Probing the molecular mechanisms of neuronal degeneration: importance of mitochondrial dysfunction and calcineurin activation

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.

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Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Biomolecules ◽

10.3390/biom11040496 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22062881 ◽

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.

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Cellular and Molecular Mechanisms Underlying Perturbed Energy Metabolism and Neuronal Degeneration in Alzheimer's and Parkinson's Diseases

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1999.tb07824.x ◽

1999 ◽

Vol 893 (1 OXIDATIVE/ENE) ◽

pp. 154-175 ◽

Cited By ~ 210

Author(s):

MARK P. MATTSON ◽

WARD A. PEDERSEN ◽

WENZHEN DUAN ◽

CARSTEN CULMSEE ◽

SIMONETTA CAMANDOLA

Keyword(s):

Energy Metabolism ◽

Molecular Mechanisms ◽

Neuronal Degeneration ◽

Parkinson’S Diseases

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Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

10.1101/808246 ◽

2019 ◽

Cited By ~ 2

Author(s):

Minhong Huang ◽

Dan Lou ◽

Adhithiya Charli ◽

Dehui Kong ◽

Huajun Jin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Neuronal Degeneration ◽

Ex Vivo ◽

Genetic Mutation ◽

Common Mechanism ◽

Enhancer Activity ◽

Active Enhancer ◽

Environmental Component

AbstractGenetic mutations explain only 10-15% of cases of Parkinson’s disease (PD), while an overriding environmental component has been implicated in the etiopathogenesis of PD. But regardless of where the underlying triggers for the onset of familial and sporadic PD fall on the gene-environment axis, mitochondrial dysfunction emerges as a common mediator of dopaminergic neuronal degeneration. Herein, we employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure- and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed the mitochondrial dysfunction induced H3K27ac during neurodegeneration in ex vivo models of PD. Our results reveal an exciting axis of ‘exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome’ for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.

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Luteolin Confers Cerebroprotection after Subarachnoid Hemorrhage by Suppression of NLPR3 Inflammasome Activation through Nrf2-Dependent Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5838101 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Zi-Huan Zhang ◽

Jia-Qiang Liu ◽

Cheng-Di Hu ◽

Xin-Tong Zhao ◽

Fei-Yun Qin ◽

...

Keyword(s):

Oxidative Stress ◽

Subarachnoid Hemorrhage ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Neuronal Degeneration ◽

Antioxidant Systems ◽

Inflammasome Activation ◽

Related Factor ◽

Beneficial Effects ◽

Nrf2 Activation

Luteolin (LUT) possesses multiple biologic functions and has beneficial effects for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of LUT against subarachnoid hemorrhage (SAH) and the involvement of underlying molecular mechanisms. In a rat model of SAH, LUT significantly inhibited SAH-induced neuroinflammation as evidenced by reduced microglia activation, decreased neutrophil infiltration, and suppressed proinflammatory cytokine release. In addition, LUT markedly ameliorated SAH-induced oxidative damage and restored the endogenous antioxidant systems. Concomitant with the suppressed oxidative stress and neuroinflammation, LUT significantly improved neurologic function and reduced neuronal cell death after SAH. Mechanistically, LUT treatment significantly enhanced the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), while it downregulated nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation. Inhibition of Nrf2 by ML385 dramatically abrogated LUT-induced Nrf2 activation and NLRP3 suppression and reversed the beneficial effects of LUT against SAH. In neurons and microglia coculture system, LUT also mitigated oxidative stress, inflammatory response, and neuronal degeneration. These beneficial effects were associated with activation of the Nrf2 and inhibitory effects on NLRP3 inflammasome and were reversed by ML385 treatment. Taken together, this present study reveals that LUT confers protection against SAH by inhibiting NLRP3 inflammasome signaling pathway, which may be modulated by Nrf2 activation.

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Identification of Molecular Mechanisms in Parkinson’s Disease Pathogenesis: Significance of Survival and Inflammation Pathways

10.21203/rs.3.rs-41609/v1 ◽

2020 ◽

Author(s):

Zerrin Karaaslan ◽

Ozlem Timirci Kahraman ◽

Elif Sanli ◽

Hayriye Arzu Ergen ◽

Basar Bilgic ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Functional Annotation ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Neuronal Degeneration ◽

Expression Profiles ◽

Quantitative Polymerase Chain Reaction ◽

Rt Pcr ◽

Peripheral Blood Mononuclear

Abstract Background: Our aim was to identify the differentially expressed genes (DEGs) between Parkinson’s disease (PD) patients and controls by microarray technology and analysis of related molecular pathways by functional annotation. Methods: Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein-protein interaction analyses were performed with STRING. Expression levels of randomly selected 5 genes among DEGs were quantified by real time quantitative polymerase chain reaction (RT-PCR) for validation. Flow cytometry was done to determine frequency of regulatory T cells (Tregs) in peripheral blood mononuclear cells. Results: A total of 361 DEGs (143 upregulated and 218 downregulated) were identified after GeneSpring analysis. DEGs were involved in 28 biological processes, 12 cellular components and 26 molecular functions. Pathway analyses demonstrated that upregulated genes mainly enriched in p53 (CASP3, TSC2, ATR, MDM4, CCNG1) and PI3K/Akt (IL2RA, IL4R, TSC2, VEGFA, PKN2, PIK3CA, ITGA4, BCL2L11) signaling pathways. TP53 and PIK3CA were identified as most significant hub proteins. Expression profiles obtained by RT-PCR were consistent with microarray findings. PD patients showed increased proportions of CD49d+ Tregs, which correlated with disability scores. Discussion: Survival pathway genes were upregulated putatively to compensate neuronal degeneration. Bioinformatics analysis showed an association between survival and inflammation genes. Increased CD49d+ Treg ratios might signify the attempt of the immune system to suppress ongoing inflammation. Conclusion: Altered functions of Tregs might have an important role in PD pathogenesis and CD49d expression could be a prognostic biomarker of PD.

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Mitochondrial Dysfunction in Obesity and Reproduction

Endocrinology ◽

10.1210/endocr/bqaa158 ◽

2020 ◽

Vol 162 (1) ◽

Author(s):

Manasi Das ◽

Consuelo Sauceda ◽

Nicholas J G Webster

Keyword(s):

Mitochondrial Dysfunction ◽

Energy Production ◽

Molecular Mechanisms ◽

Human Populations ◽

Metabolic Alterations ◽

Genetic Manipulations ◽

The Past ◽

Calcium Buffering

Abstract Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. Because of the central role of mitochondria in energy production, heme biosynthesis, calcium buffering, steroidogenesis, and apoptosis signaling within cells, understanding the molecular mechanisms behind mitochondrial dysregulation and its potential implications in disease is critical. This review will take a journey through the past and summarize what is known about mitochondrial dysfunction in various disorders, focusing on metabolic alterations and reproductive abnormalities. Evidence is presented from studies in different human populations, and rodents with genetic manipulations of pathways known to affect mitochondrial function.

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Emodin Alleviates Hydrogen Peroxide-Induced Inflammation and Oxidative Stress via Mitochondrial Dysfunction by Inhibiting the PI3K/mTOR/GSK3β Pathway in Neuroblastoma SH-SY5Y Cells

BioMed Research International ◽

10.1155/2020/1562915 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Rui Li ◽

Wenzhou Liu ◽

Li Ou ◽

Feng Gao ◽

Min Li ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Cell Damage ◽

Neuroblastoma Cells ◽

Inflammatory Factors ◽

Protective Mechanism ◽

Human Neuroblastoma ◽

Induced Apoptosis

Emodin is an active monomer extracted from rhubarb root, which has many biological functions, including anti-inflammation, antioxidation, anticancer, and neuroprotection. However, the protective effect of emodin on nerve injury needs to be further elucidated. The purpose of this study is to investigate the effect of emodin on the neuroprotection and the special molecular mechanism. Here, the protective activity of emodin inhibiting H2O2-induced apoptosis and neuroinflammation as well as its molecular mechanisms was examined using human neuroblastoma cells (SH-SY5Y cells). The results showed that emodin significantly enhanced cell viability, reduced cell apoptosis and LDH release. Simultaneously, emodin downregulated H2O2-induced inflammatory factors, including IL-6, NO, and TNF-α, and alleviated H2O2-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells. In addition, emodin inhibited the activation of the PI3K/mTOR/GSK3β signaling pathway. What is more, the PI3K/mTOR/GSK3β pathway participated in the protective mechanism of emodin on H2O2-induced cell damage. Collectively, it suggests that emodin alleviates H2O2-induced apoptosis and neuroinflammation potentially by regulating the PI3K/mTOR/GSK3β signaling pathway.

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Autophagy is Activated In Vivo during Trimethyltin-Induced Apoptotic Neurodegeneration: A Study in the Rat Hippocampus

International Journal of Molecular Sciences ◽

10.3390/ijms21010175 ◽

2019 ◽

Vol 21 (1) ◽

pp. 175 ◽

Cited By ~ 1

Author(s):

Sabrina Ceccariglia ◽

Alessandra Alvino ◽

Aurora Del Fà ◽

Ornella Parolini ◽

Fabrizio Michetti ◽

...

Keyword(s):

Western Blotting ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Neuronal Degeneration ◽

Neuronal Loss ◽

Organotin Compound ◽

Nuclear Antigen ◽

Apoptotic Pathway

Trimethyltin (TMT) is an organotin compound known to produce significant and selective neuronal degeneration and reactive astrogliosis in the rodent central nervous system. Autophagy is the main cellular mechanism for degrading and recycling protein aggregates and damaged organelles, which in different stress conditions, such as starvation, generally improves cell survival. Autophagy is documented in several pathologic conditions, including neurodegenerative diseases. This study aimed to investigate the autophagy and apoptosis signaling pathways in hippocampal neurons of TMT-treated (Wistar) rats to explore molecular mechanisms involved in toxicant-induced neuronal injury. The microtubule-associated protein light chain (LC3, autophagosome marker) and sequestosome1 (SQSTM1/p62) (substrate of autophagy-mediated degradation) expressions were examined by Western blotting at different time points after intoxication. The results demonstrate that the LC3 II/I ratio significantly increased at 3 and 5 days, and that p62 levels significantly decreased at 7 and 14 days. Immunofluorescence images of LC3/neuronal nuclear antigen (NeuN) showed numerous strongly positive LC3 neurons throughout the hippocampus at 3 and 5 days. The terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay indicated an increase in apoptotic cells starting from 5 days after treatment. In order to clarify apoptotic pathway, immunofluorescence images of apoptosis-inducing factor (AIF)/NeuN did not show nuclear translocation of AIF in neurons. Increased expression of cleaved Caspase-3 was revealed at 5–14 days in all hippocampal regions by Western blotting and immunohistochemistry analyses. These data clearly demonstrate that TMT intoxication induces a marked increase in both autophagy and caspase-dependent apoptosis, and that autophagy occurring just before apoptosis could have a potential role in neuronal loss in this experimental model of neurodegeneration.

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