a machinery for cultured astrocytes to adapt to an ischemic environment, suggesting that the overexpression of antioxidant enzymes may be an important protective mechanism that prevents brain injury (Sonnewald et al, 1994 ; Niitsu et al, 1999 ; Grelli et al, 2013 ). Overall, the in silico predictions of our model, are similar to those experimentally reported in ischemic astrocytes, suggesting the predictive value of the present model.…”

Quercetin Might Promote Autophagy in a Middle Cerebral Artery Occlusion-Mediated Ischemia Model: Comments on Fawad-Ali Shah et al.

“…The reported role of quercetin on autophagy-mediated cell survival, in order to counteract brain injury-induced apoptosis, suggested us to comment the reported data by Fawad-Ali Shah et al as we retrieved further insights on the role of quercetin in MCAO. We realized that some of the upregulated proteins reported by the authors are also involved in the modulation of autophagy [17][18][19][20].…”