Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Abstract

Significance: Disruptions in mitochondrial homeostasis are implicated in human diseases across the lifespan. Recessive mutations in PINK1, which encodes the mitochondrially targeted PTEN-induced putative kinase 1 (PINK1), cause an autosomal recessive form of Parkinson's disease. As with all kinases, PINK1 participates in multiple functional pathways, and its dysregulation has been implicated in a growing number of diseases. Recent Advances: In addition to its heavily studied role in mitophagy, PINK1 regulates mitochondrial respiratory function, reactive oxygen species generation, and mitochondrial transport. Moreover, recent studies implicate processed PINK1 in cytosolic signaling cascades that promote cell survival and neuron differentiation. Cytosolic PINK1 is also capable of suppressing autophagy and mitophagy. We propose a working hypothesis that PINK1 is released by functional mitochondria as a signal to coordinate cell growth and differentiation in response to mitochondrial status. Critical Issues: PINK1 biology needs to be better understood in primary neurons, as the stability and subcellular localization of PINK1 is differentially regulated in different cell types. Delineating factors that regulate its mitochondrial import/export, processing by different peptidases, kinase activity, subcellular localization, and degradation will be important for defining relevant downstream kinase targets. Future Directions: It is becoming clear that different subcellular pools of PINK1 mediate distinct functions. Future studies will undoubtedly expand on the spectrum of cellular functions regulated by PINK1. Continued study of cytosolic PINK1 may offer novel insights into how functional mitochondria communicate their status with the rest of the cell. Antioxid. Redox Signal. 22, 1047-1059. P arkinson's disease (PD) is a debilitating age-related neurodegenerative disorder that affects 4-5 million people in the world's most populous nations (28). PD pathology is characterized by: (i) Lewy body inclusions, which contain alpha-synuclein and ubiquitin, in autonomic, brainstem and cortical regions (10), and (ii) the loss of pigmented brain stem neurons from the substantia nigra and locus ceruleus. Degeneration of dopaminergic nigral neurons account for the classic motor signs, although other neuron groups are also affected. While the majority of PD cases are idiopathic, studies of gene products implicated in familial PD implicate common pathways that are likely to be important for disease progression (101).Mutations in PINK1, which encodes PTEN-induced putative kinase 1 (PINK1), represent the second most common cause of autosomal recessive parkinsonism (48,103). PINK1 families exhibit an earlier onset of disease (range of 9-52 years), accompanied by sustained responses to levodopa treatment (9,57,64,103). Autopsy findings have been reported from one family, showing classic Lewy body pathology (92). Pathways regulated by PINK1 appear to interact with other PD-linked genes (11,20,91), and PINK1 enhances the resistance of...

Inhibition of bioenergetics provides novel insights into recruitment of PINK1‐dependent neuronal mitophagy

“…While the role of PINK1 in promoting mitophagy has been a topic of great interest, there is also an additional body of evidence demonstrating a dual role of PINK1 as a suppressor of mitophagy. Specifically, PINK1 has been suggested to reduce the triggering of mitophagy by preserving mitochondrial membrane potential; it binds to Parkin in the cytosol to prevent its translocation to damaged mitochondria (Gegg et al 2009;Morais et al 2014;Steer et al 2015). In this view, it is conceivable that the bioenergetic dysfunction induced by complex III and IV inhibition in this work may have been below the threshold for PINK1 acting as trigger for mitophagy; thus, the turnover of mitochondria may have been suppressed in the experiments reported in this study.…”

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…When mitophagy fails to execute efficiently, the increased number of dysfunctional mitochondria in the cell can result in programmed (apoptotic) or nonprogrammed (necrotic) cell death, and degeneration into a diseased state [Mishra and Chan, 2014;Nikoletopoulou et al, 2015]. Since healthy mitochondria do not retain PINK1 on their outer membranes [Oliveras-Salv a et al, 2014;Steer et al, 2015], upregulating the PINK1/parkin mitophagic pathways should selectively remove dysfunctional mitochondria [Palikaras and Tavernarakis, 2014;Lionaki et al, 2015;Melser et al, 2015;Wei et al, 2015] thereby affording a new and actionable therapeutic target in the treatment of AD and PD [Narendra and Youle;Lazarou et al, 2012;Ashrafi et al, 2014;Hattori et al, 2014;McLelland et al, 2014;Tufi et al, 2014;Frake et al, 2015;Kazlauskaite and Muqit, 2015;Kroemer, 2015;Pickrell and Youle, 2015;Strappazzon et al, 2015].…”

Mitochondria: The Cellular Hub of the Dynamic Coordinated Network

“…The loss of mitochondrial membrane potential prevents the import of PINK1, leading to its accumulation on the outer membrane and the recruitment of the ubiquitin ligase Parkin that initiates the autophagic degradation of these mitochondria. Chu and colleagues review the roles of PINK1 in regulating other mitochondrial function such as respiration, intracellular transport, and oxidant generation, as well as its role in neuron differentiation and neuroprotection is reviewed (6). On the ground of these recent findings, the authors propose a hypothesis to explain the dual role of PINK1 in promoting the degradation of damaged mitochondria and in suppressing the removal of healthy mitochondria; dependent on its subcellular localization, PINK1 is conceptualized as a switch that not only senses damaged mitochondria but also transduces signals from healthy mitochondria to trigger intracellular signaling pathways through its retrotranslocation to the cytosol (Fig.…”