ArticleScientific reports2023
Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility.
Article in Scientific reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 34 citations in OpenAlex.
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- Sustainable tea plantations: Harnessing chemical-microbial synergy and smart application triangulation for targeted weed control.Journal of advanced research · 2026Review
- Selective inhibition of respiratory complex I reveals a bioenergetic vulnerability inbioRxiv : the preprint server for biology · 2026Article
- Melatonin Targets Mitochondrial Redox Homeostasis: Optimizing the Intracellular Microenvironment.International journal of molecular sciences · 2026Review
- Spermidine Suppresses Peripheral Inflammation and Alleviates Non-Motor Symptoms in the 6-OHDA-Induced Rat Model of Parkinson's Disease.Molecules (Basel, Switzerland) · 2026Article
- The antiseizure medication stiripentol inhibits mitochondrial complex I by blocking early-stage electron transfer.The Journal of biological chemistry · 2026Article
- Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model.Scientific reports · 2026Article
- Neuroprotective effects of paederoside against mitochondrial dysfunction in rotenone-induced cell models of Parkinson's disease.Frontiers in neuroscience · 2026Article
- Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.Nature structural & molecular biology · 2026Article
- Oral intake of aripiprazole compromises male fertility in Drosophila.Biology direct · 2025Article
- Efficient constitution of a library of rotenoid analogs active againstRSC advances · 2025Article
- WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer.Molecular medicine (Cambridge, Mass.) · 2025Article
- Redox-Activated Proton Transfer through a Redundant Network in the QJournal of chemical information and modeling · 2025Article
- Inhibition of pro-apoptotic UPR pathways PERK/CHOP and IRE1/JNK protects differentiated SH-SY5Y cells against rotenone-induced toxicity.Frontiers in molecular neuroscience · 2025Article
- Proton-Translocating NADH-Ubiquinone Oxidoreductase: Interaction with Artificial Electron Acceptors, Inhibitors, and Potential Medicines.International journal of molecular sciences · 2024Review
- ATP Restoration by ATP-Deprived Cultured Primary Astrocytes.Neurochemical research · 2024Article
- The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts.International journal of molecular sciences · 2024Article
- Linalool and Geraniol Defend Neurons from Oxidative Stress, Inflammation, and Iron Accumulation in In Vitro Parkinson's Models.Antioxidants (Basel, Switzerland) · 2024Article
- LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants.Neurobiology of disease · 2024Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Respiratory complex I is a major cellular energy transducer located in the inner mitochondrial membrane. Its inhibition by rotenone, a natural isoflavonoid, has been used for centuries by indigenous peoples to aid in fishing and, more recently, as a broad-spectrum pesticide or even a possible anticancer therapeutic. Unraveling the molecular mechanism of rotenone action will help to design tuned derivatives and to understand the still mysterious catalytic mechanism of complex I. Although composed of five fused rings, rotenone is a flexible molecule and populates two conformers, bent and straight. Here, a rotenone derivative locked in the straight form was synthesized and found to inhibit complex I with 600-fold less potency than natural rotenone. Large-scale molecular dynamics and free energy simulations of the pathway for ligand binding to complex I show that rotenone is more stable in the bent conformer, either free in the membrane or bound to the redox active site in the substrate-binding Q-channel. However, the straight conformer is necessary for passage from the membrane through the narrow entrance of the channel. The less potent inhibition of the synthesized derivative is therefore due to its lack of internal flexibility, and interconversion between bent and straight forms is required to enable efficient kinetics and high stability for rotenone binding. The ligand also induces reconfiguration of protein loops and side-chains inside the Q-channel similar to structural changes that occur in the open to closed conformational transition of complex I. Detailed understanding of ligand flexibility and interactions that determine rotenone binding may now be exploited to tune the properties of synthetic derivatives for specific applications.
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