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| Title | Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Year 2025 |
| Publish date | Nov 10, 2025 |
 Authors | Zhaoxiang He / Fei Teng / Yanqing Yang / Ruiyang Guo / Mengchen Wu / Fangzhu Han / Hongtao Tian / Jiawei Wang / Yiqi Hu / Yangwei Jiang / Leili Zhang / Chenyang Xu / Fan Yang / Jiancang Zhou / Shan Zhang / James A Letts / Ruhong Zhou / Long Zhou /   |
| PubMed Abstract | Metformin is the only antihyperglycemic biguanide targeting type 2 diabetes mellitus with proven safety. Although a mechanism of action involving tight inhibition of the respiratory complex I has ...Metformin is the only antihyperglycemic biguanide targeting type 2 diabetes mellitus with proven safety. Although a mechanism of action involving tight inhibition of the respiratory complex I has been proposed for hydrophobic biguanides, it remains elusive for the hydrophilic metformin, whose excellent pharmacological tolerance depends on weak complex I inhibition without competitive nature. Here we solved cryo-electron microscopy structures of the metformin-bound porcine respirasome. Our structural and kinetic data are consistent with a model in which metformin enters complex I only in its open state and becomes trapped at the ubiquinone redox site by ubiquinone-induced conformational closing of the enzyme. By contrast, the hydrophobic proguanil alone occupies both the entrance and the redox site of the ubiquinone channel in open and closed complex I and is kinetically consistent with competitive inhibition with conformation-dependent affinities. Our data provide the molecular basis for metformin's well-known superior properties, such as a wide therapeutic window and positive ubiquinone cooperativity, leading to its clinical success and facilitating future therapeutic developments. |
 External links | Nat Struct Mol Biol / PubMed:41214295 |
| Methods | EM (single particle) |
| Resolution | 2.74 - 3.89 Å |
| Structure data |  EMDB-60237: Cryo-EM map of respirasome open state 3 in presence of metformin (SC-MetO3)  EMDB-60238: Cryo-EM map of respirasome open state 3 in presence of metformin (SC-MetO3), complex I peripheral arm focused  EMDB-60239: Cryo-EM map of respirasome open state 3 in presence of metformin (SC-MetO3), complex I distal membrane arm focused  EMDB-60240: Cryo-EM map of respirasome open state 3 in presence of metformin (SC-MetO3), complex I proximal membrane arm focused  EMDB-60241: Cryo-EM map of respirasome open state 3 in presence of metformin (SC-MetO3), complex III2 focused  EMDB-60242: Cryo-EM map of respirasome open state 3 in presence of metformin (SC-MetO3), complex IV focused  EMDB-60264: Cryo-EM map of respirasome open state 3 in presence of metformin (SC-MetO3)  EMDB-60265: Cryo-EM map of respirasome open state 2 in presence of metformin (SC-MetO2), complex I peripheral arm focused  EMDB-60280: Cryo-EM map of respirasome open state 2 in presence of metformin (SC-MetO2), complex I proximal membrane arm focused EMDB-60284, PDB-8zo8:  EMDB-60296: Cryo-EM map of respirasome open state 2 in presence of metformin (SC-MetO2), complex I distal membrane arm focused  EMDB-60298: Cryo-EM map of respirasome open state 2 in presence of metformin (SC-MetO2), complex III2 focused  EMDB-60299: Cryo-EM map of respirasome open state 2 in presence of metformin (SC-MetO2), complex IV focused  EMDB-60306: Cryo-EM map of respirasome closed state 1 bound by metformin (SC-MetC1)  EMDB-60308: Cryo-EM map of respirasome closed state 1 bound by metformin (SC-MetC1), complex I peripheral arm focused  EMDB-60309: Cryo-EM map of respirasome closed state 1 bound by metformin (SC-MetC1), complex I proximal membrane arm focused  EMDB-60310: Cryo-EM map of respirasome closed state 1 bound by metformin (SC-MetC1), complex I distal membrane arm focused  EMDB-60311: Cryo-EM map of respirasome closed state 1 bound by metformin (SC-MetC1), complex III2 focused  EMDB-60313: Cryo-EM map of respirasome closed state 1 bound by metformin (SC-MetC1), complex IV focused EMDB-60319, PDB-8zou:  EMDB-60333: Cryo-EM map of respirasome closed state 2 in presence of metformin (SC-MetC2), complex I peripheral arm focused  EMDB-60334: Cryo-EM map of respirasome closed state 2 in presence of metformin (SC-MetC2)  EMDB-60335: Cryo-EM map of respirasome closed state 2 in presence of metformin (SC-MetC2), complex I proximal membrane arm focused  EMDB-60336: Cryo-EM map of respirasome closed state 2 in presence of metformin (SC-MetC2), complex I distal membrane arm focused  EMDB-60337: Cryo-EM map of respirasome closed state 2 in presence of metformin (SC-MetC2), complex III2 focused  EMDB-60338: Cryo-EM map of respirasome closed state 2 in presence of metformin (SC-MetC2), complex IV focused  EMDB-60339: Cryo-EM map of respirasome closed state 1 in the absence of biguanide (SC-ApoC), complex I peripheral arm focused  EMDB-60340: Cryo-EM map of respirasome closed state 1 in the absence of biguanide (SC-ApoC)  EMDB-60341: Cryo-EM map of respirasome closed state 1 in the absence of biguanide (SC-ApoC), complex I proximal membrane arm focused  EMDB-60342: Cryo-EM map of respirasome closed state 1 in the absence of biguanide (SC-ApoC), complex I distal membrane arm focused  EMDB-60343: Cryo-EM map of respirasome closed state 1 in the absence of biguanide (SC-ApoC), complex IV focused  EMDB-60344: Cryo-EM map of respirasome closed state 1 in the absence of biguanide (SC-ApoC), complex III2 focused  EMDB-60356: Cryo-EM map of respirasome closed state 1 bound by metformin alone (SC-MetC1-i), complex I peripheral arm focused  EMDB-60357: Cryo-EM map of respirasome closed state 1 bound by metformin alone (SC-MetC1-i), complex I proximal membrane arm focused  EMDB-60358: Cryo-EM map of respirasome closed state 1 bound by metformin alone (SC-MetC1-i), complex I distal membrane arm focused  EMDB-60359: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ (SC-MetC1-ii), complex I peripheral arm focused  EMDB-60360: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ (SC-MetC1-ii), complex I proximal membrane arm focused  EMDB-60361: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ (SC-MetC1-ii), complex I distal membrane arm focused  EMDB-60362: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ, alternative orientation (SC-MetC1-iii), complex I peripheral arm focused  EMDB-60363: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ, alternative orientation (SC-MetC1-iii), complex I proximal membrane arm focused  EMDB-60364: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ, alternative orientation (SC-MetC1-iii), complex I distal membrane arm focused  EMDB-60367: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ (SC-MetC1-ii)  EMDB-60368: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ, alternative orientation (SC-MetC1-iii)  EMDB-60375: Cryo-EM map of respirasome closed state bound by proguanil (SC-ProgC)  EMDB-60376: Cryo-EM map of respirasome closed state bound by proguanil (SC-ProgC), complex I peripheral arm focused  EMDB-60377: Cryo-EM map of respirasome closed state bound by proguanil (SC-ProgC), complex I proximal membrane arm focused  EMDB-60378: Cryo-EM map of respirasome closed state bound by proguanil (SC-ProgC), complex I distal membrane arm focused  EMDB-60380: Cryo-EM map of respirasome closed state 1 bound by metformin alone (SC-MetC1-i) EMDB-60418, PDB-8zsk: EMDB-60419, PDB-8zsl: EMDB-60420, PDB-8zsm: EMDB-60421, PDB-8zsn: EMDB-60422, PDB-8zso: EMDB-60424, PDB-8zsq: EMDB-60550, PDB-8zxz:  EMDB-61160: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-iv)  EMDB-61163: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-iv), complex I peripheral arm focused  EMDB-61164: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-iv), complex I proximal membrane arm focused  EMDB-61165: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-v), complex I peripheral arm focused  EMDB-61171: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-v)  EMDB-61172: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-iv), complex I distal membrane arm focused EMDB-61173, PDB-9j6h:  EMDB-61178: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-v), complex I proximal membrane arm focused  EMDB-61183: Cryo-EM map of respirasome closed state 1 bound by metformin and CoQ10 (SC-MetC1-v), complex I distal membrane arm focused EMDB-61186, PDB-9j6w: |
| Chemicals |  ChemComp-ZN:  ChemComp-PC1:  ChemComp-CDL:  ChemComp-NDP:  ChemComp-ZMP:  ChemComp-ADP:  ChemComp-3PE:  ChemComp-PLX: 
ChemComp-6F6:  ChemComp-HEA:  ChemComp-CU:  ChemComp-MG:  ChemComp-PEE:  ChemComp-HEM:  ChemComp-HEC:  ChemComp-FES:  ChemComp-SF4:  ChemComp-FMN:  ChemComp-PX2:  ChemComp-U10:  ChemComp-MF8:  ChemComp-XEW: |
| Source |
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 Keywords | MEMBRANE PROTEIN / Metformin / electron transport chain / Respirasome / mammalia |
sus scrofa (pig)