Mitochondrial stress triggers a pro-survival response through epigenetic modifications of nuclear DNA
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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.
KeywordsMitochondrial dysfunction DNA methylation Stress response Autophagy Apoptosis Mitochondrial diseases Survival
Firstly, we thank the patients and their families for contributing to research in the field. We also acknowledge: Dr. G.A. Truskey (HSkM cells—Duke University, NC, USA), Dr. E. Pusiol and Dr. E Cassone (control samples—Mendoza, Argentina), C. Tagliavini (blood sample shipping—Garrahan), R.Grosso, Dr. I. Cebrian, Dr. E. Muñoz, Dr. D.Croci, Dr. C. Fader, Dr. C. Amaya, Dr. R. Militello and Dr M.I. Colombo (reagents—IHEM, Mendoza, Argentina), Dr. M Galigniana, N. Zgajnar (IIF supplies—IBYME, Buenos Aires, Argentina), Dr. ML. Kotler (reagents - IQUIBICEN, FCEN-UBA, Buenos Aires, Argentina) and Dr. LS. Mayorga (manuscript revision—IHEM, Mendoza, Argentina).
MR conducted the research project. LM performed the experiments with the help of BS and CG. DM processed big data and did its statistical analysis. LM, ML and HE provided clinical information from the patients. FL did the muscle histological studies from the MT patients. PR designed the autophagy assays. LM and MR wrote the paper. All authors read and approved the final manuscript.
Servicio Tecnológico de Alto Nivel “Análisis genético molecular”-IHEM, CONICET-Mendoza, Argentina. Secretaría de Ciencia Técnica y Posgrado—UNCuyo.
Compliance with ethical standards
This project was approved by the Garrahan Children's Hospital (Buenos Aires–Argentina) and Central Hospital (Mendoza–Argentina) investigation and ethics committees. Written informed consent was obtained from patients and controls for research participation and publication.
Conflict of interest
The authors declare no competing interests.
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