Actin(g) on mitochondria – a role for cofilin1 in neuronal cell death pathways

2019 ◽  
Vol 400 (9) ◽  
pp. 1089-1097 ◽  
Author(s):  
Lena Hoffmann ◽  
Marco B. Rust ◽  
Carsten Culmsee
Keyword(s):  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Actin Dynamics ◽  
Organelle Transport ◽  
Mitochondrial Morphology ◽  
Cell Death Pathways ◽  
Key Factor ◽  
Mitochondrial Membrane Permeabilization ◽  
And Function

AbstractActin dynamics, the coordinated assembly and disassembly of actin filaments (F-actin), are essential for fundamental cellular processes, including cell shaping and motility, cell division or organelle transport. Recent studies highlighted a novel role for actin dynamics in the regulation of mitochondrial morphology and function, for example, through mitochondrial recruitment of dynamin-related protein 1 (Drp1), a key factor in the mitochondrial fission machinery. Mitochondria are dynamic organelles, and permanent fission and fusion is essential to maintain their function in energy metabolism, calcium homeostasis and regulation of reactive oxygen species (ROS). Here, we summarize recent insights into the emerging role of cofilin1, a key regulator of actin dynamics, for mitochondrial shape and function under physiological conditions and during cellular stress, respectively. This is of peculiar importance in neurons, which are particularly prone to changes in actin regulation and mitochondrial integrity and function. In neurons, cofilin1 may contribute to degenerative processes through formation of cofilin-actin rods, and through enhanced mitochondrial fission, mitochondrial membrane permeabilization, and the release of cytochrome c. Overall, mitochondrial impairment induced by dysfunction of actin-regulating proteins such as cofilin1 emerge as important mechanisms of neuronal death with relevance to acute brain injury and neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease.

scholarly journals Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice

1998 ◽  
Vol 141 (2) ◽  
pp. 431-441 ◽  
Author(s):  
Yoshiaki Yonekawa ◽  
Akihiro Harada ◽  
Yasushi Okada ◽  
Takeshi Funakoshi ◽  
Yoshimitsu Kanai ◽  
...  
Keyword(s):  
Cell Death ◽  
Synaptic Vesicle ◽  
Neuronal Degeneration ◽  
Critical Role ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Organelle Transport ◽  
Murine Homologue ◽  
And Function

The nerve axon is a good model system for studying the molecular mechanism of organelle transport in cells. Recently, the new kinesin superfamily proteins (KIFs) have been identified as candidate motor proteins involved in organelle transport. Among them KIF1A, a murine homologue of unc-104 gene of Caenorhabditis elegans, is a unique monomeric neuron– specific microtubule plus end–directed motor and has been proposed as a transporter of synaptic vesicle precursors (Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769–780). To elucidate the function of KIF1A in vivo, we disrupted the KIF1A gene in mice. KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances. In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease. Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies. Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wild-type neurons or exposure to a low concentration of glutamate. These results in cultures suggested that the mutant neurons might not sufficiently receive afferent stimulation, such as neuronal contacts or neurotransmission, resulting in cell death. Thus, our results demonstrate that KIF1A transports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability, maintenance, and function of neurons, particularly mature neurons.

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

2019 ◽  
Vol 39 (20) ◽  
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.

scholarly journals Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2726
Author(s):  
James R. Bamburg ◽  
Laurie S. Minamide ◽  
O’Neil Wiggan ◽  
Lubna H. Tahtamouni ◽  
Thomas B. Kuhn
Keyword(s):  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Translational Regulation ◽  
Neuronal Development ◽  
Mitochondrial Fission ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Actin Dynamics ◽  
Specific Regulation ◽  
And Function

Proteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and are essential regulators of actin dynamics and function. Mammalian neurons express cofilin-1 as the major isoform, but ADF and cofilin-2 are also expressed. All isoforms bind preferentially and cooperatively along ADP-subunits in F-actin, affecting the filament helical rotation, and when either alone or when enhanced by other proteins, promotes filament severing and subunit turnover. Although self-regulating cofilin-mediated actin dynamics can drive motility without post-translational regulation, cells utilize many mechanisms to locally control cofilin, including cooperation/competition with other proteins. Newly identified post-translational modifications function with or are independent from the well-established phosphorylation of serine 3 and provide unexplored avenues for isoform specific regulation. Cofilin modulates actin transport and function in the nucleus as well as actin organization associated with mitochondrial fission and mitophagy. Under neuronal stress conditions, cofilin-saturated F-actin fragments can undergo oxidative cross-linking and bundle together to form cofilin-actin rods. Rods form in abundance within neurons around brain ischemic lesions and can be rapidly induced in neurites of most hippocampal and cortical neurons through energy depletion or glutamate-induced excitotoxicity. In ~20% of rodent hippocampal neurons, rods form more slowly in a receptor-mediated process triggered by factors intimately connected to disease-related dementias, e.g., amyloid-β in Alzheimer’s disease. This rod-inducing pathway requires a cellular prion protein, NADPH oxidase, and G-protein coupled receptors, e.g., CXCR4 and CCR5. Here, we will review many aspects of cofilin regulation and its contribution to synaptic loss and pathology of neurodegenerative diseases.

scholarly journals Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-30 ◽  
Author(s):  
Nur Shafika Mohd Sairazi ◽  
K. N. S. Sirajudeen
Keyword(s):  
Cell Death ◽  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Bioactive Compounds ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Structure ◽  
And Function

In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.

Mitochondrial morphology and distribution in mammalian cells

2006 ◽  
Vol 387 (12) ◽  
pp. 1551-1558 ◽  
Author(s):  
Ann E. Frazier ◽  
Clement Kiu ◽  
Diana Stojanovski ◽  
Nicholas J. Hoogenraad ◽  
Michael T. Ryan
Keyword(s):  
Cell Death ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Morphological Changes ◽  
Mitochondrial Fission ◽  
Gene Mutations ◽  
Current Understanding ◽  
Mitochondrial Morphology ◽  
Cell Death Pathways ◽  
Mitochondrial Distribution

Abstract It is now appreciated that mitochondria form tubular networks that adapt to the requirements of the cell by undergoing changes in their shape through fission and fusion. Proper mitochondrial distribution also appears to be required for ATP delivery and calcium regulation, and, in some cases, for cell development. While we now realise the great importance of mitochondria for the cell, we are only beginning to work out how these organelles undergo the drastic morphological changes that are essential for cellular function. Of the few known components involved in shaping mitochondria, some have been found to be essential to life and their gene mutations are linked to neurological disorders, while others appear to be recruited in the activation of cell death pathways. Here we review our current understanding of the functions of the main players involved in mitochondrial fission, fusion and distribution in mammalian cells.

Chrysophanol Suppressed Glutamate-Induced Hippocampal Neuronal Cell Death via Regulation of Dynamin-Related Protein 1-Dependent Mitochondrial Fission

Pharmacology ◽  
2017 ◽  
Vol 100 (3-4) ◽  
pp. 153-160 ◽  
Author(s):  
Unbin Chae ◽  
Ju-Sik Min ◽  
Hyun Hee Leem ◽  
Hyun-Shik Lee ◽  
Hong Jun Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Reactive Oxygen Species Generation ◽  
Neuronal Cell ◽  
Long Term Memory ◽  
Related Protein ◽  
Neuronal Function ◽  
Short And Long Term

Chrysophanic acid, or chrysophanol, is an anthraquinone found in Rheum palmatum, which was used in the preparation of oriental medicine in ancient China. The hippocampus plays a major role in controlling the activities of the short- and long-term memory. It is one of the major regions affected by excessive cell death in Alzheimer's disease. Therefore, neuronal cell-death modulation in the hippocampus is important for maintaining neuronal function. We investigated chrysophanol's effects on glutamate-induced hippocampal neuronal cell death. Chrysophanol reduced glutamate-induced cell death via suppression of proapoptotic factors and reactive oxygen species generation. Furthermore, it downregulated glutamate-induced mitochondrial fission by inhibiting dynamin-related protein 1 (Drp1) dephosphorylation. Thus, chrysophanol suppressed hippocampal neuronal cell death via inhibition of Drp1-dependent mitochondrial fission, and can be used as a therapeutic agent for treating neuronal cell death-mediated neurodegenerative diseases.

Targeting Bid to prevent programmed cell death in neurons

2006 ◽  
Vol 34 (6) ◽  
pp. 1334-1340 ◽  
Author(s):  
C. Culmsee ◽  
N. Plesnila
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Neurological Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Tissue Loss ◽  
Functional Deficits ◽  
Central Nervous System Trauma ◽  
Mitochondrial Membrane Permeabilization

Sustained progression of neuronal cell death causes brain tissue loss and subsequent functional deficits following stroke or central nervous system trauma and in neurodegenerative diseases. Despite obvious differences in the pathology of these neurological disorders, the underlying delayed neuronal demise is carried out by a common biochemical cell death programme. Mitochondrial membrane permeabilization and subsequent release of apoptotic factors are key mechanisms during this process. Bcl-2 family proteins, e.g. the pro-apoptotic Bid, Bax or Bad and the antiapoptotic Bcl-2, Bcl-XL, play a crucial role in the regulation of this mitochondrial checkpoint in neurons. In particular, cleavage of cytosolic Bid and subsequent mitochondrial translocation have been detected in many paradigms of neuronal cell death related to acute or chronic neurodegeneration. The current review focuses on the emerging role of Bid as an integrating key regulator of the intrinsic death pathway that amplifies caspase-dependent and caspase-independent execution of neuronal apoptosis. Therefore pharmacological inhibition of Bid provides a promising therapeutic strategy in neurological diseases where programmed cell death is prominent.

scholarly journals Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

2021 ◽  
Author(s):  
Yingli Gu ◽  
Flora Guerra ◽  
Mingzheng Hu ◽  
Alexander Pope ◽  
Kijung Sung ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mitochondrial Fission ◽  
Sensory Neuropathy ◽  
Selective Vulnerability ◽  
Mitochondrial Morphology ◽  
Physiological Level ◽  
Charcot Marie Tooth ◽  
Mitochondrial Movement ◽  
And Function ◽  
Peripheral Sensory

Recent evidence has uncovered an important role of Rab7 in regulating mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigated how mitochondrial morphology and function were impacted by the CMT2B associated Rab7V162M mutation in fibroblasts from human CMT2B patients as well as in a knockin mouse model. In contrast to recently published results from studies of using heterologous overexpression systems, our results have demonstrated significant mitochondrial fragmentation in fibroblasts of both human CMT2B patients and CMT2B mouse embryonic fibroblasts (MEFs). Furthermore, we have shown that mitochondria were fragmented and axonal mitochondrial movement was dysregulated in primary cultured E18 dorsal root ganglion (DRG) sensory neurons, but not in E18 hippocampal and cortical primary neurons. We also show that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalized the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study has revealed, for the first time, that expression of CMT2B Rab7 mutation at physiological level enhances Drp1 activity to promote mitochondrial fission, that may potentially underlie selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

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