Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.
Level 5 - mechanism / opinion, no new human data
In vitro structural (cryo-EM) and kinetic bench study using porcine protein; no human data.
PubMed 41214295 · doi:10.1038/s41594-025-01710-6
What was done
Researchers solved cryo-electron microscopy (cryo-EM) structures of the metformin-bound porcine respirasome and conducted kinetic assays to compare the mechanism of mitochondrial complex I inhibition by hydrophilic metformin versus the hydrophobic biguanide proguanil.
What was found
The abstract reports no numerical values. Metformin entered complex I exclusively in its open conformational state and was trapped at the ubiquinone redox site upon ubiquinone-induced conformational closing. In contrast, proguanil occupied both the entrance and the redox site of the ubiquinone channel in open and closed states, exhibiting competitive inhibition with conformation-dependent affinities.
Why it matters
These structural findings explain the molecular basis for metformin's weak complex I inhibition, wide therapeutic index, and clinical safety compared to more toxic hydrophobic biguanides.
Limits
The study was performed in vitro using isolated porcine respiratory complexes; physiological validation in human intact cellular systems was not reported in the abstract. No quantitative kinetic constants or structural resolution values were provided in the abstract.
Cited by
- supports Metformin impairs mitochondrial complex I.