Mitochondria in cell death

2010 ◽  
Vol 47 ◽  
pp. 99-114 ◽  
Author(s):  
Melissa J. Parsons ◽  
Douglas R. Green
Keyword(s):  
Cell Death ◽  
Neurological Diseases ◽  
Mitochondrial Outer Membrane ◽  
Intermembrane Space ◽  
Apoptotic Pathway ◽  
Life And Death ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Mitochondrial Functions ◽  
A Cell ◽  
Signalling Cascade

Apoptosis can be thought of as a signalling cascade that results in the death of the cell. Properly executed apoptosis is critically important for both development and homoeostasis of most animals. Accordingly, defects in apoptosis can contribute to the development of autoimmune disorders, neurological diseases and cancer. Broadly speaking, there are two main pathways by which a cell can engage apoptosis: the extrinsic apoptotic pathway and the intrinsic apoptotic pathway. At the centre of the intrinsic apoptotic signalling pathway lies the mitochondrion, which, in addition to its role as the bioenergetic centre of the cell, is also the cell’s reservoir of pro-death factors which reside in the mitochondrial IMS (intermembrane space). During intrinsic apoptosis, pores are formed in the OMM (outer mitochondrial membrane) of the mitochondria in a process termed MOMP (mitochondrial outer membrane permeabilization). This allows for the release of IMS proteins; once released during MOMP, some IMS proteins, notably cytochrome c and Smac/DIABLO (Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI), promote caspase activation and subsequent cleavage of structural and regulatory proteins in the cytoplasm and the nucleus, leading to the demise of the cell. MOMP is achieved through the co-ordinated actions of pro-apoptotic members and inhibited by anti-apoptotic members of the Bcl-2 family of proteins. Other aspects of mitochondrial physiology, such as mitochondrial bioenergetics and dynamics, are also involved in processes of cell death that proceed through the mitochondria. Proper regulation of these mitochondrial functions is vitally important for the life and death of the cell and for the organism as a whole.

Mechanisms of mitochondrial cell death

2021 ◽  
Author(s):  
Shashank Dadsena ◽  
Cristiana Zollo ◽  
Ana J. García-Sáez
Keyword(s):  
Cell Death ◽  
Current Knowledge ◽  
B Cell Lymphoma ◽  
Membrane Lipid ◽  
Membrane Dynamics ◽  
Mitochondrial Outer Membrane ◽  
Intermembrane Space ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Cell Death Pathways ◽  
Lipid Environment

Mitochondria are double-membrane bound organelles that not only provide energy for intracellular metabolism, but also play a key role in the regulation of cell death. Mitochondrial outer membrane permeabilization (MOMP), allowing the release of intermembrane space proteins like cytochrome c, is considered a point of no return in apoptosis. MOMP is controlled by the proteins of the B-cell lymphoma 2 (BCL-2) family, including pro-and anti-apoptotic members, whose balance determines the decision between cell death and survival. Other factors such as membrane lipid environment, membrane dynamics, and inter-organelle communications are also known to influence this process. MOMP and apoptosis have been acknowledged as immunologically silent. Remarkably, a growing body of evidence indicates that MOMP can engage in various pro-inflammatory signaling functions. In this mini-review, we discuss about our current knowledge on the mechanisms of mitochondrial apoptosis, as well as the involvement of mitochondria in other kinds of programmed cell death pathways.

scholarly journals Mitochondrial outer membrane permeabilization at the single molecule level

2021 ◽  
Author(s):  
Shashank Dadsena ◽  
Andreas Jenner ◽  
Ana J. García-Sáez
Keyword(s):  
Cell Death ◽  
Outer Membrane ◽  
Single Molecule ◽  
Apoptotic Cell ◽  
Interaction Network ◽  
Regulatory Elements ◽  
Membrane Permeabilization ◽  
Mitochondrial Outer Membrane ◽  
Apoptotic Pathway ◽  
Mitochondrial Outer Membrane Permeabilization

AbstractApoptotic cell death is essential for development, immune function or tissue homeostasis, and its mis-regulation is linked to various diseases. Mitochondrial outer membrane permeabilization (MOMP) is a central event in the intrinsic apoptotic pathway and essential to control the execution of cell death. Here we review current concepts in regulation of MOMP focusing on the interaction network of the Bcl-2 family proteins as well as further regulatory elements influencing MOMP. As MOMP is a complex spatially and temporally controlled process, we point out the importance of single-molecule techniques to unveil processes which would be masked by ensemble measurements. We report key single-molecule studies applied to decipher the composition, assembly mechanism and structure of protein complexes involved in MOMP regulation.

scholarly journals Inhibition of mitochondrial carrier homolog 2 (MTCH2) suppresses tumor invasion and enhances sensitivity to temozolomide in malignant glioma

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Qiuyun Yuan ◽  
Wanchun Yang ◽  
Shuxin Zhang ◽  
Tengfei Li ◽  
Mingrong Zuo ◽  
...  
Keyword(s):  
Cell Death ◽  
Malignant Glioma ◽  
Aerobic Glycolysis ◽  
Underlying Mechanism ◽  
Bioinformatic Analysis ◽  
Mitochondrial Outer Membrane ◽  
Invasion Pathways ◽  
Western Blots ◽  
Mitochondrial Functions ◽  
Dependent Cell

Abstract Background Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions. This phenomenon offers a proliferation advantage to tumor cells and decrease mitochondria-dependent cell death. However, the underlying mechanism for mitochondrial dysfunction in glioma is not well elucidated. MTCH2 is a mitochondrial outer membrane protein that regulates mitochondrial metabolism and related cell death. This study aims to clarify the role of MTCH2 in glioma. Methods Bioinformatic analysis from TCGA and CGGA databases were used to investigate the association of MTCH2 with glioma malignancy and clinical significance. The expression of MTCH2 was verified from clinical specimens using real-time PCR and western blots in our cohorts. siRNA-mediated MTCH2 knockdown were used to assess the biological functions of MTCH2 in glioma progression, including cell invasion and temozolomide-induced cell death. Biochemical investigations of mitochondrial and cellular signaling alternations were performed to detect the mechanism by which MTCH2 regulates glioma malignancy. Results Bioinformatic data from public database and our cohort showed that MTCH2 expression was closely associated with glioma malignancy and poor patient survival. Silencing of MTCH2 expression impaired cell migration/invasion and enhanced temozolomide sensitivity of human glioma cells. Mechanistically, MTCH2 knockdown may increase mitochondrial OXPHOs and thus oxidative damage, decreased migration/invasion pathways, and repressed pro-survival AKT signaling. Conclusion Our work establishes the relationship between MTCH2 expression and glioma malignancy, and provides a potential target for future interventions.

scholarly journals Poliovirus Induces Bax-Dependent Cell Death Mediated by c-Jun NH2-Terminal Kinase

2007 ◽  
Vol 81 (14) ◽  
pp. 7504-7516 ◽  
Author(s):  
Arnaud Autret ◽  
Sandra Martin-Latil ◽  
Laurence Mousson ◽  
Aurélie Wirotius ◽  
Frédéric Petit ◽  
...  
Keyword(s):  
Cell Death ◽  
Outer Membrane ◽  
Motor Neurons ◽  
Cell Receptor ◽  
Cellular Level ◽  
Membrane Permeabilization ◽  
Paralytic Poliomyelitis ◽  
Receptor Interaction ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Outer Membrane Permeabilization

ABSTRACT Poliovirus (PV) is the causal agent of paralytic poliomyelitis, a disease that involves the destruction of motor neurons associated with PV replication. In PV-infected mice, motor neurons die through an apoptotic process. However, mechanisms by which PV induces cell death in neuronal cells remain unclear. Here, we demonstrate that PV infection of neuronal IMR5 cells induces cytochrome c release from mitochondria and loss of mitochondrial transmembrane potential, both of which are evidence of mitochondrial outer membrane permeabilization. PV infection also activates Bax, a proapoptotic member of the Bcl-2 family; this activation involves its conformational change and its redistribution from the cytosol to mitochondria. Neutralization of Bax by vMIA protein expression prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. Interestingly, we also found that c-Jun NH2-terminal kinase (JNK) is activated soon after PV infection and that the PV-cell receptor interaction alone is sufficient to induce JNK activation. Moreover, the pharmacological inhibition of JNK by SP600125 inhibits Bax activation and cytochrome c release. This is, to our knowledge, the first demonstration of JNK-mediated Bax-dependent apoptosis in PV-infected cells. Our findings contribute to our understanding of poliomyelitis pathogenesis at the cellular level.

Therapeutic Targeting of the Bcl2 Family

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-42-SCI-42
Author(s):  
Anthony Letai ◽  
Matthew S. Davids ◽  
Triona Ni Chonghaile ◽  
Jing Deng ◽  
Luv Patel
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Outer Membrane ◽  
Short Term ◽  
Provocative Test ◽  
Mitochondrial Outer Membrane Permeabilization

Abstract Many, perhaps most, cancer chemotherapy agents kill cancer cells via the mitochondrial pathway of apoptosis that is controlled by the Bcl-2 family of proteins. Bcl-2 family proteins regulate commitment to cell death by controlling mitochondrial outer membrane permeabilization (MOMP). To better understand how cancer cells commit to apoptosis, and what drugs might make them commit to apoptosis, we have studied perturbing mitochondria with BH3 peptides that are derived from pro-death Bcl-2 family proteins. Using this provocative test, which we call BH3 profiling, we are able to measure how close a cell is to the threshold of apoptosis, a property we call “priming”. Priming corresponds to sensitivity to chemotherapy. Moreover, BH3 profiling can be used to detect dependence on Bcl-2 and Bcl-xL for survival, which predicts cytotoxic response to small molecule antagonists such as ABT-199 and ABT-263. In acute lymphoblastic leukemia, we find that dependence on either Bcl-2 or Bcl-xL varies from case to case, with very important consequences for sensitivity to ABT-199 and ABT-263. In chronic lymphocytic leukemia, ABT-199 has already demonstrated significant clinical activity that corresponds to its on-target activity in mitochondria in vitro. We have been testing how this in vitro mitochondrial activity in BH3 profiling assays might be translated into a useful clinical predictive biomarker. Finally, we can measure how short term incubation with many kinds of drugs, including targeted pathway inhibitors, can increase cancer cell priming, including for primary lymphoid malignancy cells. This short term increase in priming predicts subsequent cancer cell death, including in clinical treatment. We call this method “Dynamic BH3 Profiling” and are exploring how it might best be utilized in the clinic. Disclosures: Letai: Dana-Farber Cancer Institute: Patents & Royalties; AbbVie: Consultancy.

scholarly journals The Role of Mitochondria in Pyroptosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Qian Li ◽  
Nengxian Shi ◽  
Chen Cai ◽  
Mingming Zhang ◽  
Jing He ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Pathological Process ◽  
Mitochondrial Outer Membrane ◽  
Therapeutic Effects ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Regulated Cell Death ◽  
Clinical Benefits ◽  
Regulate Cell Death

Pyroptosis is a recently discovered aspartic aspart-specific cysteine protease (Caspase-1/4/5/11) dependent mode of gene-regulated cell death cell death, which is represented by the rupture of cell membrane perforations and the production of proinflammatory mediaters like interleukin-18(IL-18) and interleukin-1β (IL-1β). Mitochondria also play an important role in apoptotic cell death. When it comes to apoptosis of mitochondrion, mitochondrial outer membrane permeabilization (MOMP) is commonly known to cause cell death. As a downstream pathological process of apoptotic signaling, MOMP participates in the leakage of cytochrome-c from mitochondrion to the cytosol and subsequently activate caspase proteases. Hence, targeting MOMP for the sake of manipulating cell death presents potential therapeutic effects among various types of diseases, such as autoimmune disorders, neurodegenerative diseases, and cancer. In this review, we highlights the roles and significance of mitochondria in pyroptosis to provide unexplored strategies that target the mitochondria to regulate cell death for clinical benefits.

scholarly journals Chemical, physical and biological triggers of evolutionary conserved Bcl-xL-mediated apoptosis

2020 ◽  
Author(s):  
Aleksandr Ianevski ◽  
Evgeny Kulesskiy ◽  
Klara Krpina ◽  
Guofeng Lou ◽  
Yahyah Aman ◽  
...  
Keyword(s):  
Mitochondrial Outer Membrane ◽  
Physical Factors ◽  
Apoptotic Pathway ◽  
Anticancer Compounds ◽  
Transfected Cells ◽  
C Elegans ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Different Origins ◽  
Specific Agent ◽  
Specific Inhibitors

ABSTRACTThe evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. Here, we show that Bcl-xL-specific agent A-1155463 prematurely kills cells of different origins and the small roundworms (C. elegans), when combined with DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO). The synergistic effect of 4NQO-A-1155463 combination was p53-dependent, was associated with the release of Bad and Bax from Bcl-xL, which triggered mitochondrial outer membrane permeabilization (MOMP). Combinations of Bcl-xL-specific inhibitors with certain anticancer compounds or physical insults also killed cells. Collectively, our results suggest that biological, chemical and physical factors trigger evolutionary conserved Bcl-xL-mediated apoptotic pathway.

scholarly journals Mitochondrial Entry of Cytotoxic Proteases: A New Insight into the Granzyme B Cell Death Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Denis Martinvalet
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Granzyme B ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Cell Death Pathway ◽  
Dependent Cell ◽  
Mitochondrial Death Pathway ◽  
Insight Into

The mitochondria represent an integration and amplification hub for various death pathways including that mediated by granzyme B (GB), a granule enzyme expressed by cytotoxic lymphocytes. GB activates the proapoptotic B cell CLL/lymphoma 2 (Bcl-2) family member BH3-interacting domain death agonist (BID) to switch on the intrinsic mitochondrial death pathway, leading to Bcl-2-associated X protein (Bax)/Bcl-2 homologous antagonist/killer- (Bak-) dependent mitochondrial outer membrane permeabilization (MOMP), the dissipation of mitochondrial transmembrane potential (ΔΨm), and the production of reactive oxygen species (ROS). GB can also induce mitochondrial damage in the absence of BID, Bax, and Bak, critical for MOMP, indicating that GB targets the mitochondria in other ways. Interestingly, granzyme A (GA), GB, and caspase 3 can all directly target the mitochondrial respiratory chain complex I for ROS-dependent cell death. Studies of ROS biogenesis have revealed that GB must enter the mitochondria for ROS production, making the mitochondrial entry of cytotoxic proteases (MECP) an unexpected critical step in the granzyme death pathway. MECP requires an intact ΔΨm and is mediated though Sam50 and Tim22 channels in a mtHSP70-dependent manner. Preventing MECP severely compromises GB cytotoxicity. In this review, we provide a brief overview of the canonical mitochondrial death pathway in order to put into perspective this new insight into the GB action on the mitochondria to trigger ROS-dependent cell death.

scholarly journals Mitochondria in Neurodegeneration: Bioenergetic Function in Cell Life and Death

1999 ◽  
Vol 19 (3) ◽  
pp. 231-245 ◽  
Author(s):  
Anne N. Murphy ◽  
Gary Fiskum ◽  
M. Flint Beal
Keyword(s):  
Cell Death ◽  
Reactive Oxygen Species Generation ◽  
Decisive Role ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Therapeutic Approaches ◽  
Life And Death ◽  
Biochemical Pathways ◽  
Cell Life ◽  
Mitochondrial Functions

The biochemical pathways to cell death in chronic and acute forms of neurodegeneration are poorly understood, limiting the ability to develop effective therapeutic approaches. As details of the apoptotic and necrotic pathways have been revealed, an appreciation for the decisive role that mitochondria play in life-death decisions for the cell has grown. As a result, the need has arisen to reevaluate the significance to cell viability of mitochondrial Ca2+ sequestration, reactive oxygen species generation, and the membrane permeability transition. This review provides basic information on these mitochondrial functions as they relate to control over cell death.

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