Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: a dose-dependent phenomenon

Chowdhury, A. R., Zielonka, J., Kalyanaraman, B., Hartley, R. C. , Murphy, M. P. and Avadhani, N. G. (2020) Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: a dose-dependent phenomenon. Redox Biology, 36, 101606. (doi: 10.1016/j.redox.2020.101606)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was in part supported by NIH RO1 Grants GM-34883 and AA022986 and an endowment from the Harriet Ellison Woodward trust to NGA and grants from the Medical Research Council UK (MC_U105663142) and by a Wellcome Trust Investigator award (110159/Z/15/Z) to MPM.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hartley, Professor Richard
• Authors: Chowdhury, A. R., Zielonka, J., Kalyanaraman, B., Hartley, R. C., Murphy, M. P., and Avadhani, N. G.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Redox Biology
• Publisher: Elsevier
• ISSN: 2213-2317
• ISSN (Online): 2213-2317
• Published Online: 21 June 2020
• Copyright Holders: Copyright © 2020 Elsevier
• First Published: First published in Redox Biology 36:101606
• Publisher Policy: Reproduced under a Creative Commons License