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MRC Mitochondrial Biology Unit



Figure Left: Inhibition of cellular oxygen consumption caused by inhibition of complex I by metformin [1], Right: Schematic and local structure of the binding site of IACS-2858 [2].

Due to the central role of complex I in cellular metabolism, it can be targeted by drugs to alter cellular processes such as redox balance, signalling pathways, reactive oxygen species (ROS) production and ATP production. When complex I is the intended target these effects are clinically desirable, but at other times they represent damaging side reactions unrelated to the drug’s intended mechanism of action. A variety of compounds and drugs have been developed as intentional inhibitors of complex I catalysis, including IACS-010759 [2], [3], rotenoids [4] and biguanides [1], [5], which have all been proposed as anticancer agents. The role of complex I inhibition in the anti-diabetic effect of the widely-used drug metformin is still under debate. Other drugs inhibit complex I as an unwanted side-effect, impairing mitochondrial function [6]. Being able to determine when complex I is acting as an unwanted drug target is necessary for the development of safer drugs with fewer toxic side effects.

In our group we are beginning projects that:

  • Survey complex I inhibition as a cause of liver toxicity by pharmacological compounds;
  • Define the biochemical and structural bases of complex I-drug interactions;
  • Pursue the cellular and mitochondrial consequences of complex I inhibition.


  1. Bridges HR, Jones JYJ, Pollak MN & Hirst J (2014)
    Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria.
    Biochem J 462, 475-487
  2. Chung I, Serreli R, Cross JB, Di Francesco ME, Marszalek JR & Hirst J (2021)
    Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.
    Sci Adv 7, eabg4000
  3. Molina JR et al (2018)
    An inhibitor of oxidative phosphorylation exploits cancer vulnerability.
    Nature Med 24, 1036-1046
  4. Russell DA, Bridges HR, Serreli R, Kidd SL, Mateu N, Osberger TJ, Sore HF, Hirst J & Spring DR (2020)
    Hydroxylated rotenoids selectively inhibit the proliferation of prostate cancer cells.
    J Nat Prod 83, 1829-1845
  5. Bridges HR, Sirviö VA, Agip A-NA & Hirst J (2016)
    Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase.
    BMC Biol 14, 65
  6. Stephenson ZA, Harvey RF, Pryde KR, Mistry S, Hardy RE, Serreli R, Chung I, Allen TEH, Stoneley M, MacFarlane M, Fischer PM, Hirst J, Kellam B & Willis AE (2020)
    Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I.
    eLife 9, e55845