@article{cab39a8633664d1b9962bf4de66589f4,
title = "Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors",
abstract = "Mitochondrial division is essential for mitosis and metazoan development, but a mechanistic role in cancer biology remains unknown. Here, we examine the direct effects of oncogenic RASG12V-mediated cellular transformation on the mitochondrial dynamics machinery and observe a positive selection for dynamin-related protein 1 (DRP1), a protein required for mitochondrial network division. Loss ofDRP1 prevents RASG12V-induced mitochondrial dysfunction and renders cells resistant to transformation. Conversely, in human tumor cell lines with activating MAPK mutations, inhibition of these signals leads to robust mitochondrial network reprogramming initiated by DRP1 loss resulting in mitochondrial hyper-fusion and increased mitochondrial metabolism. These phenotypes are mechanistically linked by ERK1/2 phosphorylation of DRP1 serine 616; DRP1S616 phosphorylation is sufficient to phenocopy transformation-induced mitochondrial dysfunction, and DRP1S616 phosphorylation status dichotomizes BRAFWT from BRAFV600E-positive lesions. These findings implicate mitochondrial division and DRP1 as crucial regulators of transformation with leverage in chemotherapeutic success.",
author = "Serasinghe, {Madhavika N.} and Wieder, {Shira Y.} and Renault, {Thibaud T.} and Rana Elkholi and Asciolla, {James J.} and Yao, {Jonathon L.} and Omar Jabado and Kyle Hoehn and Yusuke Kageyama and Hiromi Sesaki and Chipuk, {Jerry E.}",
note = "Funding Information: We would like to thank everyone in the J.E.C. laboratory for assistance and support. We also thank Drs. Stuart Aaronson, Emily Bernstein, Mark Lebwohl, Cathie Pfleger, Poulikos Poulikakos, E. Premkumar Reddy, and Garabet Yeretssian (Icahn School of Medicine at Mount Sinai) for critical reagents and/or mentorship; Dr. Cole Haynes and Christopher Fiorese (Memorial Sloan Kettering Cancer Center) and Dr. Navdeep Chandel and Lucas Sullivan (Northwestern University) for assistance with Seahorse Analyzer studies; the Stable Isotope & Metabolomics Core (Albert Einstein College of Medicine); Dr. Jodi Nunnari (University of California, Davis) for recombinant DRP1; Drs. Miriam Birge and Rajendra Singh (Mount Sinai Medical Center) for their dermatopathology expertise; Dominique Bozec for assistance with mice; and Dr. Sandra Milasta for assistance with the NDI1 studies. This work was supported by NIH grants CA157740 (to J.E.C.) and GM089853 (to H.S.), a pilot project from NIH P20AA017067 (to J.E.C.), the JJR Foundation (to J.E.C.), the William A. Spivak Fund (to J.E.C.), and the Fridolin Charitable Trust (to J.E.C.). This work was also supported in part by two research grants (5-FY11-74 and 1-FY13-416) from the March of Dimes Foundation (to J.E.C.), an Einstein Research Fellowship (to S.Y.W.), an American Skin Association Medical Students Grant (to S.Y.W.), and an American Cancer Society Research Scholar Award (to J.E.C.). Chromatographic and mass spectrometric development for metabolite profiling was supported by a Diabetes Research and Training Center (DRTC) grant (P60DK020541). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = feb,
day = "5",
doi = "10.1016/j.molcel.2015.01.003",
language = "English (US)",
volume = "57",
pages = "521--536",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",
}