scholarly journals Mitochondrial fission dysfunction alleviates heterokaryon incompatibility-triggered cell death in the industrial filamentous fungus Aspergillus oryzae

2021 ◽  
Author(s):  
Chan Lu ◽  
Takuya Katayama ◽  
Noriko Mori ◽  
Ryota Saito ◽  
Kazuhiro Iwashita ◽  
...  
Keyword(s):  
Cell Death ◽  
Protoplast Fusion ◽  
Cell Fusion ◽  
Aspergillus Oryzae ◽  
Filamentous Fungus ◽  
Cellular Response ◽  
Mitochondrial Fission ◽  
Mitochondrial Fragmentation ◽  
Parasexual Cycle ◽  
Heterokaryon Incompatibility

ABSTRACTIn filamentous fungi, cell-to-cell recognition is a fundamental requirement for the formation, development, and maintenance of complex hyphal networks. Basically, self/compatible individuals within the fungal species are capable of fusing together, a step important for crossbreeding, which results in the formation of viable vegetative heterokaryons. Conversely, the fusion of incompatible individuals does not result in the formation of viable hyphal networks, but it often leads to growth inhibition or cell death. Even though a number of studies have been conducted to investigate such incompatibility, the understanding of the associated molecular mechanism is still limited, and this restricts the possibility of crossbreeding incompatible individuals. Therefore, in this study, the characteristics of compatibility/incompatibility in the industrial filamentous fungus, Aspergillus oryzae, were comprehensively investigated. Protoplast fusion and co-culture assays indicated the existence of a correlation between strain phylogeny and compatibility/incompatibility features. Time-course fluorescence observations were employed to investigate the types of incompatible responses that are induced at different cellular levels upon incompatible cell fusion, which eventually lead to cell death. Propidium iodide-indicated cell death, ROS accumulation, and mitochondrial fragmentation were identified as the major responses, with mitochondrial fragmentation showing the most significant subcellular change immediately after incompatible cell fusion. Furthermore, the deletions of mitochondrial fission-related genes Aofis1 and Aodnm1 in incompatible pairing alleviated cell death, indicating that mitochondrial fission is an important mechanism by which incompatibility-triggered cell death occurs. Therefore, this study provides new insights about heterokaryon incompatibility.IMPORTANCEFor a long time, it was believed that as an asexual fungus, A. oryzae does not exhibit any sexual cycle. However, the fungus has two mating types, indicating the potential for sexual reproduction besides a known parasexual cycle. Therefore, given that viable heterokaryon formation following cell fusion is an important step required for genetic crossing, we explored the mechanism of incompatibility, which restricts the possibility of cell fusion in A. oryzae. Protoplast fusion and co-culture assays led to the identification of various vegetative compatible groups. Mitochondrial fragmentation was found to be the most significant incompatible cellular response that occurred in organelles during incompatible pairing, while the deletion of mitochondrial fission-related genes was identified as a strategy used to alleviate incompatibility-triggered cell death. Thus, this study revealed a novel mechanism by which mitochondrial fission regulates incompatible responses.

scholarly journals Author Correction: BiFC-based visualisation system reveals cell fusion morphology and heterokaryon incompatibility in the filamentous fungus Aspergillus oryzae

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tomoya Okabe ◽  
Takuya Katayama ◽  
Taoning Mo ◽  
Noriko Mori ◽  
Feng Jie Jin ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Aspergillus Oryzae ◽  
Filamentous Fungus ◽  
Heterokaryon Incompatibility

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract 431: Mitochondrial Fission in the Heart is an Adaptation to Increased Energetic Demands: The Role of Physiologic Fragmentation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Michael Coronado ◽  
Giovanni Fajardo ◽  
Kim Nguyen ◽  
Mingming Zhao ◽  
Kristina Bezold Kooiker ◽  
...  
Keyword(s):  
Cell Death ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Adrenergic Receptor ◽  
Mitochondrial Fission ◽  
Physiological Adaptation ◽  
Mitochondrial Fragmentation ◽  
Energetic Demand ◽  
Adaptation To Exercise

Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Current paradigms hold that mitochondrial fission and fragmentation are the result of pathologic stresses such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in cardiac impairment, suggesting that fission is important for maintaining normal mitochondrial function. In this study, we identify a novel role for mitochondrial fragmentation as a normal physiological adaptation to increased energetic demand. Using two models of exercise, we demonstrate that “physiologic” mitochondrial fragmentation occurs, results in enhanced mitochondrial function, and is mediated through beta 1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. To confirm the role of fragmentation as a physiological adaptation to exercise, we inhibited the pro-fission mediator Drp1 in mice using the peptide inhibitor P110 and had mice undergo exercise. Mice treated with P110 had significantly decreased exercise capacity, decreased fragmentation and inactive Drp1 vs controls. To further confirm these findings, we generated cardiac-specific Drp1 KO mice and had them undergo exercise. Mice with cardiac specific Drp1 KO had significantly decreased exercise capacity and abnormally large mitochondria compared to controls. These findings indicate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise and support the still evolving conceptual framework, where fragmentation plays a role in the balance between mitochondrial maintenance of normal physiology and response to disease.

scholarly journals Fzo1, a Protein Involved in Mitochondrial Fusion, Inhibits Apoptosis

2004 ◽  
Vol 279 (50) ◽  
pp. 52726-52734 ◽  
Author(s):  
Rie Sugioka ◽  
Shigeomi Shimizu ◽  
Yoshihide Tsujimoto
Keyword(s):  
Cell Death ◽  
Conformational Changes ◽  
Apoptotic Cell ◽  
Mitochondrial Fission ◽  
Apoptotic Cell Death ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Human Homolog ◽  
Mitochondrial Fragmentation ◽  
Apoptotic Death

Mitochondrial morphology and physiology are regulated by the processes of fusion and fission. Some forms of apoptosis are reported to be associated with mitochondrial fragmentation. We showed that overexpression of Fzo1A/B (rat) proteins involved in mitochondrial fusion, or silencing of Dnm1 (rat)/Drp1 (human) (a mitochondrial fission protein), increased elongated mitochondria in healthy cells. After apoptotic stimulation, these interventions inhibited mitochondrial fragmentation and cell death, suggesting that a process involved in mitochondrial fusion/fission might play a role in the regulation of apoptosis. Consistently, silencing of Fzo1A/B or Mfn1/2 (a human homolog of Fzo1A/B) led to an increase of shorter mitochondria and enhanced apoptotic death. Overexpression of Fzo1 inhibited cytochromecrelease and activation of Bax/Bak, as assessed from conformational changes and oligomerization. Silencing of Mfn or Drp1 caused an increase or decrease of mitochondrial sensitivity to apoptotic stimulation, respectively. These results indicate that some of the proteins involved in mitochondrial fusion/fission modulate apoptotic cell death at the mitochondrial level.

scholarly journals Med13p prevents mitochondrial fission and programmed cell death in yeast through nuclear retention of cyclin C

2014 ◽  
Vol 25 (18) ◽  
pp. 2807-2816 ◽  
Author(s):  
Svetlana Khakhina ◽  
Katrina F. Cooper ◽  
Randy Strich
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Mitochondrial Fission ◽  
Regulatory System ◽  
Stress Sensitivity ◽  
26S Proteasome ◽  
Mitochondrial Fragmentation ◽  
Nuclear Retention ◽  
Cyclin C

The yeast cyclin C-Cdk8 kinase forms a complex with Med13p to repress the transcription of genes involved in the stress response and meiosis. In response to oxidative stress, cyclin C displays nuclear to cytoplasmic relocalization that triggers mitochondrial fission and promotes programmed cell death. In this report, we demonstrate that Med13p mediates cyclin C nuclear retention in unstressed cells. Deleting MED13 allows aberrant cytoplasmic cyclin C localization and extensive mitochondrial fragmentation. Loss of Med13p function resulted in mitochondrial dysfunction and hypersensitivity to oxidative stress–induced programmed cell death that were dependent on cyclin C. The regulatory system controlling cyclin C-Med13p interaction is complex. First, a previous study found that cyclin C phosphorylation by the stress-activated MAP kinase Slt2p is required for nuclear to cytoplasmic translocation. This study found that cyclin C-Med13p association is impaired when the Slt2p target residue is substituted with a phosphomimetic amino acid. The second step involves Med13p destruction mediated by the 26S proteasome and cyclin C-Cdk8p kinase activity. In conclusion, Med13p maintains mitochondrial structure, function, and normal oxidative stress sensitivity through cyclin C nuclear retention. Releasing cyclin C from the nucleus involves both its phosphorylation by Slt2p coupled with Med13p destruction.

scholarly journals Inhibiting the Mitochondrial Fission Machinery Does Not Prevent Bax/Bak-Dependent Apoptosis

2006 ◽  
Vol 26 (20) ◽  
pp. 7397-7408 ◽  
Author(s):  
Philippe A. Parone ◽  
Dominic I. James ◽  
Sandrine Da Cruz ◽  
Yves Mattenberger ◽  
Olivier Donzé ◽  
...  
Keyword(s):  
Cell Death ◽  
Morphological Changes ◽  
Mitochondrial Fission ◽  
Mitochondrial Network ◽  
Mitochondrial Fragmentation ◽  
Caspase Inhibition ◽  
Precise Role

ABSTRACT Apoptosis, induced by a number of death stimuli, is associated with a fragmentation of the mitochondrial network. These morphological changes in mitochondria have been shown to require proteins, such as Drp1 or hFis1, which are involved in regulating the fission of mitochondria. However, the precise role of mitochondrial fission during apoptosis remains elusive. Here we report that inhibiting the fission machinery in Bax/Bak-mediated apoptosis, by down-regulating of Drp1 or hFis1, prevents the fragmentation of the mitochondrial network and partially inhibits the release of cytochrome c from the mitochondria but fails to block the efflux of Smac/DIABLO. In addition, preventing mitochondrial fragmentation does not inhibit cell death induced by Bax/Bak-dependent death stimuli, in contrast to the effects of Bcl-xL or caspase inhibition. Therefore, the fission of mitochondria is a dispensable event in Bax/Bak-dependent apoptosis.

scholarly journals The Mitochondrial Fission Protein hFis1 Requires the Endoplasmic Reticulum Gateway to Induce Apoptosis

2006 ◽  
Vol 17 (11) ◽  
pp. 4593-4605 ◽  
Author(s):  
Emilie Alirol ◽  
Dominic James ◽  
Denise Huber ◽  
Andrea Marchetto ◽  
Lodovica Vergani ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Cell Division ◽  
Cytochrome C ◽  
Mitochondrial Fission ◽  
Apoptosis Induction ◽  
Mitochondrial Fragmentation ◽  
Bifunctional Protein ◽  
Dependent Cell ◽  
Induced Fission

Mitochondrial fission ensures organelle inheritance during cell division and participates in apoptosis. The fission protein hFis1 triggers caspase-dependent cell death, by causing the release of cytochrome c from mitochondria. Here we show that mitochondrial fission induced by hFis1 is genetically distinct from apoptosis. In cells lacking the multidomain proapoptotic Bcl-2 family members Bax and Bak (DKO), hFis1 caused mitochondrial fragmentation but not organelle dysfunction and apoptosis. Similarly, a mutant in the intermembrane region of hFis1-induced fission but not cell death, further dissociating mitochondrial fragmentation from apoptosis induction. Selective correction of the endoplasmic reticulum (ER) defect of DKO cells restored killing by hFis1, indicating that death by hFis1 relies on the ER gateway of apoptosis. Consistently, hFis1 did not directly activate BAX and BAK, but induced Ca2+-dependent mitochondrial dysfunction. Thus, hFis1 is a bifunctional protein that independently regulates mitochondrial fragmentation and ER-mediated apoptosis.

scholarly journals Differential ROS-Mediated Phosphorylation of Drp1 in Mitochondrial Fragmentation Induced by Distinct Cell Death Conditions in Cerebellar Granule Neurons

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Carolina Cid-Castro ◽  
Julio Morán
Keyword(s):  
Cell Death ◽  
Neuronal Death ◽  
Mitochondrial Fission ◽  
Cerebellar Granule Neurons ◽  
Mitochondrial Morphology ◽  
Granule Neurons ◽  
Ros Production ◽  
Mitochondrial Fragmentation ◽  
Cerebellar Granule ◽  
Mitochondrial Ros

Reactive oxygen species (ROS) production has been associated with neuronal death. ROS are also involved in mitochondrial fission, which is mediated by Dynamin-related protein 1 (Drp1). The regulation of mitochondrial fragmentation mediated by Drp1 and its relationship to mitochondrial ROS (mtROS) in neuronal death have not been completely clarified. The aim of this study is to evaluate the role of mtROS in cell death and their involvement in the activation of Drp1 and mitochondrial fission in a model of cell death of cultured cerebellar granule neurons (CGN). Neuronal death of CGN induced by potassium deprivation (K5) and staurosporine (ST) triggers mitochondrial ROS production and mitochondrial fragmentation. K5 condition evoked an increase of Drp1 phosphorylation at Ser616, but ST treatment led to a decrease of Drp1 phosphorylation. Moreover, the death of CGN induced by both K5 and ST was markedly reduced in the presence of MitoTEMPO; however, mitochondrial morphology was not recovered. Here, we show that the mitochondria are the initial source of ROS involved in the neuronal death of CGN and that mitochondrial fragmentation is a common event in cell death; however, this process is not mediated by Drp1 phosphorylation at Ser616.

Abstract 252: Doxorubicin-induced H9c2 Cell Death is Mediated by Excessive Mitochondrial Fission and Mitophagy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Michael P Catanzaro ◽  
Ashley Weiner ◽  
Amanda Kaminaris ◽  
Satoru Kobayashi ◽  
Qiangrong Liang
Keyword(s):  
Cell Death ◽  
Fluorescent Protein ◽  
Mitochondrial Fission ◽  
Antineoplastic Agent ◽  
Cardiac Injury ◽  
H9c2 Cell ◽  
Mitochondrial Morphology ◽  
Control Mechanisms ◽  
Loss Of Function ◽  
Mitochondrial Fragmentation

Doxorubicin (DOX) is a widely used antineoplastic agent that can cause heart failure. DOX cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that help maintain a pool of healthy mitochondria. However, too much mitochondrial fission and/or mitophagy may compromise cell viability. Indeed, Mdivi-1, an inhibitor of the fission protein Drp1, can attenuate DOX-induced cardiac injury, suggesting that mitochondrial fragmentation may play a role in DOX cardiotoxicity. Using genetic gain- and loss-of function approaches, we determined whether mitochondrial fragmentation and/or mitophagy contribute to DOX-induced cardiomyocyte death. H9c2 cardiac myoblast cells were transfected with siRNA targeting Drp-1 before DOX administration. Mitochondrial morphology was examined with confocal microscopy after infection of the cells with the adenovirus encoding mitochondria-targeted fluorescent protein MitoDsRed. Morphometric analysis demonstrated that Drp-1 knockdown markedly diminished DOX-induced mitochondrial fragmentation as shown by form factor, aspect ratio, and mean mitochondrial size. This led to reduced cardiomyocyte death as revealed by the percentage of propidium iodide (PI)-positive cells and the cleavage of caspase-3 and Poly ADP ribose polymerase (PARP). Not surprisingly, Drp-1 knockdown also attenuated DOX-induced mitophagy flux as assessed by the dual fluorescent mitophagy reporter mt-Rosella. Further, knockdown of Parkin, a key regulator of mitophagy, dramatically diminished DOX-induced H9c2 cell death. Although Drp1 overexpression did not markedly increase DOX-induced cell death, Parkin overexpression predisposed H9c2 cells to DOX toxicity. Together, these results suggest that DOX-induced cardiotoxicity may be due to excessive mitochondrial fragmentation and accelerated mitochondrial degradation through autophagy. Strategies that limit mitochondrial fission and mitophagy within the physiological range may help reduce DOX cardiotoxicity. However, further studies are clearly warranted to make sure that these strategies will not compromise the antitumor efficacy of DOX.

scholarly journals Programmed Cell Death in Neurospora crassa

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
A. Pedro Gonçalves ◽  
Arnaldo Videira
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Neurospora Crassa ◽  
Filamentous Fungus ◽  
Mammalian Cells ◽  
Model Organism ◽  
Chemical Induction ◽  
Hyphal Fusion ◽  
Heterokaryon Incompatibility

Programmed cell death has been studied for decades in mammalian cells, but simpler organisms, including prokaryotes, plants, and fungi, also undergo regulated forms of cell death. We highlight the usefulness of the filamentous fungus Neurospora crassa as a model organism for the study of programmed cell death. In N. crassa, cell death can be triggered genetically due to hyphal fusion between individuals with different allelic specificities at het loci, in a process called “heterokaryon incompatibility.” Chemical induction of cell death can also be achieved upon exposure to death-inducing agents like staurosporine, phytosphingosine, or hydrogen peroxide. A summary of the recent advances made by our and other groups on the discovery of the mechanisms and mediators underlying the process of cell death in N. crassa is presented.

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