Mishra, Kumudesh and Péter, Mária and Nardiello, Anna Maria and Keller, Guy and Llado, Victoria and Török, Zsolt and Balogh, Gábor (2022) Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration. CELLS, 11 (3). ISSN 2073-4409
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Abstract
The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) has been extensively investigated as a cancer therapy mainly based on its regulation of membrane lipid composition and structure, activating various cell fate pathways. We discovered, additionally, that 2OHOA can uncouple oxi-dative phosphorylation, but this has never been demonstrated mechanistically. Here, we explored the effect of 2OHOA on mitochondria isolated by ultracentrifugation from U118MG glioblastoma cells. Mitochondria were analyzed by shotgun lipidomics, molecular dynamic simulations, spectrophotometric assays for determining respiratory complex activity, mass spectrometry for assessing beta oxidation and Seahorse technology for bioenergetic profiling. We showed that the main impact of 2OHOA on mitochondrial lipids is their hydroxylation, demonstrated by simulations to decrease co-enzyme Q diffusion in the liquid disordered membranes embedding respiratory complexes. This de-creased co-enzyme Q diffusion can explain the inhibition of disjointly measured complexes I-III activ-ity. However, it doesn’t explain how 2OHOA increases complex IV and state 3 respiration in intact mitochondria. This increased respiration probably allows mitochondrial oxidative phosphorylation to maintain ATP production against the 2OHOA-mediated inhibition of glycolytic ATP production. This work correlates 2OHOA function with its modulation of mitochondrial lipid composition, reflecting both 2OHOA anticancer activity and adaptation to it by enhancement of state 3 respiration. © 2022 by the authors. Li-censee MDPI, Basel, Switzerland.
| Item Type: | Article |
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| Additional Information: | Department of Neurology, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, 91120, Israel Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, 9112102, Israel Lipodom Ltd., Dorottya utca 35-37, Szeged, 6726, Hungary Biological Research Centre, Institute of Biochemistry, Szeged, 6726, Hungary Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, SA, Fisciano, 84084, Italy Bionam Center for Biomaterials, University of Salerno, Via Giovanni Paolo II, 132, SA, Fisciano, 84084, Italy Department of Genetics, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, 9112102, Israel Laminar Pharmaceuticals, Ctra. de Valldemossa Km. 7, 4 Parc BIT Ed. Naorte Bolque A-1°-3, Palma de Mallorca, 07121, Spain Molecular and Experimental Surgery, Clinic for General, Visceral, Vascular, and Transplant Surgery, Medical Faculty, University Hospital Magdeburg, Magdeburg, 39120, Germany Mass Spectrometry Unit, Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, 9112102, Israel Department of Biology, University of the Balearic Islands, Palma de Mallorca, 07122, Spain Export Date: 11 February 2022 Correspondence Address: Escriba, P.V.; Laminar Pharmaceuticals, Ctra. de Valldemossa Km. 7, 4 Parc BIT Ed. Naorte Bolque A-1°-3, Spain; email: pablo.escriba@uib.es Correspondence Address: Piotto, S.; Department of Pharmacy, Via Giovanni Paolo II, 132, SA, Italy; email: piotto@unisa.it Correspondence Address: Kakhlon, O.; Department of Neurology, Ein Kerem, Israel; email: ork@hadassah.org.il |
| Uncontrolled Keywords: | Mitochondria; Respiration; molecular dynamics; Glycolysis; Bioenergetics; Shotgun lipidomics; 2-Hydroxyoleic acid; Membrane Lipid Therapy; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 17 Feb 2023 12:52 |
| Last Modified: | 17 Feb 2023 12:52 |
| URI: | http://real.mtak.hu/id/eprint/159346 |
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