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

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

Author information

1
Instituto de Histología y Embriología de Mendoza (IHEM, Universidad Nacional de Cuyo, CONICET)-Centro Universitario UNCuyo, 5500, Mendoza, Argentina. liamayorga@fcm.uncu.edu.ar.
2
Instituto de Histología y Embriología de Mendoza (IHEM, Universidad Nacional de Cuyo, CONICET)-Centro Universitario UNCuyo, 5500, Mendoza, Argentina.
3
Facultad de Odontología, Univeridad Nacional de Cuyo- Centro Universitario UNCuyo, 5500, Mendoza, Argentina.
4
John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA.
5
Hospital de Pediatría J.P. Garrahan, Combate de los Pozos 1881, 1245, Buenos Aires, Argentina.
6
Facultad de Ciencias Médicas, Universidad Nacional de Cuyo-Centro Universitario UNCuyo, 5500, Mendoza, Argentina.
7
Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo-Centro Universitario UNCuyo, 5500, Mendoza, Argentina.

Abstract

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

PMID:
30673822
DOI:
10.1007/s00018-019-03008-5
[Indexed for MEDLINE]

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