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

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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.

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Acknowledgements

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).

Funding

Servicio Tecnológico de Alto Nivel “Análisis genético molecular”-IHEM, CONICET-Mendoza, Argentina. Secretaría de Ciencia Técnica y Posgrado—UNCuyo.

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Authors and Affiliations

  1. Instituto de Histología y Embriología de Mendoza (IHEM, Universidad Nacional de Cuyo, CONICET)-Centro Universitario UNCuyo, 5500, Mendoza, Argentina

    Lía Mayorga, Betiana N. Salassa, Patricia S. Romano & María Roqué

  2. John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA

    Diego M. Marzese

  3. Hospital de Pediatría J.P. Garrahan, Combate de los Pozos 1881, 1245, Buenos Aires, Argentina

    Mariana A. Loos, Hernán D. Eiroa & Fabiana Lubieniecki

  4. Facultad de Ciencias Médicas, Universidad Nacional de Cuyo-Centro Universitario UNCuyo, 5500, Mendoza, Argentina

    Clara García Samartino & Patricia S. Romano

  5. Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo-Centro Universitario UNCuyo, 5500, Mendoza, Argentina

    María Roqué

  6. Facultad de Odontología, Univeridad Nacional de Cuyo- Centro Universitario UNCuyo, 5500, Mendoza, Argentina

    Betiana N. Salassa

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  1. Lía Mayorga
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  2. Betiana N. Salassa
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Contributions

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.

Corresponding author

Correspondence to Lía Mayorga.

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Ethical approval

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.

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The authors declare no competing interests.

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Supplementary Figure 1: Assessment of mitochondrial dysfunction in Rotenone treatments. S1a:

Flow cytometry mitochondrial membrane potential measurements in Rotenone treatments using TMRE: Mitochondrial membrane potential was measured at day 1 and 4 into treatment. Cell population was divided into TMRE (+) and (-) using a threshold based on autofluorescence. Then, the percentage of TMRE (+) cells was relativized to the control’s (DMSO) value. The dose dependent mitochondrial dysfunction was evident at day 1. At day 4, low and high dose treated cells showed the same level of mitochondrial dysfunction (*p<0.05, **p<0.01, ***p<0.001, One-way ANOVA + Dunnett’s Multiple Comparison Test). S1b: Fluorescent microscopy to measure mitochondrial membrane potential changes in Rotenone treatments using TMRE: We show fluorescent images of control cells (DMSO), Rot-10µM (1-day treatment) and the mitochondrial uncoupler CCCP, confirming that Rot decreased mitochondrial membrane potential and that TMRE is functioning in a non-quenching manner. S1c:Evaluation of ROS generation using DCF-DA through flow cytometry: Median fluorescence values relative to the control condition (DMSO) were used for quantification (*p<0.05, One-way ANOVA + Dunnett’s Multiple Comparison Test). Control (DMSO), Rot-0.1µM (1-day), Rot 10 µM (1 and 4-days) treatments were analyzed. Low dose long-term experiments were not tested due to their high mortality rate. (JPEG 1483 kb)

Supplementary Figure 2: Cell death and autophagy assays in Rot 1-day treated cells. S2a

. Flow cytometry cell death assays using Annexin V (apoptosis) and TO-PRO-3 (necrosis). These assays were performed with the cells that were attached to the well at day 1 (no supernatants were used due to diverging results). There was no significant difference in the level of cell death between conditions. S2b.LC3 Western Blot Rot-1-day. LC3 forms from low and high dose treated cells are shown next to their corresponding control condition (DMSO). LC3 was increased in the high dose situation, and the contrary happened in the low dose group (*p<0.05, Student’s T-Tests) (JPEG 1234 kb)

Supplementary figure 3. Further characterization of autophagy in Rot treated cells. S3a.

LC3 Western Blot with short (4h) Bafilomycin treatment to determine autophagy flow at day 4 of Rotenone treatment. Bafilomycin (Baf) was added for the last 4 hours of the 4-day Rot treatment in control (DMSO) and Rot-10µM treated cells. LC3-II was increased in the Rot-10 µM+Baf condition compared to the same condition without Baf, indicating an enhanced autophagy flow at the expense of autophagosome degradation. (*p<0.05, One-tailed Paired Student’s T-test). S3b.Mitophagy evaluation with fluorescence microscopy. EGFP-LC3 transfected HSkM cells were treated with Rot 10µM for 1 and 4 days. Then, Indirect immunofluorescence for the mitochondrial TOM20 protein was performed. Images were taken under confocal fluorescent microscopy. LC3 recruitment to mitochondria was not evidenced as shown in the merged images. White bar: 10µm. (JPEG 1127 kb)

Supplementary figure 4: ATP and S-adenosylmethionine (SAM) cell content in Rot treatment. S4a.

Intracellular ATP content measured with Quinacrine through flow cytometry: A threshold based on autofluorescence was set to divide cell populations as ATP (+) or (-). Quantification was performed in comparison to the control value. ATP content is shown significantly decreased in the high-dose long-term treatment. (**p<0.01, One-way ANOVA+ Dunnett’s Multiple Comparison Test). A control for ATP reduction was performed using CCCP+ Oligomycin. S4b.S-Adenosyl Methionine (SAM) concentration measured through fluorometry. Comparing to a SAM standard curve, SAM concentration from the different conditions was calculated. Quantification is represented as relative to the control condition. (*p<0.05, One-way ANOVA+ Dunnett’s Multiple Comparison Test). (JPEG 1329 kb)

Supplementary figure 5: Corroboration of Methylation of

CAMK2A’s promoter region.CAMK2A methylation detected by methyl-sensitive digestion (HpaII) + absolute quantification with ddPCR. To evaluate CAMK2A’s methylation, each sample was digested with HpaII (that only cuts the non-methylated CpG in CAMK2A’s promoter) and as control, the same sample was digested in parallel with MboI (not able to cut the amplicon). In the upper panel, we show the ddPCR dot plots, where blue dots are considered “positive droplets” and black dots are “negative droplets”. Concentration is calculated based on Poisson’s binomial distribution and are shown in the bottom panel. To quantify the methylation of this CpG site we use the [HpaII amplicon]/ [MboI amplicon]. CM8: control muscle 8, MTM7: MT patient muscle 7; NTC: no-template control (blank). *p<0.05, One-tailed Unpaired Student’s T-test. (JPEG 1237 kb)

Supplementary figure 6: Enrichment plots of the hypermethylated GO gene sets in MT patient muscle determined by GREAT

. Significant differentially hypermethylated GO gene sets identified by GREAT analysis of RRBS study in muscle from MT disease patients. Arrows point to gene sets that could be more important in mitochondrial disease skeletal muscle. (JPEG 1970 kb)

Supplementary figure 7: Enrichment plots of the hypomethylated GO gene sets in MT patient muscle determined by GREAT

. Significant differentially hypomethylated GO gene sets identified by GREAT analysis of RRBS study in muscle from MT disease patients. Arrows point to gene sets that could be more important in mitochondrial disease skeletal muscle. (JPEG 2358 kb)

Supplementary file 1: Differentially methylated CpGs (DMCs) and regions (DMRs) in MT patient muscles determined by RRBS.

We provide the list of the differentially methylated sites and regions, using the hg19 refGene and CpG island annotation from UCSC (Univeristy of California Santa Cruz) genome browser. The annotations are not mutually exclusive since there is a large overlapping between the different categories. (+) differential methylations read as hypermethylated in the MTM state, (-) differential methylations read as hypomethylated in the MTM state. (XLSX 9479 kb)

Supplementary file 2: Metascape analysis of the differentially methylated promoters that have “membership” in apoptosis, autophagy or DNA methylation.

We provide the list of genes that were differentially methylated in the promoter category and have “membership” in apoptosis, autophagy or DNA methylation when analyzed with Metascape. Sheets are separated as DM (+) prom: promoters differentially hypermethylated in MT patient muscle, DM (-) prom: promoters differentially hypomethylated in MT patient muscle, associated to each term. The GO annotations by which the genes are members of the different terms are provided in the last column. (XLSX 32 kb)

Supplementary file 3: Differentially methylated and expressed genes in MT muscle.

Comparison of our RRBS analysis + public expression data sets: GSE42986 - GSE1462. From the 615 differentially expressed genes, 116 were associated with the differentially methylated genomic regions (Hypergeometric test; RF: 0.7, p < 1.6e-04) (XLSX 10 kb)

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Mayorga, L., Salassa, B.N., Marzese, D.M. et al. Mitochondrial stress triggers a pro-survival response through epigenetic modifications of nuclear DNA. Cell. Mol. Life Sci. 76, 1397–1417 (2019). https://doi.org/10.1007/s00018-019-03008-5

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