Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes

Toxicol Lett. 2018 Jun 1;289:1-13. doi: 10.1016/j.toxlet.2018.02.026. Epub 2018 Mar 6.

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.

Keywords: Epigenomics; Mitochondrial dysfunction; Primary human hepatocytes; Proteomics; Steatosis; Transcriptomics.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Anticonvulsants / adverse effects*
  • Cells, Cultured
  • DNA Methylation / drug effects
  • DNA, Mitochondrial / drug effects*
  • DNA, Mitochondrial / metabolism
  • Electron Transport Complex I / antagonists & inhibitors
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex III / antagonists & inhibitors
  • Electron Transport Complex III / genetics
  • Electron Transport Complex III / metabolism
  • Electron Transport Complex IV / antagonists & inhibitors
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Epigenomics
  • Gene Expression Profiling
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Kinetics
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / enzymology
  • Mitochondria, Liver / metabolism
  • Mitochondrial Proteins / agonists
  • Mitochondrial Proteins / antagonists & inhibitors
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Models, Biological*
  • Proteomics
  • Valproic Acid / adverse effects*

Substances

  • Anticonvulsants
  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Valproic Acid
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • Electron Transport Complex I
  • Electron Transport Complex III