High Glucose-induced P66Shc Mitochondrial Translocation Regulates Autophagy Initiation and Autophagosome Formation in Syncytiotrophoblast and Extravillous Trophoblast

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2024 Apr 20

PMID 38643181

Authors

Lulu Ji

Xiaoli Zhang

Zhiguo Chen

Yuexiao Wang

Hengxuan Zhu

Yaru Nai

Yanyi Huang

Rujie Lai

Yu Zhong

Xiting Yang

Qiongtao Wang

Hanyang Hu

Lin Wang

Affiliations

Soon will be listed here.

Abstract

Background: p66Shc, as a redox enzyme, regulates reactive oxygen species (ROS) production in mitochondria and autophagy. However, the mechanisms by which p66Shc affects autophagosome formation are not fully understood.

Methods: p66Shc expression and its location in the trophoblast cells were detected in vivo and in vitro. Small hairpin RNAs or CRISPR/Cas9, RNA sequencing, and confocal laser scanning microscope were used to clarify p66Shc's role in regulating autophagic flux and STING activation. In addition, p66Shc affects mitochondrial-associated endoplasmic reticulum membranes (MAMs) formation were observed by transmission electron microscopy (TEM). Mitochondrial function was evaluated by detected cytoplastic mitochondrial DNA (mtDNA) and mitochondrial membrane potential (MMP).

Results: High glucose induces the expression and mitochondrial translocation of p66Shc, which promotes MAMs formation and stimulates PINK1-PRKN-mediated mitophagy. Moreover, mitochondrial localized p66Shc reduces MMP and triggers cytosolic mtDNA release, thus activates cGAS/STING signaling and ultimately leads to enhanced autophagy and cellular senescence. Specially, we found p66Shc is required for the interaction between STING and LC3II, as well as between STING and ATG5, thereby regulates cGAS/STING-mediated autophagy. We also identified hundreds of genes associated several biological processes including aging are co-regulated by p66Shc and ATG5, deletion either of which results in diminished cellular senescence.

Conclusion: p66Shc is not only implicated in the initiation of autophagy by promoting MAMs formation, but also helps stabilizing active autophagic flux by activating cGAS/STING pathway in trophoblast.

References

Haslem L, Hays J, Hays F . p66Shc in Cardiovascular Pathology. Cells. 2022; 11(11). PMC: 9180016. DOI: 10.3390/cells11111855. View

Ciciliot S, Fadini G . Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66. Int J Mol Sci. 2019; 20(4). PMC: 6412263. DOI: 10.3390/ijms20040985. View

Amini M, Sheikhhossein F, Djafari F, Jafari A, Djafarian K, Shab-Bidar S . Effects of chromium supplementation on oxidative stress biomarkers. Int J Vitam Nutr Res. 2021; 93(3):241-251. DOI: 10.1024/0300-9831/a000706. View

Lorenzo-Almoros A, Hang T, Peiro C, Soriano-Guillen L, Egido J, Tunon J . Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases. Cardiovasc Diabetol. 2019; 18(1):140. PMC: 6820966. DOI: 10.1186/s12933-019-0935-9. View

Li Y, Chen H, Yang Q, Wan L, Zhao J, Wu Y . Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway. J Exp Clin Cancer Res. 2022; 41(1):76. PMC: 8867650. DOI: 10.1186/s13046-022-02262-z. View

Onnis A, Cianfanelli V, Cassioli C, Samardzic D, Pelicci P, Cecconi F . The pro-oxidant adaptor p66SHC promotes B cell mitophagy by disrupting mitochondrial integrity and recruiting LC3-II. Autophagy. 2018; 14(12):2117-2138. PMC: 6984773. DOI: 10.1080/15548627.2018.1505153. View

Giorgi C, Missiroli S, Patergnani S, Duszynski J, Wieckowski M, Pinton P . Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. Antioxid Redox Signal. 2015; 22(12):995-1019. DOI: 10.1089/ars.2014.6223. View

Nakashima A, Yamanaka-Tatematsu M, Fujita N, Koizumi K, Shima T, Yoshida T . Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia. Autophagy. 2013; 9(3):303-16. PMC: 3590252. DOI: 10.4161/auto.22927. View

Gelmetti V, De Rosa P, Torosantucci L, Marini E, Romagnoli A, Di Rienzo M . PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation. Autophagy. 2017; 13(4):654-669. PMC: 5388214. DOI: 10.1080/15548627.2016.1277309. View

10.

Liu D, Wu H, Wang C, Li Y, Tian H, Siraj S . STING directly activates autophagy to tune the innate immune response. Cell Death Differ. 2018; 26(9):1735-1749. PMC: 6748081. DOI: 10.1038/s41418-018-0251-z. View

11.

Yu C, Davidson S, Harapas C, Hilton J, Mlodzianoski M, Laohamonthonkul P . TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020; 183(3):636-649.e18. PMC: 7599077. DOI: 10.1016/j.cell.2020.09.020. View

12.

Sobrevia L, Valero P, Grismaldo A, Villalobos-Labra R, Pardo F, Subiabre M . Mitochondrial dysfunction in the fetoplacental unit in gestational diabetes mellitus. Biochim Biophys Acta Mol Basis Dis. 2020; 1866(12):165948. DOI: 10.1016/j.bbadis.2020.165948. View

13.

Wu S, Lu Q, Wang Q, Ding Y, Ma Z, Mao X . Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo. Circulation. 2017; 136(23):2248-2266. PMC: 5716911. DOI: 10.1161/CIRCULATIONAHA.117.030235. View

14.

Bhattamisra S, Koh H, Lim S, Choudhury H, Pandey M . Molecular and Biochemical Pathways of Catalpol in Alleviating Diabetes Mellitus and Its Complications. Biomolecules. 2021; 11(2). PMC: 7924042. DOI: 10.3390/biom11020323. View

15.

Wu S, Lu Q, Ding Y, Wu Y, Qiu Y, Wang P . Hyperglycemia-Driven Inhibition of AMP-Activated Protein Kinase α2 Induces Diabetic Cardiomyopathy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes In Vivo. Circulation. 2019; 139(16):1913-1936. PMC: 6465113. DOI: 10.1161/CIRCULATIONAHA.118.033552. View

16.

Hu Y, Chen H, Zhang L, Lin X, Li X, Zhuang H . The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses. Autophagy. 2020; 17(5):1142-1156. PMC: 8143230. DOI: 10.1080/15548627.2020.1749490. View

17.

Yang X, Zhuang J, Song W, Shen W, Wu W, Shen H . Mitochondria-associated endoplasmic reticulum membrane: Overview and inextricable link with cancer. J Cell Mol Med. 2023; 27(7):906-919. PMC: 10064038. DOI: 10.1111/jcmm.17696. View

18.

Nakashima A, Tsuda S, Kusabiraki T, Aoki A, Ushijima A, Shima T . Current Understanding of Autophagy in Pregnancy. Int J Mol Sci. 2019; 20(9). PMC: 6539256. DOI: 10.3390/ijms20092342. View

19.

Bronner D, ORiordan M . Measurement of Mitochondrial DNA Release in Response to ER Stress. Bio Protoc. 2019; 6(12). PMC: 6519464. DOI: 10.21769/BioProtoc.1839. View

20.

Rizwan H, Pal S, Sabnam S, Pal A . High glucose augments ROS generation regulates mitochondrial dysfunction and apoptosis via stress signalling cascades in keratinocytes. Life Sci. 2019; 241:117148. DOI: 10.1016/j.lfs.2019.117148. View