Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway

Ultraviolet (UV) radiation is a major cause of photoaging that can induce DNA damage, oxidative stress, and cellular aging. Metformin (MF) can repair DNA damage, scavenge reactive oxygen species (ROS), and protect cells. However, the mechanism by which MF inhibits cell senescence in chronic skin damage induced by UVA is unclear. In this study, human foreskin fibroblasts (HFFs) treated with UVA were used as an in vitro model and UVA-induced skin photoaging in Kunming mice was used as an in vivo model to investigate the potential skin protective mechanism of MF. The results revealed that MF treatment attenuated UVA-induced cell viability, skin aging, and activation of the PI3K/AKT/mTOR signaling pathway. Furthermore, MF treatment alleviated the mitochondrial oxidative stress and decreased mitophagy. Knockdown of Parkin by siRNA increased the clearance of MF in senescent cells. The treatment of Kunming mice with MF at a dose of 10 mg/kg/day significantly reduced UVA-induced skin roughness, epidermal thinning, collagen degradation, and skin aging. In conclusion, our experimental results suggest that MF exerts anti-photoaging effects by inhibiting mitophagy and the PI3K/AKT/mTOR signaling pathway. Therefore, our study improves the current understanding of the protective mechanism of MF against photoaging.

[1]  Hsiu-Mei Chiang,et al.  Protective Effect of Djulis (Chenopodium formosanum) Extract against UV- and AGEs-Induced Skin Aging via Alleviating Oxidative Stress and Collagen Degradation , 2022, Molecules.

[2]  Ziyi Wu,et al.  The Function of Metformin in Aging-Related Musculoskeletal Disorders , 2022, Frontiers in Pharmacology.

[3]  G. Lopes,et al.  Cyanobacteria Secondary Metabolites as Biotechnological Ingredients in Natural Anti-Aging Cosmetics: Potential to Overcome Hyperpigmentation, Loss of Skin Density and UV Radiation-Deleterious Effects , 2022, Marine drugs.

[4]  C. Cavadas,et al.  Skin senescence: mechanisms and impact on whole-body aging. , 2022, Trends in molecular medicine.

[5]  Y. Ibuki,et al.  4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Histone Acetylation via α7nAChR-Mediated PI3K/Akt Activation and Its Impact on γ-H2AX Generation. , 2021, Chemical research in toxicology.

[6]  B. Yousefi,et al.  Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk , 2021, Journal of cellular physiology.

[7]  S. Frank,et al.  VCP/p97 cofactor UBXN1/SAKS1 regulates mitophagy by modulating MFN2 removal from mitochondria , 2021, Autophagy.

[8]  Mikolaj Ogrodnik,et al.  Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo , 2021, Aging cell.

[9]  M. V. Vander Heiden,et al.  The Metabolic Landscape of RAS-Driven Cancers from biology to therapy , 2021, Nature Cancer.

[10]  Chi-Ying F. Huang,et al.  The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis , 2021, Biomolecules.

[11]  J. Rok,et al.  The role of UVA radiation in ketoprofen-mediated BRAF-mutant amelanotic melanoma cells death - A study at the cellular and molecular level. , 2021, Toxicology in vitro : an international journal published in association with BIBRA.

[12]  M. Yu,et al.  Metformin inhibits chronic kidney disease‐induced DNA damage and senescence of mesenchymal stem cells , 2021, Aging cell.

[13]  Y. Ke,et al.  TGFβ Signaling in Photoaging and UV-Induced Skin Cancer. , 2020, The Journal of investigative dermatology.

[14]  D. Baker,et al.  Cellular senescence in ageing: from mechanisms to therapeutic opportunities , 2020, Nature Reviews Molecular Cell Biology.

[15]  Ying-ai Shi,et al.  Sirt3 Attenuates Oxidative Stress Damage and Rescues Cellular Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Superoxide Dismutase 2 , 2020, Frontiers in Cell and Developmental Biology.

[16]  A. Barzegari,et al.  Astaxanthin protects mesenchymal stem cells from oxidative stress by direct scavenging of free radicals and modulation of cell signaling. , 2020, Chemico-biological interactions.

[17]  A. Sunjaya,et al.  Targeting ageing and preventing organ degeneration with metformin. , 2020, Diabetes & metabolism.

[18]  N. Barzilai,et al.  Benefits of Metformin in Attenuating the Hallmarks of Aging. , 2020, Cell metabolism.

[19]  Peng Huang,et al.  Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence , 2020, Aging.

[20]  Soumyadeep Sarkar,et al.  Solar UV-induced DNA damage response: Melanocytes story in transformation to environmental melanomagenesis. , 2020, Environmental and molecular mutagenesis.

[21]  M. Brini,et al.  PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease , 2020, International journal of molecular sciences.

[22]  Paul D. Morton,et al.  PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis , 2019, Cell reports.

[23]  M. Rapala-Kozik,et al.  UVA and UVB radiation induce the formation of neutrophil extracellular traps by human polymorphonuclear cells. , 2019, Journal of photochemistry and photobiology. B, Biology.

[24]  H. Parsian,et al.  Crosstalk between Phosphoinositide 3‐kinase/Akt signaling pathway with DNA damage response and oxidative stress in cancer , 2019, Journal of cellular biochemistry.

[25]  H. Yu,et al.  Dermoscopic assessment of xerosis severity, pigmentation pattern and vascular morphology in subjects with physiological aging and photoaging , 2019, European Journal of Dermatology.

[26]  A. Bhushan,et al.  Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium. , 2019, American journal of physiology. Lung cellular and molecular physiology.

[27]  A. Gomes,et al.  Impaired proteostasis in senescent vascular endothelial cells: a perspective on estrogen and oxidative stress in the aging vasculature. , 2019, American journal of physiology. Heart and circulatory physiology.

[28]  Q. Zhan,et al.  Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway. , 2018, Carcinogenesis.

[29]  N. Prasad,et al.  Alpha pinene modulates UVA‐induced oxidative stress, DNA damage and apoptosis in human skin epidermal keratinocytes , 2018, Life sciences.

[30]  S. Dokudovskaya,et al.  mTORC1 pathway in DNA damage response. , 2018, Biochimica et biophysica acta. Molecular cell research.

[31]  Zhenhua Zhu,et al.  N-Acetylcysteine Reduces ROS-Mediated Oxidative DNA Damage and PI3K/Akt Pathway Activation Induced by Helicobacter pylori Infection , 2018, Oxidative medicine and cellular longevity.

[32]  H. Arab,et al.  L-carnitine mitigates UVA-induced skin tissue injury in rats through downregulation of oxidative stress, p38/c-Fos signaling, and the proinflammatory cytokines. , 2018, Chemico-biological interactions.

[33]  D. Noonan,et al.  Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment. , 2018, Cancer treatment reviews.

[34]  C. Menck,et al.  Direct participation of DNA in the formation of singlet oxygen and base damage under UVA irradiation , 2017, Free radical biology & medicine.

[35]  M. Goldberg,et al.  Parkin and PINK1 functions in oxidative stress and neurodegeneration , 2017, Brain Research Bulletin.

[36]  G. Piontek,et al.  Effects of topoisomerase inhibitors that induce DNA damage response on glucose metabolism and PI3K/Akt/mTOR signaling in multiple myeloma cells. , 2015, American journal of cancer research.

[37]  Xuping Wang,et al.  Resveratrol Inhibits the Growth of Gastric Cancer by Inducing G1 Phase Arrest and Senescence in a Sirt1-Dependent Manner , 2013, PloS one.

[38]  J. Janda,et al.  Cyclophilin 40 alters UVA-induced apoptosis and mitochondrial ROS generation in keratinocytes , 2012, Experimental Cell Research.

[39]  H. Swalwell,et al.  Investigating the role of melanin in UVA/UVB- and hydrogen peroxide-induced cellular and mitochondrial ROS production and mitochondrial DNA damage in human melanoma cells. , 2012, Free radical biology & medicine.

[40]  M. Mimeault,et al.  Recent advances on skin-resident stem/progenitor cell functions in skin regeneration, aging and cancers and novel anti-aging and cancer therapies , 2009, Journal of cellular and molecular medicine.

[41]  M. Shih,et al.  Potential protective effect of fresh grown unicellular green algae component (resilient factor) against PMA- and UVB-induced MMP1 expression in skin fibroblasts. , 2008, European journal of dermatology : EJD.

[42]  T. Squier,et al.  Oxidative stress and protein aggregation during biological aging , 2001, Experimental Gerontology.

[43]  L. Belov,et al.  The MTT cell viability assay for cytotoxicity testing in multidrug-resistant human leukemic cells. , 1992, Leukemia research.

[44]  K. Kasahara,et al.  Paclitaxel Impedes EGFR-mutated PC9 Cell Growth via Reactive Oxygen Species-mediated DNA Damage and EGFR/PI3K/AKT/mTOR Signaling Pathway Suppression , 2021, Cancer Genomics & Proteomics.

[45]  Xin Wang,et al.  Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. , 2018, The international journal of biochemistry & cell biology.

[46]  Zhenhua Zhu,et al.  -Acetylcysteine Reduces ROS-Mediated Oxidative DNA Damage and PI3K/Akt Pathway Activation Induced by Infection. , 2018 .

[47]  4(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Histone Acetylation via 7nAChR-Mediated PI3K/Akt Activation and Its Impact on H2AX Generation , 2022 .