DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma

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.

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Publication Details

Journal
Blood
Published
2026-08-03
DOI
https://doi.org/10.1182/blood.2025030349
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
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article

DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma

Luka Jedlovčnik, Roberta Torcasio, Maria Eugenia Gallo Cantafio, Nicola Cuscino et al.
Blood
Multiple Myeloma Research and Treatments
article

DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma

Luka Jedlovčnik, Roberta Torcasio, Maria Eugenia Gallo Cantafio, Nicola Cuscino, Enrica Antonia Martino, Alessia Ciarrocchi, Massimo Gentile, Noemi Puccio, Eugenio Morelli, Stephen L. Archer, Yuanyuan Jin, Alessia Gallo, Antonino Neri, Mariateresa Fulciniti, Anıl Aktaş Samur, Cesarina Giallongo, Daniele Tibullo, Ida Perrotta, Danchen Wu, Giuseppe Viglietto, Ernestina Marianna De Francesco, Federico Tallarigo, Ross D. Jansen‐van Vuuren, Pierpaolo Murfone, Ludovica Ganino, Ilenia Valentino, Davide Barbuto, Nicola Amodio, Mehmet K. Samur, Nikhil C. Munshi, Francesco Di Raimondo
article en

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.

Blood
University of Ljubljana (SI), Queen's University (CA), Università degli Studi di Enna Kore (IT), Magna Graecia University (IT), University of Catania (IT), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Istituto S.Anna Crotone (IT), Dana-Farber Cancer Institute (US), Ospedale Annunziata di Cosenza (IT), Candiolo Cancer Institute (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco" (IT), University of Calabria (IT), Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IT)
Good health and well-being
Openalex Percentile: Top 9%
Multiple Myeloma Research and Treatments
DOISourceOpenAlex
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