Martinou JC, Youle RJMitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 1:92-101

Department of Cell Biology, University of Geneva, Faculty of Sciences, 30 quai Ernest-Ansermet, Geneva 4, Switzerland.
Developmental Cell (Impact Factor: 9.71). 07/2011; 21(1):92-101. DOI: 10.1016/j.devcel.2011.06.017
Source: PubMed


Mitochondria participate in apoptosis through a range of mechanisms that vary between vertebrates and invertebrates. In vertebrates, they release intermembrane space proteins, such as cytochrome c, to promote caspase activation in the cytosol. This process is the result of the loss of integrity of the outer mitochondrial membrane caused by proapoptotic members of the Bcl-2 family. This event is always accompanied by a fissioning of the organelle. Fission of mitochondria has also been reported to participate in apoptosis in Drosophila and Caenorhabditis elegans. However, in these organisms, mitochondrial membrane permeabilization does not occur and the mechanism by which mitochondrial dynamics participates in cell death remains elusive.

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    • "Bax translocation to the mitochondrial membrane creates a pore, which otherwise depolarize the mitochondria membrane potential (Henry-Mowatt et al., 2004). Members of the Bcl-2 family proteins are known to play a critical regulatory role in the apoptosis pathway (Martinou and Youle, 2011). Bcl-2 has been shown to form a heterodimer with Fig. 5. (A) The B103 cells were treated with or without MARE and NAC, and subjected to annexin V/7-AAD staining by FACS. "
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    ABSTRACT: Morus alba root extract (MARE) has been used to treat hyperglycaemic conditions in oriental medicine. Here, we studied whether MARE possesses a cytotoxic effect on neuroblastoma. To check the cytotoxicity generated by MARE was whether relatively higher against the cancer cells rather than normal cells, we chose a neuroblastoma cell line (B103) and a normal cell line (Rat-2). A CCK assay revealed that MARE (10 g/ml) reduced cell viability to approximately 60% compared to an untreated control in B103 cells. But in Rat-2 cells, MARE induced relatively lower cytotoxicity. To investigate the mechanisms underlying the cytotoxic effect of MARE, we used flow cytometry combined with immunoblot analyses. We found that MARE-treatment could accumulate ROS and depolarize mitochondria membrane potential of B103 cells. Further treatment with MARE in B103 cells also could damage DNA and induce apoptosis. An expression study of p-Akt also suggested that there was a reduction in cellular proliferation and transcription along with the process of apoptosis, which was further evidenced by an increase in Bax and cleaved-caspase 3 activity. Together, our findings suggest that MARE produces more cytotoxicity in cancer cells while having a relatively attenuated effect on normal cells. As such, MARE may be a safer option in cancer therapeutics, and it also shows potential for the patients with symptoms of hyperglycemia and cancer.
    Moleculer Cells 04/2015; DOI:10.14348/molcells.2015.0030 · 2.09 Impact Factor
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    • "Recent literature suggests that ER-mitochondrial communication regulates multiple aspects of cell biology, including mitochondrial dynamics, which is responsible for maintaining optimal mitochondrial function by balancing the fusion and fission of the mitochondrial network (Hoppins and Nunnari, 2012; Youle and van der Bliek, 2012). Mitochondrial dynamics is regulated by a set of large GTPases that are found in mitochondrial membranes ; the most critical proteins are mitofusins 1 and 2 (Mfn1/ 2) and optic atrophy 1 (OPA1), which cause fusion, and dynamin related protein 1 (DRP1), which promotes fission (Martinou and Youle, 2011). When a cell's mitochondrial network becomes either hyperfused or hyperfragmented, there are metabolic disruptions and collateral negative influences on the mitigation of UPR and cellular fitness. "
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    ABSTRACT: Proapoptotic BCL-2 proteins converge upon the outer mitochondrial membrane (OMM) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Here we investigated the mechanistic relationship between mitochondrial shape and MOMP and provide evidence that BAX re-quires a distinct mitochondrial size to induce MOMP. We utilized the terminal unfolded protein response pathway to systematically define proapoptotic BCL-2 protein composition after stress and then directly interrogated their requirement for a productive mito-chondrial size. Complementary biochemical, cellular, in vivo, and ex vivo studies reveal that Mfn1, a GTPase involved in mitochondrial fusion, establishes a mito-chondrial size that is permissive for proapoptotic BCL-2 family function. Cells with hyperfragmented mitochondria, along with size-restricted OMM model systems, fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAXa9$membrane interactions. This work identifies a mechanistic contribution of mito-chondrial size in dictating BAX activation, MOMP, and apoptosis. INTRODUCTION
    Molecular Cell 01/2015; 57(1). DOI:10.1016/j.molcel.2014.10.028 · 14.02 Impact Factor
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    • "Proteins such as Bcl-2 and Bcl-XL prevent the release of apoptogenic proteins from mitochondria. On the other hand, pro-apoptotic Bcl-2 family members, Bax and Bak, induce outer membrane permeabilization and increased levels of pro-apoptotic factors, such as cytochrome c [8] [17] [20] [37]. "
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