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The MIRO1-BAX Complex Dictates Life and Death at the Mitochondrial Gate

Alva G Sainz1, Chulhwan S Kwak1, Kwang Bog Cho1

  • 1Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.

Biorxiv : the Preprint Server for Biology
|July 10, 2026
PubMed

Insights

MIRO1 modulates BAX pore formation to control cell death. This protein triggers ferroptosis resistance in glioma cells and apoptosis in Parkinsonian neurons, offering new therapeutic targets.

Area of Science:

  • Mitochondrial biology
  • Cell death pathways
  • Neuroscience

Background:

  • BAX-mediated outer mitochondrial membrane (OMM) permeabilization is key to apoptosis.
  • The role of OMM pores in diverse cell death mechanisms is not fully understood.

Purpose of the Study:

  • Investigate MIRO1's role in modulating BAX activity and its impact on cell fate.
  • Identify therapeutic strategies targeting the MIRO1-BAX interaction for disease intervention.

Main Methods:

  • Protein-protein interaction studies (MIRO1-BAX).
  • Mitochondrial DNA (mtDNA) release assays.
  • Signaling pathway analysis (STING-pIRF3).
  • Cell viability assays in glioma and neuronal models.
  • Structure-guided small molecule drug discovery.

Main Results:

  • MIRO1 acts as a context-specific modulator of BAX, promoting OMM pore formation.
  • MIRO1-BAX interaction releases mtDNA, activating the STING-pIRF3 axis.
  • In glioma cells, this pathway confers ferroptosis resistance by sustaining GPX4 expression.
  • In Parkinsonian neurons, the MIRO1-BAX complex induces apoptosis.
  • Developed small molecules that disrupt the MIRO1-BAX complex, sensitizing glioma cells to ferroptosis and protecting neurons.

Conclusions:

  • MIRO1 functions as a mitochondrial switch, directing cell fate decisions (ferroptosis vs. apoptosis) based on cellular context.
  • Targeting the MIRO1-BAX interaction offers a novel therapeutic approach for diseases involving aberrant cell death, such as cancer and neurodegeneration.

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