Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

被引:453
作者
Basit, Farhan [1 ]
van Oppen, Lisanne M. P. E. [1 ]
Schoeckel, Laura [2 ]
Bossenbroek, Hasse M. [1 ]
van Emst-de Vries, Sjenet E. [1 ]
Hermeling, Johannes C. W. [1 ]
Grefte, Sander [1 ,4 ]
Kopitz, Charlotte [2 ]
Heroult, Melanie [3 ]
Willems, Peter H. G. M. [1 ]
Koopman, Werner J. H. [1 ]
机构
[1] Radboud Univ Nijmegen, Med Ctr Radboudumc, RIMLS, Dept Biochem, Nijmegen, Netherlands
[2] Bayer Pharma AG, Global Therapeut Res Grp Oncol 2, Berlin, Germany
[3] Bayer AG Innovat Strategy, Leverkusen, Germany
[4] Wageningen Univ & Res, Dept Human & Anim Physiol, Wageningen, Netherlands
关键词
OXIDATIVE STRESS; PERMEABILITY TRANSITION; AUTOPHAGY; CANCER; DEATH; PINK1; APOPTOSIS; FISSION; TRAP1; DYSFUNCTION;
D O I
10.1038/cddis.2017.133
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Inhibition of complex I (CI) of the mitochondrial respiratory chain by BAY 87-2243 ('BAY') triggers death of BRAF(V600E) melanoma cell lines and inhibits in vivo tumor growth. Here we studied the mechanism by which this inhibition induces melanoma cell death. BAY treatment depolarized the mitochondrial membrane potential (Delta Psi), increased cellular ROS levels, stimulated lipid peroxidation and reduced glutathione levels. These effects were paralleled by increased opening of the mitochondrial permeability transition pore (mPTP) and stimulation of autophagosome formation and mitophagy. BAY-induced cell death was not due to glucose shortage and inhibited by the antioxidant alpha-tocopherol and the mPTP inhibitor cyclosporin A. Tumor necrosis factor receptor-associated protein 1 (TRAP1) overexpression in BAY-treated cells lowered ROS levels and inhibited mPTP opening and cell death, whereas the latter was potentiated by TRAP1 knockdown. Knockdown of autophagy-related 5 (ATG5) inhibited the BAY-stimulated autophagosome formation, cellular ROS increase and cell death. Knockdown of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) inhibited the BAY-induced Delta Psi depolarization, mitophagy stimulation, ROS increase and cell death. Dynamin-related protein 1 (Drp1) knockdown induced mitochondrial filamentation and inhibited BAY-induced cell death. The latter was insensitive to the pancaspase inhibitor z-VAD-FMK, but reduced by necroptosis inhibitors (necrostatin-1, necrostatin-1s)) and knockdown of key necroptosis proteins (receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and mixed lineage kinase domain-like (MLKL)). BAY-induced cell death was also reduced by the ferroptosis inhibitor ferrostatin-1 and overexpression of the ferroptosis-inhibiting protein glutathione peroxidase 4 (GPX4). This overexpression also inhibited the BAY-induced ROS increase and lipid peroxidation. Conversely, GPX4 knockdown potentiated BAY-induced cell death. We propose a chain of events in which: (i) CI inhibition induces mPTP opening and Delta Psi depolarization, that (ii) stimulate autophagosome formation, mitophagy and an associated ROS increase, leading to (iii) activation of combined necroptotic/ferroptotic cell death.
引用
收藏
页码:e2716 / e2716
页数:11
相关论文
共 72 条
[1]   Molecular drivers of cellular metabolic reprogramming in melanoma [J].
Abildgaard, Cecilie ;
Guldberg, Per .
TRENDS IN MOLECULAR MEDICINE, 2015, 21 (03) :164-171
[2]   Bioenergetic Consequences of PINK1 Mutations in Parkinson Disease [J].
Abramov, Andrey Yurevich ;
Gegg, Matthew ;
Grunewald, Anne ;
Wood, Nicholas William ;
Klein, Christine ;
Schapira, Anthony Henry Vernon .
PLOS ONE, 2011, 6 (10)
[3]   Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells [J].
Baenke, Franziska ;
Chaneton, Barbara ;
Smith, Matthew ;
Van Den Broek, Niels ;
Hogan, Kate ;
Tang, Haoran ;
Viros, Amaya ;
Martin, Matthew ;
Galbraith, Laura ;
Girotti, Maria R. ;
Dhomen, Nathalie ;
Gottlieb, Eyal ;
Marais, Richard .
MOLECULAR ONCOLOGY, 2016, 10 (01) :73-84
[4]   Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes [J].
Basit, F. ;
Cristofanon, S. ;
Fulda, S. .
CELL DEATH AND DIFFERENTIATION, 2013, 20 (09) :1161-1173
[5]   Photo-Induction and Automated Quantification of Reversible Mitochondrial Permeability Transition Pore Opening in Primary Mouse Myotubes [J].
Blanchet, Lionel ;
Grefte, Sander ;
Smeitink, Jan A. M. ;
Willems, Peter H. G. M. ;
Koopman, Werner J. H. .
PLOS ONE, 2014, 9 (11)
[6]   Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization [J].
Cassidy-Stone, Ann ;
Chipuk, Jerry E. ;
Ingerman', Elena ;
Song, Cheng ;
Yoo, Choong ;
Kuwana, Tomomi ;
Kurth, Mark J. ;
Shaw, Jared T. ;
Hinshaw, Jenny E. ;
Green, Douglas R. ;
Nunnari, Jodi .
DEVELOPMENTAL CELL, 2008, 14 (02) :193-204
[7]   The miR-290-295 cluster suppresses autophagic cell death of melanoma cells [J].
Yong Chen ;
Ruediger Liersch ;
Michael Detmar .
Scientific Reports, 2 (1)
[8]   Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway: A novel strategy for human BRAF-driven colorectal carcinoma [J].
Condelli, Valentina ;
Maddalena, Francesca ;
Sisinni, Lorenza ;
Lettini, Giacomo ;
Matassa, Danilo Swann ;
Piscazzi, Annamaria ;
Palladino, Giuseppe ;
Amoroso, Maria Rosaria ;
Esposito, Franca ;
Landriscina, Matteo .
ONCOTARGET, 2015, 6 (26) :22298-22309
[9]   Regulated necrosis: disease relevance and therapeutic opportunities [J].
Conrad, Marcus ;
Angeli, Jose Pedro Friedmann ;
Vandenabeele, Peter ;
Stockwell, Brent R. .
NATURE REVIEWS DRUG DISCOVERY, 2016, 15 (05) :348-366
[10]   Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors [J].
Corazao-Rozas, Paola ;
Guerreschi, Pierre ;
Andre, Fanny ;
Gabert, Pierre-Elliott ;
Lancel, Steve ;
Dekiouk, Salim ;
Fontaine, Delphine ;
Tardivel, Meryem ;
Savina, Ariel ;
Quesnel, Bruno ;
Mortier, Laurent ;
Marchetti, Philippe ;
Kluza, Jerome .
ONCOTARGET, 2016, 7 (26) :39473-39485