Programmed switch in the mitochondrial degradation pathways during human retinal ganglion cell differentiation from stem cells is critical for RGC survival

Das, Arupratan; Bell, Claire; Berlinicke, Cynthia; Marsh-Armstrong, Nicholas; Zack, Donald J.

doi:10.1016/j.redox.2020.101465

Cited by 13 publications

(25 citation statements)

References 64 publications

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“…Previously, it was reported, that the mitochondrial biogenesis activation could be pro cell survival as it associates with exercise induced muscle growth 24 and synaptic plasiticity 25 . In support to this notion, we found robust increase of mitochondrial biogenesis in RGCs with minimal cell death under mitochondrial stress as we previously reported 19 .…”

Section: Discussionsupporting

confidence: 92%

“…As mitochondria are the primary source for cellular ATP, it is likely that RGCs will be highly sensitive towards mitochondrial damage. However, we had shown even after 24h of treatment with a potent mitochondrial stressor CCCP, hRGCs degrade damaged mitochondria with minimal cell death 19 . This suggests the existence of a compensatory pathway for the loss of mitochondria or hRGCs are well-tolerated for mitochondrial loss.…”

Section: Resultsmentioning

confidence: 87%

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Enhanced mitochondrial biogenesis promotes neuroprotection in human stem cell derived retinal ganglion cells of the central nervous system

Das

Anbarasu

Huang

et al. 2022

Preprint

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Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding on how to improve mitochondrial homeostasis to promote neuroprotection. Here we used human stem cell differentiated retinal ganglion cells (hRGCs) of the CNS, which are highly sensitive towards mitochondrial dysfunctions due to their unique structure and function, to identify mechanisms for improving mitochondrial quality control (MQC). We found that hRGCs are efficient in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria under acute damage. Using a glaucomatous Optineurin mutant (E50K) stem cell lines, we saw that at basal level mutant hRGCs possess less mitochondrial mass and suffer mitochondrial swelling due to excess ATP production load. Activation of mitochondrial biogenesis through pharmacological inhibition of the Tank binding kinase 1 (TBK1) restored energy homeostasis, mitigated mitochondrial swelling with neuroprotection against acute mitochondrial damage for glaucomatous E50K hRGCs, revealing a novel neuroprotection mechanism.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 87%

Enhanced mitochondrial biogenesis promotes neuroprotection in human stem cell derived retinal ganglion cells of the central nervous system

Das

Anbarasu

Huang

et al. 2022

Preprint

Self Cite

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“…Mitochondrial turnover, which includes the biogenesis of new functional organelles, degradation of damaged organelles (a process termed ‘mitophagy’) and recycling of existing pools of organelles through fission and fusion processes, is a highly dynamic process that, if malfunctioning, can ultimately trigger apoptotic cascades. In particular, functional impairment of mitophagy-related proteins such as PINK1 (PTEN-induced kinase 1), Parkin and Optineurin has been shown to occur in both glaucoma [ 314 , 315 , 316 ] and diabetic retinopathy [ 317 ]. The relevance of these processes to glutamate excitotoxicity is demonstrated, for instance, by the overexpression of Parkin in RGCs, which protects isolated RGCs from glutamate and NMDA exposure, as well as in models of glaucoma [ 318 , 319 ].…”

Section: Cellular Mechanisms Of Nmda Receptor-induced Excitotoxicity ...mentioning

confidence: 99%

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

Boccuni

Fairless

2022

Life

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Glutamate neurotransmission and metabolism are finely modulated by the retinal network, where the efficient processing of visual information is shaped by the differential distribution and composition of glutamate receptors and transporters. However, disturbances in glutamate homeostasis can result in glutamate excitotoxicity, a major initiating factor of common neurodegenerative diseases. Within the retina, glutamate excitotoxicity can impair visual transmission by initiating degeneration of neuronal populations, including retinal ganglion cells (RGCs). The vulnerability of RGCs is observed not just as a result of retinal diseases but has also been ascribed to other common neurodegenerative and peripheral diseases. In this review, we describe the vulnerability of RGCs to glutamate excitotoxicity and the contribution of different glutamate receptors and transporters to this. In particular, we focus on the N-methyl-d-aspartate (NMDA) receptor as the major effector of glutamate-induced mechanisms of neurodegeneration, including impairment of calcium homeostasis, changes in gene expression and signalling, and mitochondrial dysfunction, as well as the role of endoplasmic reticular stress. Due to recent developments in the search for modulators of NMDA receptor signalling, novel neuroprotective strategies may be on the horizon.

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“…Mitochondrial fission can isolate damaged components, which can then be degraded by mitophagy ( Ito and Di Polo, 2017 ). This mechanism is essential for the quality control of mitochondria ( Das et al, 2020 ).…”

Section: Mitochondria Of Rgcs: Critical Target Of Metal Ionsmentioning

confidence: 99%

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Tang

Zhuo

2021

Front. Cell Dev. Biol.

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Glaucoma is the most substantial cause of irreversible blinding, which is accompanied by progressive retinal ganglion cell damage. Retinal ganglion cells are energy-intensive neurons that connect the brain and retina, and depend on mitochondrial homeostasis to transduce visual information through the brain. As cofactors that regulate many metabolic signals, iron and zinc have attracted increasing attention in studies on neurons and neurodegenerative diseases. Here, we summarize the research connecting iron, zinc, neuronal mitochondria, and glaucomatous injury, with the aim of updating and expanding the current view of how retinal ganglion cells degenerate in glaucoma, which can reveal novel potential targets for neuroprotection.

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Programmed switch in the mitochondrial degradation pathways during human retinal ganglion cell differentiation from stem cells is critical for RGC survival

Cited by 13 publications

References 64 publications

Enhanced mitochondrial biogenesis promotes neuroprotection in human stem cell derived retinal ganglion cells of the central nervous system

Enhanced mitochondrial biogenesis promotes neuroprotection in human stem cell derived retinal ganglion cells of the central nervous system

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

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