Antagonistic Pleiotropy in Mitochondria ROS Signaling Responses to Manganese

SUMMARY Antagonistic pleiotropy refers to opposing beneficial and adverse signaling by a single agent. Understanding opposing signaling is important because pathologic outcome can result from adverse causative agents or 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 pleiotropy is a generalized cell systems response to mitochondrial ROS signaling.