Abstract
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 pro-apoptotic 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.
Highlights
While autophagy and apoptosis are interrelated, they are, at least to some extent, alternative cellular functions that play a crucial role in survival and homeostasis
It is involved in the removal of misfolded proteins through autophagy and the ubiquitin-proteasome system [9], and a recent study demonstrated that enhanced PINK1 activity rescues amyloid pathology in Alzheimer’s disease (AD) [10]
We previously demonstrated that a direct interaction of PINK1 with Beclin1 is responsible for regulation of autophagy and initiation of autophagosome formation upon mitophagic stimuli [21,22]
Summary
While autophagy and apoptosis are interrelated, they are, at least to some extent, alternative cellular functions that play a crucial role in survival and homeostasis. Its most well-characterized function is the regulation of mitophagy, the autophagic degradation of damaged mitochondria, but other pro-survival and neuroprotective functions of this protein have been described [4] It is a positive regulator of cell cycle [5], it participates in maintenance of calcium homeostasis [6,7], and cells depleted of PINK1 show defects in mitochondrial bioenergetics [8]. It is involved in the removal of misfolded proteins through autophagy and the ubiquitin-proteasome system [9], and a recent study demonstrated that enhanced PINK1 activity rescues amyloid pathology in AD [10]. Our data demonstrate that PINK1 impairs the pro-apoptotic cleavage of Beclin, favoring an activation of autophagy and preventing the switch towards cell death
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