Get started
Work

Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia

Year: 2025
Type: article
Abstract: Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.
DOI: 10.1126/sciadv.adx8662
Authors: Sofia La Vecchia, Saurav Doshi, Petros Antonoglou, Tanima Kundu, Wafa Al Santli, Kleopatra Avrampou, Matthew T. Witkowski, Anna Pellattiero, Federico Magrin, Kristina Ames, Amit Verma, Kira Gritsman, Xiaoyang Su, Andrea Mattarei, Iannis Aifantis, Luca Scorrano, Christina Glytsou
Institutions: Rutgers, The State University of New Jersey, Rutgers Cancer Institute, New York University, University of Colorado Anschutz, University of Colorado Denver, University of Padua, Veneto Institute of Molecular Medicine, Albert Einstein College of Medicine, Montefiore Medical Center
Language: English
Subfield: Hematology
Field: Medicine
Open Access status: gold
Estimated APC paid: $4,500
Awards: Regulation of emergency hematopoiesis by the ubiquitin-proteasome system, PI3 Kinase Inactivation in Myelodysplastic Syndrome, Beckman Coulter MoFlo Astrios EQ Cell Sorter, Targeting an RNA Binding Protein Network in Acute Myeloid Leukemia, G6742143970, PI3K Isoform Dependence in Adult Hematopoiesis and Myeloid Leukemia, Role of the Class IA PI3K in Hematopoietic Stem Cell Self-Renewal, The role of inflammation in the regulation of immune response in acute myeloid leukemia, PI3 Kinase Inactivation in Myelodysplastic Syndrome, Rutgers Center for Environmental Exposure and Disease (CEED), Targeting mitochondrial dynamics in drug-resistant acute myeloid leukemia
OpenAlex ID: W4415221163
FWCI: 5.714
Cites: 96
Cited by: 9
Related to: