DOI QR코드

DOI QR Code

AMPK-induced mitochondrial biogenesis decelerates retinal pigment epithelial cell degeneration under nutrient starvation

  • Yujin Park (Department of Bioscience and Biotechnology, Konkuk University) ;
  • Yeeun Jeong (Department of Bioscience and Biotechnology, Konkuk University) ;
  • Sumin Son (Department of Bioscience and Biotechnology, Konkuk University) ;
  • Dong-Eun Kim (Department of Bioscience and Biotechnology, Konkuk University)
  • 투고 : 2022.08.17
  • 심사 : 2022.09.15
  • 발행 : 2023.02.28

초록

The implications of nutrient starvation due to aging on the degeneration of the retinal pigment epithelium (RPE) is yet to be fully explored. We examined the involvement of AMPK activation in mitochondrial homeostasis and its relationship with the maintenance of a healthy mitochondrial population and epithelial characteristics of RPE cells under nutrient starvation. Nutrient starvation induced mitochondrial senescence, which led to the accumulation of reactive oxygen species (ROS) in RPE cells. As nutrient starvation persisted, RPE cells underwent pathological epithelial-mesenchymal transition (EMT) via the upregulation of TWIST1, a transcription regulator which is activated by ROS-induced NF-κB signaling. Enhanced activation of AMPK with metformin decelerated mitochondrial senescence and EMT progression through mitochondrial biogenesis, primed by activation of PGC1-α. Thus, by facilitating mitochondrial biogenesis, AMPK protects RPE cells from the loss of epithelial integrity due to the accumulation of ROS in senescent mitochondria under nutrient starvation.

키워드

과제정보

This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government, Ministry of Science, and ICT (RS-2022-00165439).

참고문헌

  1. Chen M, Rajapakse D, Fraczek M, Luo C, Forrester JV and Xu HP (2016) Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis. Aging Cell 15, 436-445 https://doi.org/10.1111/acel.12447
  2. Lidgerwood GE, Senabouth A, Smith-Anttila CJA et al (2021) Transcriptomic profiling of human pluripotent stem cell-derived retinal pigment epithelium over time. Genom Proteom Bioinform 19, 223-242 https://doi.org/10.1016/j.gpb.2020.08.002
  3. Lipecz A, Miller L, Kovacs I et al (2019) Microvascular contributions to age-related macular degeneration (AMD): from mechanisms of choriocapillaris aging to novel interventions. Geroscience 41, 813-845 https://doi.org/10.1007/s11357-019-00138-3
  4. Swerdlow RH (2009) Mitochondrial medicine and the neurodegenerative mitochondriopathies. Pharmaceuticals (Basel) 2, 150-167 https://doi.org/10.3390/ph2030150
  5. Scherz-Shouval R and Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36, 30-38 https://doi.org/10.1016/j.tibs.2010.07.007
  6. Song SB and Hwang ES (2019) A rise in ATP, ROS, and mitochondrial content upon glucose withdrawal correlates with a dysregulated mitochondria turnover mediated by the activation of the protein deacetylase SIRT1. Cells 8, 11
  7. Baek A, Son S, Baek YM and Kim DE (2021) KRT8 (keratin 8) attenuates necrotic cell death by facilitating mitochondrial fission-mediated mitophagy through interaction with PLEC (plectin). Autophagy 17, 3939-3956 https://doi.org/10.1080/15548627.2021.1897962
  8. Zhao C, Yasumura D, Li X et al (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121, 369-383 https://doi.org/10.1172/JCI44303
  9. Boles NC, Fernandes M, Swigut T et al (2020) Epigenomic and transcriptomic changes during human rpe emt in a stem cell model of epiretinal membrane pathogenesis and prevention by nicotinamide. Stem Cell Rep 14, 631-647 https://doi.org/10.1016/j.stemcr.2020.03.009
  10. Jiang JW, Wang K, Chen Y, Chen HN, Nice EC and Huang CH (2017) Redox regulation in tumor cell epithelial-mesenchymal transition: molecular basis and therapeutic strategy. Sig Transduct Target Ther 2, 17036
  11. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S and Nakshatri H (2007) NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26, 711-724 https://doi.org/10.1038/sj.onc.1209808
  12. Julien S, Puig I, Caretti E et al (2007) Activation of NF-κB by Akt upregulates snail expression and induces epithelium mesenchyme transition. Oncogene 26, 7445-7456 https://doi.org/10.1038/sj.onc.1210546
  13. Storci G, Sansone P, Mari S et al (2010) TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J Cell Physiol 225, 682-691 https://doi.org/10.1002/jcp.22264
  14. Chatterjee R and Chatterjee J (2020) ROS and oncogenesis with special reference to EMT and stemness. Eur J Cell Biol 99, 151073
  15. Gonzalez A, Hall MN, Lin SC and Hardie DG (2020) AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth control. Cell Metab 31, 472-492 https://doi.org/10.1016/j.cmet.2020.01.015
  16. Picca A, Mankowski RT, Burman JL et al (2018) Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol 15, 543-554 https://doi.org/10.1038/s41569-018-0059-z
  17. Herzig S and Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol 19, 121-135 https://doi.org/10.1038/nrm.2017.95
  18. Ferree AW, Trudeau K, Zik E et al (2013) MitoTimer probe reveals the impact of autophagy, fusion, and motility on subcellular distribution of young and old mitochondrial protein and on relative mitochondrial protein age. Autophagy 9, 1887-1896 https://doi.org/10.4161/auto.26503
  19. Cottet-Rousselle C, Ronot X, Leverve X and Mayol JF (2011) Cytometric assessment of mitochondria using fluorescent probes. Cytometry A 79, 405-425 https://doi.org/10.1002/cyto.a.21061
  20. Marin TL, Gongol B, Zhang F et al (2017) AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Sci Signal 10, eaaf7478
  21. Pernicova I and Korbonits M (2014) Metformin-mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10, 143-156 https://doi.org/10.1038/nrendo.2013.256