2. Academic Validation
  3. Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia

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

  • Sci Adv. 2025 Oct 17;11(42):eadx8662. doi: 10.1126/sciadv.adx8662.
Sofia La Vecchia 1 2 3,  Saurav Doshi 1 2 3,  Petros Antonoglou 1 2 3,  Tanima Kundu 1 2 3,  Wafa Al Santli 4,  Kleopatra Avrampou 4,  Matthew T Witkowski 5,  Anna Pellattiero 6 7,  Federico Magrin 6 7,  Kristina Ames 8,  Amit Verma 8 9 10,  Kira Gritsman 8 10 11,  Xiaoyang Su 3 12,  Andrea Mattarei 13,  Iannis Aifantis 4,  Luca Scorrano 6 7,  Christina Glytsou 1 2 3
Affiliations

Affiliations

  • 1 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
  • 2 Department of Pediatrics at Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
  • 3 Rutgers Cancer Institute, New Brunswick, NJ 08901, USA.
  • 4 Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 5 Department of Pediatrics Hematology/Oncology/Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus, Aurora, CO 13123, USA.
  • 6 Veneto Institute of Molecular Medicine, Padua 35129, Italy.
  • 7 Department of Biology, University of Padua, Padua 35121, Italy.
  • 8 Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 9 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 10 Montefiore Medical Center, Bronx, NY 10467, USA.
  • 11 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 12 Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
  • 13 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua 35121, Italy.
PMID: 41091864 DOI: 10.1126/sciadv.adx8662
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.

Figures
Products