Acute myeloid leukemia (AML) remains one of the most challenging hematological malignancies to treat. Venetoclax (Venclexta), a BCL-2 inhibiting BH3 mimetic, has significantly improved outcomes for many patients — but resistance is common and almost inevitable. A new study from a team led by Christina Glytsou at Rutgers reveals a surprising, non-genetic resistance mechanism, and identifies a potentially druggable vulnerability.
The Discovery: Mitochondrial Shape-Shifting via OPA1
- The researchers used CRISPRi genetic screening along with high-resolution electron microscopy to analyze venetoclax-resistant AML cells. They discovered that resistant cells dramatically up-regulate OPA1, a GTPase that organizes mitochondrial cristae.
- Elevated OPA1 changes mitochondrial ultrastructure: cristae become more tightly folded (“narrower” cristae), which has a functional consequence — cytochrome c is trapped, reducing its release, and thereby blocking apoptosis.
- Importantly, this morphological adaptation was confirmed in patient AML samples: relapsed patients (especially those previously treated with venetoclax) showed narrower cristae compared to treatment‑naïve patients.
“We found that mitochondria change their shape to prevent apoptosis … cancer cells reshape their energy‑producing mitochondria … to protect themselves from venetoclax.” – Christina Glytsou, Rutgers
Targeting OPA1: Small-Molecule Inhibitors Restore Venetoclax Sensitivity
To test whether inactivating OPA1 could reverse resistance, the team employed two lead small-molecule inhibitors of OPA1: MYLS22 and Opitor‑0. Key findings included:
- Synergy with Venetoclax
- In AML cell lines and patient-derived xenografts (PDX), combining venetoclax with OPA1 inhibitors induced stronger apoptosis than either agent alone.
- In in vivo mouse models, the combination significantly extended survival compared to venetoclax monotherapy.
- Mechanistic Insights
- Electron microscopy confirmed that OPA1 inhibition re-opens or loosens cristae, facilitating cytochrome c release and restoring apoptotic signaling.
- Beyond apoptosis, OPA1-depleted AML cells showed metabolic rewiring: they become heavily dependent on glutamine and show increased sensitivity to ferroptosis, an iron-driven form of cell death.
- Transcriptomic and stress-response analyses indicated activation of an integrated stress response (ISR), specifically via ATF4, when OPA1 is inhibited, further sensitizing cells.
- Safety Profile (Preclinical)
- In the mouse studies, the OPA1 inhibitors did not significantly impair normal hematopoiesis — a crucial consideration for any therapeutic targeting mitochondria.
- Nevertheless, the current inhibitors are still lead compounds; the authors note they require further medicinal chemistry (e.g., improving solubility) before clinical translation.
Broader Context & Relevance for Molecular Biologists and Biotech Labs
- Mitochondrial Architecture as a Therapeutic Target
- Mitochondrial morphology is an active regulator of cell fate. For labs working on metabolic vulnerabilities, mitochondrial dynamics should increasingly be part of experimental design — not only bioenergetics but the physical cristae structure.
- Non-genetic Mechanisms of Resistance
- OPA1-mediated resistance is non-mutational: cells re-wire their organelle architecture to survive. Monitoring mitochondrial structure may serve as a predictive marker of emerging resistance.
- Metabolic & Cell‑Death Cross-Talk
- OPA1 inhibition forces reliance on glutamine and sensitizes to ferroptosis, offering potential dual-modal therapeutic strategies.
- Drug Development Implications
- Lead OPA1 inhibitors are promising but not yet optimized for human use. Safety signals in mice and OPA1 overexpression in other cancers suggest broader oncology applications.
Caveats & Future Questions
- Translational Timeline: Early-stage inhibitors; further optimization required.
- Patient Heterogeneity: How universal is OPA1 upregulation across AML subtypes?
- Compensatory Pathways: Might other mitochondrial-shaping proteins mediate resistance?
- In Vivo Complexity: Human microenvironment may affect efficacy.
- Target Safety: Long-term inhibition effects on healthy cells remain to be fully understood.
Implications for Lab Strategy & Procurement
- Assay Design: Add mitochondrial ultrastructure readouts (cristae imaging, network assays) when profiling resistant vs sensitive AML cells.
- Cell-Line Development: Engineer or monitor OPA1 expression and mitochondrial morphology changes.
- Drug Screening: Include mitochondrial-shaping activity and metabolic stress (glutamine dependency, ferroptosis susceptibility) as phenotypic endpoints.
- Procurement: Evaluate imaging platforms and reagent kits compatible with mitochondrial morphology assays.
- Quality Control: Incorporate mitochondrial morphology checks in cell-based production or bioreactor workflows.
Conclusion
This study from Rutgers et al. uncovers a novel, non-genetic mechanism of resistance to venetoclax in AML, mediated by OPA1-driven mitochondrial remodeling. For molecular biologists, biotechnologists, diagnostics professionals, and lab managers, it highlights that mitochondrial architecture is a pivotal player in drug response. Integrating mitochondrial-morphology awareness into experimental workflows, screening pipelines, and procurement strategies can keep your lab at the forefront of therapeutic resistance research.
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Source: “One protein may hold the key to fixing leukemia treatment failure,” ScienceDaily, Rutgers University, 24 Nov 2025. (sciencedaily.com)
Primary Research: La Vecchia, S., Doshi, S., Antonoglou, P., et al. Small‑molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia. Science Advances (2025). DOI: 10.1126/sciadv.adx8662. (researchwithrutgers.com)