DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma
Abstract
Mitochondrial dynamics is a key regulator of cellular homeostasis, orchestrating metabolic reprogramming that fuels tumor progression and treatment resistance. In multiple myeloma (MM), however, the functional relevance of mitochondrial remodeling has not been fully defined. Using ultrastructural analyses, we reveal that MM cells display a highly fragmented mitochondrial network, a phenotype further exacerbated in both cell lines and primary MM cells resistant to proteasome inhibitors. Transcriptomic profiling across multiple patient-derived datasets consistently demonstrated upregulation of DNM1L gene, which encodes the mitochondrial fission GTPase DRP1, particularly in relapsed and refractory MM, and revealed a significant association with inferior overall survival. Disrupting mitochondrial fission, either through genetic targeting of DNM1L or pharmacologic inhibition of DRP1 with the selective small molecule inhibitor Drpitor1a, resulted in pronounced mitochondrial dysfunction, impaired oxidative phosphorylation, and potent anti-myeloma activity in vitro, culminating in a hybrid cell death program with a predominant apoptotic component accompanied by ferroptotic features. These effects were recapitulated in vivo in a bortezomib-resistant xenograft model, where either DNM1L depletion or DRP1 inhibition produced similar outcomes. Mechanistically, the transcription factor c-MYC upregulated DNM1L expression, and DRP1-dependent mitochondrial fragmentation sustained MYC-driven oxidative metabolism and lipid synthesis. Altogether, these findings establish aberrant mitochondrial fission as a pathogenic hallmark of MM and highlight DRP1 inhibition as a promising therapeutic approach, especially for relapsed or refractory disease.
Article Details
Authors (31)
Maria Eugenia Gallo Cantafio
University Magna Graecia of Catanzaro, Catanzaro, Italy
Noemi Puccio
Azienda USL-IRCCS di Reggio Emilia; Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Reggio Emilia, Italy
Roberta Torcasio
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Ilenia Valentino
University Magna Graecia of Catanzaro, Catanzaro, Italy
Ludovica Ganino
University Magna Graecia of Catanzaro, Catanzaro, Italy
Yuanyuan Jin
Anil Aktas Samur
Dana Farber Cancer Institution, Boston, Massachusetts, United States
Pierpaolo Murfone
University of Catanzaro, Catanzaro, Italy
Alessia Gallo
IRCCS ISMETT, Palermo, Italy
Mehmet K. Samur
Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts, United States
Nicola Cuscino
IRCCS ISMETT, Palermo, Italy
Cesarina Giallongo
Ida Daniela Perrotta
University of Calabria, Rende CS, Italy
Alessia Ciarrocchi
Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Federico Tallarigo
anatomia patologica, Crotone, Italy
Ernestina Marianna De Francesco
University of Enna "Kore", Enna, Italy
Davide Barbuto
Ross David Jansen-van Vuuren
University of Ljubljana, Ljubljana, Slovenia
Luka Jedlovčnik
University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia
Danchen Wu
Queen's University, Kingston, Ontario, Canada
Enrica Antonia Martino
Azienda Ospedaliera Annunziata, Cosenza, Italy
Daniele Tibullo
Francesco Di Raimondo
Massimo Gentile
Azienda Ospedaliera Annunziata, Cosenza, Italy
Antonino Neri
Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Stephen L. Archer
Translational Institute of Medicine (TIME), Queen's University, Kingston, Canada
Eugenio Morelli
INOC - Istituto Nazionale Oncologico Candiolo, Candiolo, Italy
Nikhil C. Munshi
Giuseppe Viglietto
University of Catanzaro, Catanzaro, Italy
Mariateresa Fulciniti
Dana Farber Cancer Institute, Boston, Massachusetts, United States
Nicola Amodio
University of Catanzaro, Catanzaro, Italy