Description:
<jats:p>Neurodegeneration are associated with multiple hits at metabolic pathways including those involved in metabolism (mitochondria and glycolysis) cell signaling (Keap1‐Nrf2 or apoptosis) or cell repair pathways (fission/fusion and autophagy). We investigated the regulation of autophagy in neuronal response to oxidative and nitrative stress. 4‐hydroxynonenal (HNE) is a lipid peroxidation product formed during oxidative stress, accumulated in neurodegenerative diseases, and can further induce formation of other reactive species. DETA‐NONOate is a nitric oxide donor, used to mimick excessive nitric oxide produced by both neurons and glia in neurodegeneration. We found that HNE and DETA‐NONOate decrease mitochondrial oxygen consumption. Interestingly, HNE inhibited, and DETA‐NONOate stimulated glycolysis. The glycolysis response was inversely correlated with autophagy, as HNE stimulated and DETA‐NONOate inhibited autophagy. To investigate how glucose metabolism and autophagy play a role in mitochondrial quality control and cell death, we blocked glycolysis using 2‐DG, and found that 2‐DG abolished glycolysis, decreased mitochondrial reserve capacity, inhibited autophagy and exacerbated HNE‐ and DETA‐NONOate‐induced cell death. Inhibition of autophagy by 3‐MA, while increased glycolysis which is in contrary to 2‐DG, decreased mitochondrial reserve capacity and exacerbated HNE‐ and DETA‐NONOate‐induced cell death, effects similar to 2‐DG. Moreover, we found that 2‐DG played an important role in regulation of Bcl‐2 expression and 3‐MA played an important role in regulation of Drp1 and JNK activity. Our studies provide novel insights into how regulation of autophagy and glucose metabolism plays an important role in neuronal bioenergetics and survival in response to oxidative and nitrative stress. Funded by NIH and VA.</jats:p>