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

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.

SUBMITTER: Chowdhury AR

PROVIDER: S-EPMC7327929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.

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Communication between mitochondria and nucleus: defining a retrograde response in fission yeast

Project description:Retrograde response was widely studied in budding yeast but the main transcription factors that transmit it (RTG1,2 and 3) are not conserved in other organisms, thus it is interesting to study how communication between mitochondria and nucleus evolved in distantly related fission yeast, and which are the common aspects of this conserved pathway between yeast and higher organisms.To analyse any retrograde response in fission yeast, we inhibited the electron transport chain activity by antimycin A and studied cellular gene expression changes by microarrays. Cells treated with antimycin A in fermentative medium (YE with 3% glucose), showed the same growth rate as untreated cells, but they reached a lower biomass in stationary phase. Antimycin A treated cells consumed glucose at a faster rate and produced more ethanol, indicating that the energy metabolism was shifted even more towards fermentation. We analyzed the transcriptomes of antimycin A-treated cells to untreated control cells during early exponential growth phase (OD 0.5).

2016-11-01 | E-MTAB-4520 | biostudies-arrayexpress

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