Oxidative Stress and Hypoxia Modify Mitochondrial Homeostasis During Glaucoma

Jassim, Assraa Hassan; Fan, Yan; Pappenhagen, Nathaniel; Nsiah, Nana Yaa; Inman, Denise M.

doi:10.1089/ars.2020.8180

Cited by 32 publications

(20 citation statements)

References 69 publications

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“…Created with Biorender.com Chiozzi et al, 2019, Petersen et al, 2008 cell. Although high reliance on glycolysis was recently shown in glaucomatous D2 ON (Jassim et al, 2021), degeneration proceeds, indicating that ATP produced from glycolysis is insufficient to meet the high energy demand of axons during glaucoma.…”

Section: Dysfunctional Mitophagy Exacerbates Inflammationmentioning

confidence: 98%

“…However, prolonged hypoxia during glaucoma introduces dysfunctional feedback, impairing mitophagic induction and amplifying the accumulation of dysfunctional mitochondria that result in exacerbated oxidative stress and inflammation. Evidence exists for hypoxia at early stages of glaucoma in the D2 and microbead models ( Jassim et al, 2021 ), and for oxidative stress ( Jassim and Inman, 2019 ), mitochondrial dysfunction and limited mitophagy ( Coughlin et al, 2015 ; Kleesattel et al, 2015 ) in glaucoma models.…”

Section: Hypoxia Contributes To Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Metabolic vulnerability also contributes to glaucomatous degeneration ( Inman and Harun-or-Rashid, 2017 ; Williams et al, 2017 ; Harun-or-Rashid et al, 2018 ; Harun-or-Rashid et al, 2020 ). Axons rely primarily on glycolysis during glaucoma to compensate for mitochondrial dysfunction, though glycolysis is ultimately insufficient to rescue metabolic vulnerability associated with glaucoma ( Jassim et al, 2021 ). Interestingly, the increased oxidative phosphorylation accompanying a ketogenic diet rescued RGC degeneration due, at least in part, to a reduction in inflammation ( Harun-or-Rashid and Inman, 2018 ).…”

Section: Hypoxia Contributes To Mitochondrial Dysfunctionmentioning

confidence: 99%

“…During hypoxia, oxidative phosphorylation is expected to decline and glycolysis would become the primary ATP source in the cell. Although high reliance on glycolysis was recently shown in glaucomatous D2 ON ( Jassim et al, 2021 ), degeneration proceeds, indicating that ATP produced from glycolysis is insufficient to meet the high energy demand of axons during glaucoma.…”

Section: Dysfunctional Mitophagy Exacerbates Inflammationmentioning

confidence: 99%

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Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

2021

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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-1β 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-1β 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.

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Section: Dysfunctional Mitophagy Exacerbates Inflammationmentioning

confidence: 98%

Section: Hypoxia Contributes To Mitochondrial Dysfunctionmentioning

confidence: 99%

Section: Hypoxia Contributes To Mitochondrial Dysfunctionmentioning

confidence: 99%

Section: Dysfunctional Mitophagy Exacerbates Inflammationmentioning

confidence: 99%

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Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

2021

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“…Scutellarin has also been shown to alleviate hypoxia-induced cognitive impairment by promoting the proliferation and differentiation of neural stem cells in a mouse model ( 35 ). Chronic IOP elevation can induce ischemia and hypoxia of the optic nerve and its surrounding retinal tissue ( 36 – 38 ) causing retinal cell loss or neurodegeneration, which may lead to inner retinal thinning ( 39 , 40 ). On the other hand, scutellarin can improve the axoplasmic flow and blood supply of the optic nerve ( 41 ), as well as the growth promotion and apoptosis inhibition of RGCs ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Oral Scutellarin Treatment Ameliorates Retinal Thinning and Visual Deficits in Experimental Glaucoma

et al. 2021

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Purpose: Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that can exert neuroprotective effects in the eye and brain. Here, we investigated the neurobehavioral effects of scutellarin treatment in a chronic IOP elevation model.Methods: Ten adult C57BL/6J mice were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice received unilateral intracameral injection of phosphate-buffered saline only. Another eight mice with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin. Tonometry, optical coherence tomography, and optokinetics were performed longitudinally for 4 weeks to monitor the IOP, retinal nerve fiber layer thickness, total retinal thickness, visual acuity, and contrast sensitivity of both eyes in all three groups.Results: Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant inter-eye IOP difference between scutellarin treatment and untreated groups. Upon scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes. No significant difference in retinal thickness or optokinetic measures was found in the contralateral, non-treated eyes over time or between all groups.Conclusion: Using the non-invasive measuring platform, oral scutellarin treatment appeared to preserve retinal structure and visual function upon chronic IOP elevation in mice. Scutellarin may be a novel neurotherapeutic agent for glaucoma treatment.

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Hypoxia expedites the progression of papillary thyroid carcinoma by promoting the CPT1A‐mediated fatty acid oxidative pathway

Liang,

He,

Zhang

et al. 2024

Drug Development Research

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Hypoxia has been reported to promote the proliferation and migration of thyroid cancer, while the special mechanism was still unclear. HIF‐1α/carnitine palmitoyl‐transferase 1A (CPT1A) was found to be associated with papillary thyroid carcinoma (PTC) but the biological role of CPT1A in PTC was not explored. The effects of hypoxia and carnitine palmitoyl‐transferase 1A (CPT1A) expression on PTC cells were determined by cell counting kit‐8 assay, detection of oxidative stress, inflammation response and mitochondrial membrane motential (MMP). Oil Red O staining and the detection of free fatty acids were performed to assess the status of lipid metabolism. Flow cytometric analysis was performed to assess cell apoptosis. Quantitative polymerase chain reaction (qPCR) and western blot analysis were applied to investigate the expressions of CPT1A and HIF‐1α and the molecules involved cell function. The expressions of CPT1A and HIF‐1α were significantly increased in PTC cells with or without hypoxia treatment. CPT1A overexpression or silencing promoted or inhibited cell viability, and hypoxia further repressed cell viability. In addition, CPT1A overexpression alleviates hypoxia‐induced increased oxidative stress, inflammation response and elevated MMP. CPT1A overexpression enhanced palmitic acid‐induced decreased cell growth, enhanced the metabolic capacity of free fatty acid and suppressed cell apoptosis. Animal experiments showed that CPT1A overexpression promoted PTC tumor growth, reduced lipid deposition, oxidative stress and inflammation, as well as enhancing cell function indicators. However, CPT1A silencing showed the opposite effects both in vitro and in vivo. Hypoxia induces the high expression of HIF‐1α/CPT1A, thereby reprogramming the lipid metabolism of PTC cells for adapting the hypoxia environment, meanwhile inhibiting the cell damage and apoptosis caused by oxidative stress.

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Oxidative Stress and Hypoxia Modify Mitochondrial Homeostasis During Glaucoma

Cited by 32 publications

References 69 publications

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

Oral Scutellarin Treatment Ameliorates Retinal Thinning and Visual Deficits in Experimental Glaucoma

Hypoxia expedites the progression of papillary thyroid carcinoma by promoting the CPT1A‐mediated fatty acid oxidative pathway

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