Skip to content

OMA1 (Mitochondrial Metalloendopeptidase)

Summary

OMA1 (Metalloendopeptidase OMA1, mitochondrial) is a metalloprotease situated in the inner mitochondrial membrane that plays a central role in mitochondrial quality control, stress signaling, and metabolic homeostasis. In response to mitochondrial stress, OMA1 is activated to cleave substrate proteins, including OPA1 (regulating mitochondrial fusion) and DELE1 (triggering the integrated stress response). Recent large-scale genetic burden analyses using the RisQ framework have linked rare loss-of-function variants in OMA1 to elevated risk for stress-related psychiatric and eating disorders (as of 2026-07-09).

Biological Function and Substrates

  • Mitochondrial Fusion Regulation: Under physiological conditions, OMA1 works in tandem with YME1L to process OPA1. Upon mitochondrial depolarization or stress, OMA1 rapidly cleaves OPA1, leading to mitochondrial fragmentation.
  • Integrated Stress Response (ISR): OMA1 cleaves DELE1 during stress, producing a fragment that translocates to the cytosol and activates EIF2AK1 (HRI), initiating the ISR pathway.
  • Quality Control: OMA1 acts as a sensor and effector for mitochondrial damage, balancing cell survival and apoptosis.

Disease Associations

  • Neuropsychiatric and Eating Disorders: Exome-wide gene-level burden analyses in 343,477 UK Biobank participants using the RisQ model identified a significant association between OMA1 loss-of-function (LoF) burden and stress-related psychiatric outcomes, including stress and adjustment disorders (OR = 1.48, P = 5.68e-18) and eating disorders (OR = 1.44, P = 3.32e-4). This suggests mitochondrial stress signaling may be a candidate pathway in mood and anxiety phenotypes.
  • Cancer and Metabolic States: Aberrant OMA1 activity has been linked to metabolic reprogramming in colorectal, gastric, and breast cancers, as well as obesity and defective thermogenesis in animal models.

Citations

  • Hager, P., et al. (2026). Learning the shared structure of human health across diseases, modalities, and time. medRxiv preprint. DOI: 10.64898/2026.07.07.26357373. Source paper: 2026.07.07.26357373v1.full.pdf
  • Anand, R., et al. (2014). The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. Journal of Cell Biology, 204(6), 919-929.