Mitochondrial stress triggers a pro-survival response through epigenetic modifications of nuclear DNA

Cell Mol Life Sci. 2019 Apr;76(7):1397-1417. doi: 10.1007/s00018-019-03008-5. Epub 2019 Jan 23.


Mitochondrial dysfunction represents an important cellular stressor and when intense and persistent cells must unleash an adaptive response to prevent their extinction. Furthermore, mitochondria can induce nuclear transcriptional changes and DNA methylation can modulate cellular responses to stress. We hypothesized that mitochondrial dysfunction could trigger an epigenetically mediated adaptive response through a distinct DNA methylation patterning. We studied cellular stress responses (i.e., apoptosis and autophagy) in mitochondrial dysfunction models. In addition, we explored nuclear DNA methylation in response to this stressor and its relevance in cell survival. Experiments in cultured human myoblasts revealed that intense mitochondrial dysfunction triggered a methylation-dependent pro-survival response. Assays done on mitochondrial disease patient tissues showed increased autophagy and enhanced DNA methylation of tumor suppressor genes and pathways involved in cell survival regulation. In conclusion, mitochondrial dysfunction leads to a "pro-survival" adaptive state that seems to be triggered by the differential methylation of nuclear genes.

Keywords: Apoptosis; Autophagy; DNA methylation; Mitochondrial diseases; Mitochondrial dysfunction; Stress response; Survival.

MeSH terms

  • Adolescent
  • Autophagy / drug effects
  • Case-Control Studies
  • Cell Nucleus / genetics*
  • Cell Nucleus / metabolism
  • Cell Shape / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Child
  • Child, Preschool
  • DNA Methylation
  • Epigenesis, Genetic* / drug effects
  • Female
  • Humans
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Rotenone / pharmacology


  • Rotenone