Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. (1st June 2018)

• Record Type: Journal Article
• Authors: Wolters, Jarno E.J.; van Breda, Simone G.J.; Grossmann, Jonas; Fortes, Claudia; Caiment, Florian; Kleinjans, Jos C.S.
• Is Part Of: Toxicology letters. Volume 289(2018)
• Page Start: 1
• Page End: 13
• Publication Date: 2018-06-01
• Subjects: Steatosis -- Mitochondrial dysfunction -- Primary human hepatocytes -- Epigenomics -- Transcriptomics -- Proteomics; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2018.02.026
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: 'Omics analysis allowed for discriminating between toxicity of VPA and adaptation. A mitochondrial-nuclear signaling axis, MT-CO2–FN1–MYC–CPT1, was identified. 'Omics study showed dynamic responses leading to constant mitochondrial dysfunction. Abstract: We performed a multiple 'omics study by integrating data on epigenomic, transcriptomic, and proteomic perturbations associated with mitochondrial dysfunction in primary human hepatocytes caused by the liver toxicant valproic acid (VPA), to deeper understand downstream events following epigenetic alterations in the mitochondrial genome. Furthermore, we investigated persistence of cross-omics changes after terminating drug treatment. Upon transient methylation changes of mitochondrial genes during VPA-treatment, increasing complexities of gene-interaction networks across time were demonstrated, which normalized during washout. Furthermore, co-expression between genes and their corresponding proteins increased across time. Additionally, in relation to persistently decreased ATP production, we observed decreased expression of mitochondrial complex I and III–V genes. Persistent transcripts and proteins were related to citric acid cycle and β-oxidation. In particular, we identified a potential novel mitochondrial-nuclear signaling axis, MT-CO2–FN1–MYC–CPT1. In summary, this cross-omics study revealed dynamic responses of the mitochondrial epigenome to an impulse toxicant challenge resulting in persistent mitochondrial dysfunctioning. Moreover, this approach allowed for discriminating between the toxic effect of VPA and adaptation.