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

• Published in: Cellular and molecular life sciences : CMLS Vol. 76; no. 7; pp. 1397 - 1417
• Main Authors: Mayorga, Lía, Salassa, Betiana N., Marzese, Diego M., Loos, Mariana A., Eiroa, Hernán D., Lubieniecki, Fabiana, García Samartino, Clara, Romano, Patricia S., Roqué, María
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2019; Springer Nature B.V
• Subjects: Adolescent; Apoptosis; Autophagy; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Cell Biology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Shape - drug effects; Cell survival; Cell Survival - drug effects; Cells, Cultured; Cellular stress response; Child; Child, Preschool; Deoxyribonucleic acid; DNA; DNA Methylation; Epigenesis, Genetic - drug effects; Female; Gene expression; Genes; Humans; Life Sciences; Male; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Mitochondrial DNA; Myoblasts; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; Original; Original Article; Phagocytosis; Rotenone - pharmacology; Survival; Transcription; Tumor suppressor genes; Mitochondrial dysfunction; DNA methylation; Mitochondrial diseases; Stress response; Autophagy; Survival; Apoptosis
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03008-5

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.