TY - JOUR
T1 - PINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage
AU - Brunelli, Francesco
AU - Torosantucci, Liliana
AU - Gelmetti, Vania
AU - Franzone, Davide
AU - Grünewald, Anne
AU - Krüger, Rejko
AU - Arena, Giuseppe
AU - Valente, Enza Maria
N1 - Funding Information:
Funding: This research was funded by CARIPLO Foundation (grant number 2017-0575 to EMV), and Italian Ministry of Health (Ricerca Corrente 2021 to IRCCS Mondino Foundation). The work wasalsosupportedbygrantsfromtheLuxembourgNationalResearchFund(FNR)fortheNational Centre for Excellence in Research on Parkinson’s disease (NCER-PD), the PEARL program (FNR/P13/6682797toRK)andMiRisk-PD(C17/BM/11676395toRKandAG).
Funding Information:
This research was funded by CARIPLO Foundation (grant number 2017-0575 to EMV), and Italian Ministry of Health (Ricerca Corrente 2021 to IRCCS Mondino Foundation). The work was also supported by grants from the Luxembourg National Research Fund (FNR) for the National Centre for Excellence in Research on Parkinson?s disease (NCER-PD), the PEARL program (FNR/P13/6682797 to RK) and MiRisk-PD (C17/BM/11676395 to RK and AG). The authors acknowledge Wolfdieter Springer and Philippe J Kahle (Laboratory of Functional Neurogenetics, Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T?bingen, T?bingen, Germany) which kindly provided Parkin-inducible SH-SY5Y cells.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/15
Y1 - 2022/2/15
N2 - PINK1 is a causative gene for Parkinson’s disease and the corresponding protein has been identified as a master regulator of mitophagy—the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson’s disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the proapoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1–Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases.
AB - PINK1 is a causative gene for Parkinson’s disease and the corresponding protein has been identified as a master regulator of mitophagy—the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson’s disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the proapoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1–Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases.
KW - Apoptosis
KW - Autophagy
KW - Beclin1
KW - Cancer
KW - Neurodegeneration
KW - PINK1
UR - http://www.scopus.com/inward/record.url?scp=85124487284&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35203326
U2 - 10.3390/cells11040678
DO - 10.3390/cells11040678
M3 - Article
C2 - 35203326
AN - SCOPUS:85124487284
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 4
M1 - 678
ER -