Denise Inman, Ph.D.
Permanent URI for this communityhttps://hdl.handle.net/20.500.12503/31770
North Texas Eye Research Institute
Associate Professor, Pharmaceutical Sciences
Email: denise.inman@unthsc.edu
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Browsing Denise Inman, Ph.D. by Subject "astrocyte"
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Item Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration(Frontiers Media S.A., 2021-07-21) Jassim, Assraa Hassan; Inman, Denise M.; Mitchell, Claire H.Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial and inflammatory signaling can exacerbate issues in chronic neurodegenerations. This review discusses evidence for the interaction between mitochondrial damage and inflammation, with a focus on glaucomatous neurodegeneration, and proposes that positive feedback resulting from this crosstalk drives pathology. Mitochondrial dysfunction exacerbates inflammatory signaling in multiple ways. Damaged mitochondrial DNA is a damage-associated molecular pattern, which activates the NLRP3 inflammasome; priming and activation of the NLRP3 inflammasome, and the resulting liberation of IL-1beta and IL-18 via the gasdermin D pore, is a major pathway to enhance inflammatory responses. The rise in reactive oxygen species induced by mitochondrial damage also activates inflammatory pathways, while blockage of Complex enzymes is sufficient to increase inflammatory signaling. Impaired mitophagy contributes to inflammation as the inability to turnover mitochondria in a timely manner increases levels of ROS and damaged mtDNA, with the latter likely to stimulate the cGAS-STING pathway to increase interferon signaling. Mitochondrial associated ER membrane contacts and the mitochondria-associated adaptor molecule MAVS can activate NLRP3 inflammasome signaling. In addition to dysfunctional mitochondria increasing inflammation, the corollary also occurs, with inflammation reducing mitochondrial function and ATP production; the resulting downward spiral accelerates degeneration. Evidence from several preclinical models including the DBA/2J mouse, microbead injection and transient elevation of IOP, in addition to patient data, implicates both mitochondrial damage and inflammation in glaucomatous neurodegeneration. The pressure-dependent hypoxia and the resulting metabolic vulnerability is associated with mitochondrial damage and IL-1beta release. Links between mitochondrial dysfunction and inflammation can occur in retinal ganglion cells, microglia cells and astrocytes. In summary, crosstalk between damaged mitochondria and increased inflammatory signaling enhances pathology in glaucomatous neurodegeneration, with implications for other complex age-dependent neurodegenerations like Alzheimer's and Parkinson's disease.Item Stretch stress propels glutamine dependency and glycolysis in optic nerve head astrocytes(Frontiers Media S.A., 2022-08-05) Pappenhagen, Nathaniel; Yin, Eric; Morgan, Autumn B.; Kiehlbauch, Charles C.; Inman, Denise M.Glaucoma is an optic neuropathy that leads to irreversible blindness, the most common subtype of which is typified by a chronic increase in intraocular pressure that promotes a stretch injury to the optic nerve head. In rodents, the predominant glial cell in this region is the optic nerve head astrocyte that provides axons with metabolic support, likely by releasing lactate produced through astrocytic glycolysis. Our primary hypothesis is that stretching of the optic nerve head astrocytes alters their metabolic activity, thereby advancing glaucoma-associated degeneration by compromising the metabolic support that the astrocytes provide to the axons in the optic nerve head. Metabolic changes in optic nerve head astrocytes were investigated by subjecting them to 24 h of 12% biaxial stretch at 1 Hz then measuring the cells' bioenergetics using a Seahorse XFe24 Analyzer. We observed significant glycolytic and respiratory activity differences between control and stretched cells, including greater extracellular acidification and lower ATP-linked respiration, yet higher maximal respiration and spare capacity in stretched optic nerve head astrocytes. We also determined that both control and stretched optic nerve head astrocytes displayed a dependency for glutamine over pyruvate or long-chain fatty acids for fuel. The increased use of glycolysis as indicated by the extracellular acidification rate, concomitant with a dependency on glutamine, suggests the need to replenish NAD + for continued glycolysis and provision of carbon for TCA cycle intermediates. Stretch alters optic nerve astrocyte bioenergetics to support an increased demand for internal and external energy.