Mitochondrial-Targeted Therapies Require Mitophagy to Prevent Oxidative Stress Induced by SOD2 Inactivation in Hypertrophied Cardiomyocytes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Model
2.2. Cell Culture
2.2.1. Primary Cultures of Neonatal Rat Cardiomyocytes and Fibroblasts
2.2.2. Transfection
2.2.3. Primary Cultures of Adult Rat Cardiomyocytes
2.2.4. Human Cardiomyocytes
2.3. Cell Index Quantification by Real Time Cell Analysis (RTCA)
2.4. RNA Extraction and qRT-PCR Analyses
2.5. Protein Extraction and Western Blot
2.5.1. Protein Extraction
2.5.2. Cytosol-Mitochondria Fractionation
2.5.3. Cytoplasm-Nuclei Fractionation
2.5.4. Western Blot (WB)
2.6. Cell Staining
2.6.1. Immunofluorescence (IF)
2.6.2. Proximity Ligation Assay (PLA)
2.6.3. Detection of Mitochondrial Hydrogen Peroxide Levels Using MitoPY1
2.6.4. Transmission Electronic Microscopy
2.7. Antibodies
2.8. Oxygraphy Analysis
2.9. Statistical Analysis
3. Results
3.1. Characterization of Mitochondrial Oxidative Stress in Hypertrophied Neonatal Rat Cardiomyocytes
3.2. Modulation of SOD2 by SIRT3 Impacts Mitochondrial Oxidative Stress in Hypertrophied Neonatal Rat Cardiomyocytes
3.3. SIRT3 Regulates SOD2 Deacetylation in Ischemic Heart In Vivo
3.4. Characterization of Mitochondrial Biogenesis and Mito(auto)phagy in Hypertrophied Neonatal Rat Cardiomyocytes
3.5. Effect of Mitochondrial Antioxidant (MitoQ) on Oxidative Stress and Mitochondrial Biogenesis in Hypertrophied Neonatal Rat Cardiomyocytes
3.6. Cardiomyocyte Specificity of the Detrimental Effect of Mitochondrial Antioxidant (MitoQ) on Mitophagy in Hypertrophied Rat Cardiomyocytes
3.7. Effect of Parkin Depletion on Hypertrophy, Oxidative Stress and Mitophagy in Neonatal Rat Cardiomyocytes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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PBS | Iso | |||||
---|---|---|---|---|---|---|
NT siRNA | SIRT3 siRNA | p Value | NT siRNA | SIRT3 siRNA | p Value | |
SIRT3 | 0.97 (0.7–1.3) | 0.46 (0.3–0.6) | 0.0023 | 0.96 (0.9–1.1) | 0.31 (0.3–0.4) | 0.0006 |
SIRT1 | 1.03 (0.6–1.3) | 4.46 (0.9–2.3) | 0.180 | 1.07 (0.8–1.2) | 0.98 0.9–1.4) | 0.937 |
SOD2 | 1.12 (0.7–1.3) | 1.08 (0.6–1.6) | 0.699 | 1.02 (0.8–1.2) | 0.74 (0.5–0.8) | 0.0281 |
SOD2acK68/SOD2 | 0.92 (0.85–1) | 0.94 (0.8–1.3) | 0.970 | 1.00 (0.8–1.2) | 1.03 (0.7–1.5) | 0.937 |
Bcl-2 | 1.00 (0.6–1.4) | 0.62 (0.6–0.7) | 0.200 | 1.00 (0.9–1.1) | 0.82 (0.5–1.1) | 0.400 |
PBS | Iso | |||||
---|---|---|---|---|---|---|
Ctl | SIRT3 | p Value | Ctl | SIRT3 | p Value | |
SIRT3 | 1.00 (0.9–1.1) | 1.99 (1.1–3.2) | 0.022 | 0.92 (0.7–1.2) | 1.77 (1.7–3.2) | <0.0001 |
SIRT1 | 1.00 (0.9–1.1) | 1.52 (1.1–2.6) | 0.0207 | 1.00 (0.9–1.1) | 2.21 (1.3–3.2) | 0.0173 |
SOD2 | 1.00 (0.9–1.1) | 1.13 (0.9–1.5) | 0.461 | 1.00 (0.8–1.2) | 0.72 (0.5–1) | 0.102 |
SOD2acK68/SOD2 | 1.00 (0.9–1.1) | 0.69 (0.4–0.9) | 0.0195 | 1.00 (0.9–1.1) | 0.79 (0.3–0.9) | 0.0043 |
Bcl-2 | 1.00 (0.8–1.2) | 2.25 (1.4–2.5) | 0.057 | 1.00 (0.9–1.1) | 1.11 (0.8–1.4) | 0.886 |
PBS | Iso | p Value * | MitoQ | p Value * | MitoQ + Iso | p Value # | |
---|---|---|---|---|---|---|---|
PGC1α | 1.01 (1–1.1) | 0.40 (0.3–0.6) | <0.0001 | 0.37 (0.3–0.6) | 0.008 | 0.53 (0.4–1.1) | 0.214 |
NRF2 | 1.02 (0.9–1.1) | 0.66 (0.6–0.8) | 0.0005 | 2.10 (1.5–2.8) | 0.003 | 2.32 (1.9–2.9) | 0.008 |
Mfn2 | 0.99 (0.9–1.1) | 0.65 (0.6–0.8) | <0.0001 | 1.20 (1.1–1.4) | 0.095 | 1.40 (1.2–1.6) | 0.095 |
Fis1 | 0.95 (0.9–1.2) | 0.64 (0.6–0.7) | 0.0002 | 1.04 (0.9–1.1) | 0.683 | 1.14 (0.9–1.3) | 0.421 |
Aconitase 2 | 1.00 (0.9–1.3) | 0.74 (0.7–0.9) | 0.049 | 0.11 (0.1–0.4) | 0.003 | 0.11 (0.1–0.2) | 0.006 |
Parkin | 1.00 (0.8–1.1) | 0.67 (0.5–0.9) | 0.014 | 0.17 (0.1–0.3) | <0.0001 | 0.19 (0.1–0.3) | <0.0001 |
LC3II/I | 1.00 (1–1.1) | 0.88 (0.7–1.1) | 0.026 | 1.11 (0.8–1.6) | 0.777 | 1.3 (1.1–2.3) | <0.0001 |
Ubiquitin | 1.00 (0.8–1.2) | 0.89 (0.8–1.1) | 0.306 | 0.78 (0.6–1.1) | 0.076 | 0.8 (0.4–1.1) | 0.249 |
Beclin–1 | 1.00 (0.8–1.2) | 0.82 (0.7–1.2) | 0.530 | 0.65 (0.4–0.9) | 0.0002 | 0.34 (0.3–0.8) | 0.009 |
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Peugnet, V.; Chwastyniak, M.; Mulder, P.; Lancel, S.; Bultot, L.; Fourny, N.; Renguet, E.; Bugger, H.; Beseme, O.; Loyens, A.; et al. Mitochondrial-Targeted Therapies Require Mitophagy to Prevent Oxidative Stress Induced by SOD2 Inactivation in Hypertrophied Cardiomyocytes. Antioxidants 2022, 11, 723. https://doi.org/10.3390/antiox11040723
Peugnet V, Chwastyniak M, Mulder P, Lancel S, Bultot L, Fourny N, Renguet E, Bugger H, Beseme O, Loyens A, et al. Mitochondrial-Targeted Therapies Require Mitophagy to Prevent Oxidative Stress Induced by SOD2 Inactivation in Hypertrophied Cardiomyocytes. Antioxidants. 2022; 11(4):723. https://doi.org/10.3390/antiox11040723
Chicago/Turabian StylePeugnet, Victoriane, Maggy Chwastyniak, Paul Mulder, Steve Lancel, Laurent Bultot, Natacha Fourny, Edith Renguet, Heiko Bugger, Olivia Beseme, Anne Loyens, and et al. 2022. "Mitochondrial-Targeted Therapies Require Mitophagy to Prevent Oxidative Stress Induced by SOD2 Inactivation in Hypertrophied Cardiomyocytes" Antioxidants 11, no. 4: 723. https://doi.org/10.3390/antiox11040723
APA StylePeugnet, V., Chwastyniak, M., Mulder, P., Lancel, S., Bultot, L., Fourny, N., Renguet, E., Bugger, H., Beseme, O., Loyens, A., Heyse, W., Richard, V., Amouyel, P., Bertrand, L., Pinet, F., & Dubois-Deruy, E. (2022). Mitochondrial-Targeted Therapies Require Mitophagy to Prevent Oxidative Stress Induced by SOD2 Inactivation in Hypertrophied Cardiomyocytes. Antioxidants, 11(4), 723. https://doi.org/10.3390/antiox11040723