Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon
The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-M...
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doaj-58c1fa1d4a5f46729fb31d06fda46e762020-11-25T03:41:09ZengElsevierRedox Biology2213-23172020-09-0136101606Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenonAnindya Roy Chowdhury0Jacek Zielonka1Balaraman Kalyanaraman2Richard C. Hartley3Michael P. Murphy4Narayan G. Avadhani5Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USADepartment of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USASchool of Chemistry, University of Glasgow, Glasgow, G128QQ, UKMRC-Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge, CB2 OXY, UKDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author.The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP+) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O2•–) production by acting on complex I. In Raw264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O2•– and H2O2). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1α activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca2+/Cn pathway and is independent of ROS-induced HIF1α or AMPK pathways.http://www.sciencedirect.com/science/article/pii/S2213231720308119Mitochondrial ROSCalcineurin activationHIF1αRetrograde signalingHypoxia mediated stressMacrophage cell line |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anindya Roy Chowdhury Jacek Zielonka Balaraman Kalyanaraman Richard C. Hartley Michael P. Murphy Narayan G. Avadhani |
spellingShingle |
Anindya Roy Chowdhury Jacek Zielonka Balaraman Kalyanaraman Richard C. Hartley Michael P. Murphy Narayan G. Avadhani Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon Redox Biology Mitochondrial ROS Calcineurin activation HIF1α Retrograde signaling Hypoxia mediated stress Macrophage cell line |
author_facet |
Anindya Roy Chowdhury Jacek Zielonka Balaraman Kalyanaraman Richard C. Hartley Michael P. Murphy Narayan G. Avadhani |
author_sort |
Anindya Roy Chowdhury |
title |
Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon |
title_short |
Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon |
title_full |
Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon |
title_fullStr |
Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon |
title_full_unstemmed |
Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon |
title_sort |
mitochondria-targeted paraquat and metformin mediate ros production to induce multiple pathways of retrograde signaling: a dose-dependent phenomenon |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2020-09-01 |
description |
The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP+) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O2•–) production by acting on complex I. In Raw264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O2•– and H2O2). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1α activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca2+/Cn pathway and is independent of ROS-induced HIF1α or AMPK pathways. |
topic |
Mitochondrial ROS Calcineurin activation HIF1α Retrograde signaling Hypoxia mediated stress Macrophage cell line |
url |
http://www.sciencedirect.com/science/article/pii/S2213231720308119 |
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