scholarly journals Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 496
Author(s):  
Alessandra Maresca ◽  
Valerio Carelli
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Mitochondrial Dynamics ◽  
Unmet Need ◽  
Deep Understanding ◽  
Genetic Landscape ◽  
Innovative Therapies ◽  
Energy Dependent

Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

2019 ◽  
Vol 25 (28) ◽  
pp. 3057-3073 ◽  
Author(s):  
Kobra B. Juybari ◽  
Azam Hosseinzadeh ◽  
Habib Ghaznavi ◽  
Mahboobeh Kamali ◽  
Ahad Sedaghat ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Ganglion Cells ◽  
Axon Growth ◽  
Nerve Fibers ◽  
Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

scholarly journals Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

2021 ◽  
Vol 22 (6) ◽  
pp. 2881
Author(s):  
Clara Lefranc ◽  
Malou Friederich-Persson ◽  
Fabienne Foufelle ◽  
Aurélie Nguyen Dinh Cat ◽  
Frédéric Jaisser
Keyword(s):  
Quality Control ◽  
Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Oxidative Stress ◽  
Specific Effects

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

scholarly journals Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy

2021 ◽  
Author(s):  
Marta Zaninello ◽  
Konstantinos Palikaras ◽  
Aggeliki Sotiriou ◽  
Nektarios Tavernarakis ◽  
Luca Scorrano
Keyword(s):  
Mitochondrial Dysfunction ◽  
Motor Neurons ◽  
Optic Atrophy ◽  
Autosomal Dominant ◽  
Ganglion Cells ◽  
Mitochondrial Dynamics ◽  
Second Messengers ◽  
Mitochondrial Density ◽  
Autosomal Dominant Optic Atrophy ◽  
Dominant Optic Atrophy

AbstractMitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.

scholarly journals Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Daniela M. Arduíno ◽  
A. Raquel Esteves ◽  
Sandra M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Growing Body ◽  
Parkinsonian Disorders ◽  
Mitochondrial Trafficking

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance.

scholarly journals The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1593
Author(s):  
Nicole A. Muench ◽  
Sonia Patel ◽  
Margaret E. Maes ◽  
Ryan J. Donahue ◽  
Akihiro Ikeda ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Pressure Gradient ◽  
Ganglion Cells ◽  
Mitochondrial Dynamics ◽  
Metabolic Stress ◽  
Neuronal Cell ◽  
Retinal Ganglion ◽  
Support Functions ◽  
Dynamics And Function ◽  
And Function

The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs.

scholarly journals αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson’s Disease?

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
David Protter ◽  
Charmaine Lang ◽  
Antony A. Cooper
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Term Therapy ◽  
Central Component ◽  
Cellular Targets

Parkinson’s Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization.

scholarly journals The Potential of Visible and Far-Red to Near-Infrared Light in Glaucoma Neuroprotection

2021 ◽  
Vol 11 (13) ◽  
pp. 5872
Author(s):  
Loredana Bergandi ◽  
Francesca Silvagno ◽  
Giulia Grisolia ◽  
Antonio Ponzetto ◽  
Emilio Rapetti ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Ganglion Cells ◽  
Nerve Repair ◽  
Treatment Strategies ◽  
Neuronal Cell ◽  
Infrared Light ◽  
Near Infrared Light ◽  
The Impact

Alternative treatment strategies are necessary to reduce the severity of glaucoma, a group of eye conditions that progressively damage the optic nerve and impair vision. The aim of this review is to gain insight into potentially exploitable molecular mechanisms to slow down the death of retinal ganglion cells (RGCs), a fundamental element in the pathophysiology of all forms of glaucoma, and to stimulate adult optic nerve repair. For this purpose, we focus our analysis on both visible and far-red to near-infrared light photobiomodulation (PBM) as phototherapeutic agents, which were recently proposed in RGCs, and on the nerve lamina region neural progenitor cell (ONLR-NPC) niche. Both are suggested as potential strategies in glaucoma neuroprotection. We discuss the impact of beneficial molecular effects of PBM on both mitochondrial derangement and the alteration of ion fluxes that are considered important causes of RGC damage, as well as on the stimulation of progenitor cells. We suggest these are the most promising approaches to prevent excessive neuronal cell loss. We describe the experimental evidence supporting the validity of PBM therapy which, despite being a safe, non-invasive, inexpensive, and easy to administer procedure, has not yet been fully explored in the clinical practice of glaucoma treatment.

INVESTIGATING CRMP4 FUNCTION IN NERVE REGENERATION

2008 ◽  
Vol 31 (4) ◽  
pp. 18
Author(s):  
S Ong Tone ◽  
Y Z Alabed ◽  
A Di Polo ◽  
A E Fournier
Keyword(s):  
Optic Nerve ◽  
Neurite Outgrowth ◽  
Nerve Regeneration ◽  
Nerve Injury ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Growth State

Background: The failure of CNS neurons to spontaneously regenerate following injury can be partially attributed to the expression of neurite outgrowth inhibitory myelin associated inhibitors (MAIs). MAIs signal through a tripartite receptor complex to activate the cytosolic protein RhoA and influence cytoskeletal dynamics. RhoA antagonists promote neuronal survival and regeneration in animal models of nerve injury. However, RhoA's potential as a therapeutic target may be limited by its widespread roles in multiple cellular processes and cell types. In an attempt to discover more specific therapeutic targets to promote nerve regeneration, our lab identified the cytosolic phosphoprotein CRMP4b (Collapsin Response Mediator Protein 4b) as a protein that functionally interacts with RhoA to mediate neurite outgrowth inhibition. Blockade of the RhoA-CRMP4b interaction with a competitive peptide (C4RIP) attenuates myelin-dependent neurite outgrowth inhibition. Methods: We are currently investigating the in vivo roles of CRMP4in regeneration in an optic nerve injury model by developing a readily deliverable version of C4RIP. Results: Preliminary results suggest that overexpression of C4RIP in retinal ganglion cells by adeno-associated virus does not promote regeneration. However, studies investigating the ability of C4RIP to promote nerve regeneration into the optic nerve following stimulation of neurons into anactive growth state are currently in progress. Conclusion: Elucidating the role of CRMP4 in nerve regeneration may provide insight into the molecular mechanisms following nervous system injury and lead to the development of more specific therapeutic interventions. Reference: Alabed YZ, Pool M, Ong Tone S, Fournier AE.Identification of CRMP4 as a convergent regulator of axon outgrowth inhibition. J Neurosci 2007;27:1702-11.

scholarly journals Correlation between Retinal Ganglion Cell Loss and Nerve Crush Force-Impulse Established with Instrumented Tweezers in Mice

2019 ◽  
Author(s):  
Xiaorong Liu ◽  
Liang Feng ◽  
Ishan Shinde ◽  
James D. Cole ◽  
John B. Troy ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Real Time ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Nerve Crush ◽  
Axon Loss ◽  
Axon Damage ◽  
First Time

AbstractObjectivesRodent models of optic nerve crush (ONC) have often been used to study degeneration and regeneration of retinal ganglion cells (RGCs) and their axons as well as the underlying molecular mechanisms. However, ONC results from different laboratories exhibit a range of RGC injury with varying degree of axonal damage. We developed an instrumented tweezers to measure optic nerve (ON) crush forces in real time and studied the correlation between RGC axon loss and force-impulse, the product of force and duration, applied through the instrumented tweezers in mice.MethodsA pair of standard self-closing #N7 tweezers were instrumented with miniature foil strain gauges at optimal locations on both tweezer arms. The instrumented tweezers were capable of recording the tip closure forces in the form of voltages, which were calibrated through load cells to corresponding tip closure forces over the operating range. Using the instrumented tweezers, the ONs of multiple mice were crushed with varied forces and durations and the axons in the immunostained sections of the crushed ONs were counted.ResultsWe found that the surviving axon density correlated with crush force, with longer duration and stronger crush forces producing consistently more axon damage.DiscussionThe instrumented tweezers enable a simple technique for measurement of ONC forces in real-time for the first time. Using the instrumented tweezers, experimenters can quantify crush forces during ONC to produce consistent and predictable post-crush cell death. This should permit future studies a way to produce nerve damage more consistently than is available now.

scholarly journals Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups

2021 ◽  
Vol 12 ◽  
Author(s):  
Valeria Lo Faro ◽  
Ilja M. Nolte ◽  
Jacoline B. Ten Brink ◽  
Harold Snieder ◽  
Nomdo M. Jansonius ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Genome ◽  
Mitochondrial Dysfunction ◽  
Primary Open Angle Glaucoma ◽  
Ganglion Cells ◽  
Open Angle Glaucoma ◽  
Mitochondrial Gene ◽  
Meta Analysis ◽  
Nucleotide Polymorphisms ◽  
Open Angle

Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG.Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs.Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) = 0.64; p = 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR = 0.75; p = 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p = 1.2 × 10−05), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7–13.1).Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.

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