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

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Basit, Farhan, van Oppen, Lisanne MPE, Schöckel, Laura, Bossenbroek, Hasse M, van Emst-de Vries, Sjenet E, Hermeling, Johannes CW, Grefte, Sander, Kopitz, Charlotte, Heroult, Melanie, HGM Willems, Peter, Koopman, Werner JH·2017·Cell Death & Disease
DOI 10.1038/cddis.2017.133
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Abstract

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 (Δ ψ), 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 α-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 Δ ψ 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 Δ ψ depolarization, that (ii) stimulate autophagosome formation, mitophagy and an associated ROS increase, leading to (iii) activation of combined necroptotic/ferroptotic cell death.

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Research works printed but not linked: 52

  1. Abildgaard C, Guldberg P . Molecular drivers of cellular metabolic reprogramming in melanoma. TR Mol Med 2015; 21: 164–171. · DOI
  2. Shakya A, Cooksey R, Cox JE, Wang V, McClain DA, Tantin D . Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nat Cell Biol 2009; 11: 320–327. · DOI
  3. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE . Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 2009; 324: 1713–1716. · DOI · Paper page
  4. Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA . Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 2004; 64: 985–993. · DOI · Paper page
  5. Garnett MJ, Marais R . Guilty as charged: B-RAF is a human oncogene. Cancer Cell 2004; 6: 313–319. · DOI · Paper page
  6. Sullivan RJ, Flaherty KT . Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer 2013; 49: 1297–1304. · DOI · Paper page
  7. Gopal YN, Rizos H, Chen G, Deng W, Frederick DT, Cooper ZA et al. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Cancer Res 2014; 74: 7037–7047. · DOI · Paper page
  8. Weinberg SE, Chandel NS . Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol 2015; 11: 9–15. · DOI · Paper page
  9. Vazquez F, Lim JH, Chim H, Bhalla K, Gimun G, Pierce K et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 2013; 23: 287–301. · DOI · Paper page
  10. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R et al. Mitochondrial diseases. Nat Rev Dis Primers 2016; 2: 16080. · DOI · Paper page
  11. Koopman WJH, Beyrath J, Fung CW, Koene S, Rodenburg RJ, Willems PH et al. Mitochondrial disorders in children: toward development of small-molecule treatment strategies. EMBO Mol Med 2016; 8: 311–327. · DOI
  12. Vafai SB, Mootha VK . Mitochondrial disorders as windows into an ancient organelle. Nature 2012; 491: 374–383. · DOI · Paper page
  13. Mitchell P . Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 1961; 191: 144–148. · DOI · Paper page
  14. Koopman WJH, Distelmaier F, Esseling JJ, Smeitink JAM, Willems PH . Computer-assisted live cell analysis of mitochondrial membrane potential, morphology and calcium handling. Methods 2008; 46: 304–311. · DOI
  15. Ellinghaus P, Heisler I, Unterschemmann K, Haerter M, Beck H, Greschat S et al. BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med 2013; 2: 611–624. · DOI · Paper page
  16. Schöckel L, Glasauer A, Basit F, Bitschar K, Truong H, Erdmann G et al. Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth. Cancer Metab 2015; 3: 11. · DOI · Paper page
  17. Condelli V, Maddalena F, Sisinni L, Lettini G, Matassa DS, Piscazzi A et al. Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway: a novel strategy for human BRAF-driven colorectal carcinoma. Oncotarget 2015; 6: 22298–22309. · DOI
  18. Im CN . Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells. Cell Stress Chaperones 2016; 21: 553–562. · DOI
  19. Blanchet L, Grefte S, Smeitink JA, Willems PH, Koopman WJ . Photo-induction and automated quantification of reversible mitochondrial permeability transition pore opening in primary mouse myotubes. PLoS ONE 2014; 9: e114090. · DOI
  20. Iannetti EF, Smeitink JA, Beyrath J, Willems PH, Koopman WJ . Multiplexed high-content analysis of mitochondrial morphofunction using live-cell microscopy. Nat Protoc 2016; 11: 1693–1710. · DOI
  21. Sica V, Galluzzi L, Bravo-San Pedro JM, Izzo V, Maiuri MC, Kroemer G . Organelle-specific initiation of autophagy. Mol Cell 2015; 59: 522–539. · DOI · Paper page
  22. Klionsky DJ . The autophagosome is overrated!. Autophagy 2011; 7: 353–354. · DOI
  23. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y . Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 2009; 10: 458–467. · DOI · Paper page
  24. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J . Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 2011; 108: 10190–10195. · DOI · Paper page
  25. Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJH . Redox homeostasis and mitochondrial dynamics. Cell Metab 2015; 22: 207–218. · DOI · Paper page
  26. Goodall ML, Fitzwalter BE, Zahedi S, Wu M, Rodriguez D, Mulcahy-Levy JM et al. The autophagy machinery controls cell death switching between apoptosis and necroptosis. Dev Cell 2016; 37: 337–349. · DOI · Paper page
  27. Fitzwalter BE, Thorburn A . Recent insights into cell death and autophagy. FEBS J 2015; 282: 4279–4288. · DOI · Paper page
  28. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 2006; 8: 1124–1132. · DOI · Paper page
  29. Vandenabeele P, Grootjans S, Callewaert N, Takahashi N . Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models. Cell Death Diff 2013; 20: 185–187. · DOI · Paper page
  30. Galluzzi L, Kepp O, Chan FK, Kroemer G . Necroptosis: mechanisms and relevance to disease. Annu Rev Pathol Mech Dis 2017; 12: 103–130. · DOI · Paper page
  31. Remijsen Q, Goossens V, Grootjans S, Van den Haute C, Vanlangenakker N, Dondelinger Y et al. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis 2014; 5: e1004. · DOI · Paper page
  32. Wallach D, Kang TB, Dillon CP, Green DR . Programmed necrosis in inflammation: toward identification of the effector molecules. Science 2016; 352: aaf2154. · DOI · Paper page
  33. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060–1072. · DOI · Paper page
  34. Galadari S, Rahman A, Pallichankandy S, Thayyullathil F . Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic Biol Med 2017; 104: 144–164. · DOI · Paper page
  35. Liemburg-Apers DC, Schirris TJ, Russel FG, Willems PH, Koopman WJH . Mitoenergetic dysfunction triggers a rapid compensatory increase in steady-state glucose flux. Biophys J 2015; 109: 1372–1386. · DOI
  36. Liemburg-Apers DC, Wagenaars JAL, Smeitink JAM, Willems PH, Koopman WJH . Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR-RAPTOR. J Cell Sci 2016; 129: 4411–4423. · DOI
  37. Distelmaier F, Valsecchi F, Liemburg-Apers DC, Lebiedzinska M, Rodenburg RJ, Heil S et al. Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α. Biochim Biophys Acta 2015; 1852: 529–540. · DOI
  38. Chen Y, Liersch R, Detmar M . The miR-290-295 cluster suppresses autophagic cell death of melanoma cells. Sci Rep 2012; 2: 808. · DOI
  39. Hua G, Zhang Q, Fan Z . Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis. J Biol Chem 2007; 282: 20553–20560. · DOI · Paper page
  40. Pryde KR, Smith HL, Chau KY, Schapira AH . PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J Cell Biol 2016; 213: 163–171. · DOI · Paper page
  41. Nguyen TN, Padman BS, Lazarou M . Deciphering the molecular signals of PINK1/Parkin mitophagy. TR Cell Biol 2016; 26: 733–744. · DOI · Paper page
  42. Du J, Teng RJ, Guan T, Eis A, Kaul S, Konduri GG et al. Role of autophagy in angiogenesis in aortic endothelial cells. Am J Physiol Cell Physiol 2012; 302: C383–C391. · DOI · Paper page
  43. Gautier CA, Giame E, Caballero E, Núnez L, Song Z, Chan D et al. Regulation of mitochondrial transition pore by PINK1. Mol Neurodegener 2012; 7: 22. · DOI
  44. Abramov AY, Gegg M, Grunewald A, Wood NW, Klein C, Schapira AH . Bioenergetic consequences of PINK1 mutations in Parkinson disease. PLoS ONE 2011; 6: e25662. · DOI
  45. Graef M . A dividing matter: Drp1/Dnm1-independent mitophagy. J Cell Biol 2016; 215: 599–601. · DOI
  46. Yamashita SI, Jin X, Furukawa K, Hamasaki M, Nezu A, Otera H et al. Mitochondrial division occurs concurrently with autophagosome formation but independently of Drp1 during mitophagy. J Cell Biol 2016; 215: 649–665. · DOI · Paper page
  47. Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H . Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem 2005; 280: 25060–25070. · DOI · Paper page
  48. Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, Vogel H et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA 2008; 105: 7070–7075. · DOI · Paper page
  49. Baenke F, Chaneton B, Smith M, Van Den Broek N, Hogan K, Tang H et al. Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells. Mol Oncol 2016; 10: 73–84. · DOI · Paper page
  50. Corazao-Rozas P, Guerreschi P, Andre F, Gabert PE, Lancel S, Dekiouk S et al. Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors. Oncotarget 2016; 7: 39473–39485. · DOI
  51. Schenk B, Fulda S . Reactive oxygen species regulate Smac mimetic/TNFα-induced necroptotic signaling and cell death. Oncogene 2015; 34: 5796–5806. · DOI · Paper page
  52. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS et al. Oxidized arachidonic acid and adrenic Pes navigate cells to ferroptosis. Nat Chem Biol 2017; 13: 81–90. · DOI · Paper page

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Metadata

Authors
Basit, F., van Oppen, L. M., Schöckel, L., Bossenbroek, H. M., van Emst-de Vries, S. E., Hermeling, J. C., Grefte, S., Kopitz, C., Heroult, M., HGM Willems, P., & Koopman, W. J.
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2017-03-30
Volume
8
Issue
3
Pages
e2716-e2716
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/cddis.2017.133
OpenAlex
W2601166832
Cited by
565
References
20
FWCI
9.90
Type
journal article
Language
en
Open access
gold
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CoChat. (2026). Citation check: Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. https://app.cochat.ai/papers/10.1038/cddis.2017.133
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Basit, F., van Oppen, L. M., Schöckel, L., Bossenbroek, H. M., van Emst-de Vries, S. E., Hermeling, J. C., Grefte, S., Kopitz, C., Heroult, M., HGM Willems, P., & Koopman, W. J. (2017). Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death & Disease. https://doi.org/10.1038/cddis.2017.133

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