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Updated: Aug 1, 2025

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Published on: February 24, 2018
Antagonistic Interactions in Mitochondria ROS Signaling Responses to Manganese
Jolyn Fernandes1,2, Karan Uppal2, Ken H Liu2
1Section of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Abstract:
Antagonistic interaction refers to opposing beneficial and adverse signaling by a single agent. Understanding opposing signaling is important because pathologic outcomes can result from adverse causative agents or the failure of beneficial mechanisms. To test for opposing responses at a systems level, we used a transcriptome-metabolome-wide association study (TMWAS) with the rationale that metabolite changes provide a phenotypic readout of gene expression, and gene expression provides a phenotypic readout of signaling metabolites. We incorporated measures of mitochondrial oxidative stress (mtOx) and oxygen consumption rate (mtOCR) with TMWAS of cells with varied manganese (Mn) concentration and found that adverse neuroinflammatory signaling and fatty acid metabolism were connected to mtOx, while beneficial ion transport and neurotransmitter metabolism were connected to mtOCR. Each community contained opposing transcriptome-metabolome interactions, which were linked to biologic functions. The results show that antagonistic interaction is a generalized cell systems response to mitochondrial ROS signaling.
Insights
Antagonistic interactions, where a single agent causes opposing signals, are a generalized cell response to mitochondrial reactive oxygen species (ROS) signaling. This study reveals connections between cellular functions and these complex signaling pathways.
Area of Science:
- Cellular biology
- Systems biology
- Biochemistry
Background:
- Antagonistic interactions involve opposing beneficial and adverse signaling from a single agent.
- Understanding these interactions is crucial for addressing pathologies caused by harmful agents or failed beneficial mechanisms.
Purpose of the Study:
- To investigate opposing cellular responses at a systems level.
- To explore the relationship between gene expression, metabolite changes, and mitochondrial function.
Main Methods:
- Utilized a transcriptome-metabolome-wide association study (TMWAS).
- Incorporated measurements of mitochondrial oxidative stress (mtOx) and oxygen consumption rate (mtOCR).
- Analyzed cells with varying manganese (Mn) concentrations.
Main Results:
- Adverse neuroinflammatory and fatty acid metabolism signaling linked to mtOx.
- Beneficial ion transport and neurotransmitter metabolism linked to mtOCR.
- Identified opposing transcriptome-metabolome interactions within cellular communities, connected to biological functions.
Conclusions:
- Antagonistic interaction is a generalized cellular system response to mitochondrial ROS signaling.
- TMWAS provides a systems-level readout of complex cellular signaling pathways.
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