Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo

Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.

Download Full-text

MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress

Life Science Alliance ◽

10.26508/lsa.201900308 ◽

2019 ◽

Vol 2 (4) ◽

pp. e201900308 ◽

Cited By ~ 7

Author(s):

Shun Nagashima ◽

Keisuke Takeda ◽

Nobuhiko Ohno ◽

Satoshi Ishido ◽

Motohide Aoki ◽

...

Keyword(s):

Oxidative Stress ◽

Microglial Activation ◽

Developmental Disorders ◽

Inflammatory Diseases ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Three Dimensional ◽

Abnormal Behavior ◽

Mitochondrial Abnormalities

Mitochondrial abnormalities are associated with developmental disorders, although a causal relationship remains largely unknown. Here, we report that increased oxidative stress in neurons by deletion of mitochondrial ubiquitin ligase MITOL causes a potential neuroinflammation including aberrant astrogliosis and microglial activation, indicating that mitochondrial abnormalities might confer a risk for inflammatory diseases in brain such as psychiatric disorders. A role of MITOL in both mitochondrial dynamics and ER-mitochondria tethering prompted us to characterize three-dimensional structures of mitochondria in vivo. In MITOL-deficient neurons, we observed a significant reduction in the ER-mitochondria contact sites, which might lead to perturbation of phospholipids transfer, consequently reduce cardiolipin biogenesis. We also found that branched large mitochondria disappeared by deletion of MITOL. These morphological abnormalities of mitochondria resulted in enhanced oxidative stress in brain, which led to astrogliosis and microglial activation partly causing abnormal behavior. In conclusion, the reduced ER-mitochondria tethering and excessive mitochondrial fission may trigger neuroinflammation through oxidative stress.

Download Full-text

Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells

Molecular and Cellular Biology ◽

10.1128/mcb.00148-19 ◽

2019 ◽

Vol 39 (20) ◽

Cited By ~ 6

Author(s):

Mi Hye Kim ◽

Hong Jun Lee ◽

Sang-Rae Lee ◽

Hyun-Shik Lee ◽

Jae-Won Huh ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Glutamate Toxicity ◽

Ht22 Cells ◽

Peroxidase Enzyme ◽

The Central Nervous System

ABSTRACT Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

Download Full-text

Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/3640753 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Youngmun Lee ◽

Sunyoung Kim ◽

Yeonsoo Oh ◽

Young-Mi Kim ◽

Young-Won Chin ◽

...

Keyword(s):

Oxidative Stress ◽

Memory Impairment ◽

Neuronal Damage ◽

Biological Activities ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ros Generation ◽

Garcinia Mangostana

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer’s disease.

Download Full-text

Protective peptides derived from novel glial proteins

Biochemical Society Transactions ◽

10.1042/bst0280452 ◽

2000 ◽

Vol 28 (4) ◽

pp. 452-455 ◽

Cited By ~ 4

Author(s):

D. E. Brenneman ◽

C. Y. Spong ◽

I. Gozes

Keyword(s):

Oxidative Stress ◽

Central Nervous System ◽

Nervous System ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Short Peptides ◽

Significant Efficacy ◽

The Central Nervous System ◽

Human Neurodegenerative Disease

In studying the mediators of VIP neurotrophism in the central nervous system, two glial proteins have been discovered. Both of these proteins contain short peptides that exhibit femtomolar potency in preventing neuronal cell death from a wide variety of neurotoxic substances. Extension of these peptides to models of oxidative stress or neurodegeneration in vivo have indicated significant efficacy in protection. These peptides, both as individual agents and in combination, have promise as possible protective agents in the treatment of human neurodegenerative disease and in pathologies involving oxidative stress.

Download Full-text

P38 Initiates Diabetic Neurodegeneration Through Glutamatergic and GABAergic Neurons

10.21203/rs.3.rs-41603/v1 ◽

2020 ◽

Author(s):

Aisan Farhadi ◽

Mehdi Totonchi ◽

Seyed Masood Nabavi ◽

Hossein Baharvand ◽

Hossein Pakdaman ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Diabetic Mouse ◽

Gabaergic Neurons ◽

Expression Data ◽

Tau Pathology

Abstract Background: Diabetes mellitus may cause neurodegeneration, but the exact mechanism by which diabetic conditions induce neuronal cell death remains unclear. Tau protein hyperphosphorylation is considered to be a major pathological hallmark of neurodegeneration and can be triggered by diabetes. Various tau-directed kinases, including P38, can be activated upon diabetic stress and induce tau hyperphosphorylation. Despite extensive research efforts and the known importance of tau pathology in neurodegeneration, the exact tau specie(s) and kinases driving neurodegeneration in diabetes mellitus have not been clearly elucidated. Methods: We herein employed protein expression data analysis as well as immunofluorescence and immunoblotting techniques to determine the exact molecular mechanism of tau pathology triggered by diabetes in both in vitro and in vivo systems.Results: We found that P38, a major tau kinase, was increased in Glutamatergic & GABAergic neuron subtypes under diabetic conditions. This rendered them more responsive to oxidative stress caused by diabetes. We observed that oxidative stress activated P38, which in turn directly and indirectly drove tau pathology in the brainstem (enriched by Glutamatergic & GABAergic neurons), which gradually spread to neighboring brain areas. Notably, P38 inhibition suppressed tau pathogenicity and neurodegeneration in diabetic mouse models. Conclusion: The data establish P38 as a central mediator of diabetes mellitus induced tau pathology. Furthermore, the inhibition of P38 at early stages of diabetes-induced stress can inhibit tau pathology. Our findings provide mechanistic insight on the consequences of this metabolic disorder on the nervous system.

Download Full-text

Bacopa monnierias an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/615384 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 24

Author(s):

Tamara Simpson ◽

Matthew Pase ◽

Con Stough

Keyword(s):

Oxidative Stress ◽

Cognitive Function ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Bacopa Monnieri ◽

Aging Brain ◽

Resonance Spectroscopy ◽

Age Related

The detrimental effect of neuronal cell death due to oxidative stress and mitochondrial dysfunction has been implicated in age-related cognitive decline and neurodegenerative disorders such as Alzheimer’s disease. The Indian herbBacopa monnieriis a dietary antioxidant, with animal andin vitrostudies indicating several modes of action that may protect the brain against oxidative damage. In parallel, several studies using the CDRI08 extract have shown that extracts ofBacopa monnieriimprove cognitive function in humans. The biological mechanisms of this cognitive enhancement are unknown. In this review we discuss the animal studies andin vivoevidence forBacopa monnierias a potential therapeutic antioxidant to reduce oxidative stress and improve cognitive function. We suggest that future studies incorporate neuroimaging particularly magnetic resonance spectroscopy into their randomized controlled trials to better understand whether changes in antioxidant statusin vivocause improvements in cognitive function.

Download Full-text

Abstract 568: Deletion of AMP-activated Protein Kinase-alpha Triggers Mitochondrial Fission and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.568 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Qqilong Wang ◽

Zhonglin Xie ◽

Huaiping Zhu ◽

Ye Ding ◽

Ming-Hui Zou

Keyword(s):

Protein Kinase ◽

Endothelial Dysfunction ◽

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Chronic Administration ◽

Mitochondrial Fragmentation ◽

Aortic Endothelium ◽

Amp Activated Protein Kinase

Introduction: AMP-activated protein kinase (AMPK) has been reported to regulate mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which AMPK regulates mitochondrial dynamics remain poorly characterized. We hypothesized that AMPK deficiency regulates mitochondrial fission that will result in endothelial dysfunction. Methods/Results: Deletion of AMPKα2 resulted in defective autophagy, dynamin-related protein (Drp1) accumulation, and aberrant mitochondrial fragmentation in the aortic endothelium of mice. Furthermore, autophagy inhibition by chloroquine treatment or Atg7 small interfering RNA (siRNA) transfection upregulated Drp1 expression and triggered Drp1-mediated mitochondrial fragmentation. In contrast, autophagy activation by overexpression of Atg7 or chronic administration of rapamycin, the mammalian target of rapamycin kinase inhibitor, promoted Drp1 degradation and attenuated mitochondrial fission in AMPKα2 -/- mice, suggesting that defective autophagy contributes to enhanced Drp1 expression and mitochondrial fragmentation. Interesting, the genetic (Drp1 siRNA) or pharmacological (mdivi-1) inhibition of Drp1 ablated mitochondrial fragmentation in the mouse aortic endothelium and prevented the acetylcholine-induced relaxation of isolated mouse aortas from AMPKα2 -/- mice. This suggests that aberrant Drp1 is responsible for enhanced mitochondrial fission and endothelial dysfunction in AMPKα knockout mice. Conclusions: Our results show that AMPKα deletion promoted mitochondrial fission in vascular endothelial cells by inhibiting the autophagy-dependent degradation of Drp1.

Download Full-text

Abstract 392: Angiotensin II TypeI Receptor-mediated Mitochondrial Fission and Suppression of Mitophagy Play Crucial Role in Vascular Senescence and Arteriosclerosis

Circulation Research ◽

10.1161/res.127.suppl_1.392 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Yoshihiro Uchikado ◽

Yoshiyuki Ikeda ◽

Yuichi Sasaki ◽

Yuichi Akasaki ◽

Mitsuru Ohishi

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Mitochondrial Dysfunction ◽

Cellular Senescence ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Double Knockout ◽

Apoe Ko ◽

Vascular Senescence

Introduction: Metabolic stress including oxidized low density lipoprotein (ox-LDL) cause mitochondrial dysfunction and evoke vascular senescence and atherosclerosis. Mitochondria are highly dynamic organelles that undergo quality control by mitochondrial dynamics and mitophagy. This study aims to clarify whether and how mitochondrial dynamics and mitophagy are involved in the etiology of vascular senescence and arteriosclerosis. Methods: VSMC were stimulated by ox-LDL. We also conducted in vivo experiment using C57BL6 (WT), apolipoprotein E (ApoE) deficient and the double knockout of ApoE mice and Angiotensin II Type1 Receptor (AT1R). Results: Treatment of ox-LDL forced mitochondria to fission through activation of Drp1, induced mitochondrial dysfunction and oxidative stress, and developed cellular senescence. Inhibition of either Drp1, AT1R, MAPK retarded them, suggesting that mitochondrial fission plays key roles to develop premature cellular senescence and is modulated by AT1R/MAPK signal.Administration of ox-LDL decreased the number of mitophagy assessed by electron microscopy and immunohistochemistry of LAMP2 and TOMM20. AT1R signal inhibition increased mitophagy which was not affected by Atg7 knockdown, whereas it was decreased by either Rab9 or Ulk1 knockdown. Immunohistochemistry showed Rab9 dots were co-localized to TOMM20 and LAMP2, whereas LC3 dots were not, suggesting that AT1R signal induces mitophagy through Rab9-dependent alternative autophagy. The degree of vascular senescence was higher, the number of fused mitochondria and mitochondrial function were lower and mitochondrial oxidative stress was higher in ApoE KO than those in WT. DKO attenuated these adverse effect of ApoE KO. Conclusion: AT1R regulates vascular senescence and arteriosclerosis via induction of mitochondrial fission and inhibition of mitophagy.

Download Full-text

Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline

Journal of Alzheimer s Disease ◽

10.3233/jad-215175 ◽

2021 ◽

pp. 1-13

Author(s):

Luwen Wang ◽

Mengyu Liu ◽

Ju Gao ◽

Amber M. Smith ◽

Hisashi Fujioka ◽

...

Keyword(s):

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Neuronal Loss ◽

Mitochondrial Fusion ◽

Barnes Maze ◽

Mitochondrial Fragmentation ◽

Tau Pathology ◽

Marked Suppression

Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer’s disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.

Download Full-text