Neuronal Mitophagy: Lessons from a Pathway Linked to Parkinson's
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Neurotoxicity Research (2019) 36:292–305 https://doi.org/10.1007/s12640-019-00060-8 ORIGINAL ARTICLE Neuronal Mitophagy: Lessons from a Pathway Linked to Parkinson’s Disease Olga Corti1,2,3,4 Received: 26 July 2018 /Revised: 17 April 2019 /Accepted: 6 May 2019 /Published online: 17 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Neurons are specialized cells with complex and extended architecture and high energy requirements. Energy in the form of adenosine triphosphate, produced essentially by mitochondrial respiration, is necessary to preserve neuronal morphology, maintain resting potential, fire action potentials, and ensure neurotransmission. Pools of functional mitochondria are required in all neuronal compartments, including cell body and dendrites, nodes of Ranvier, growth cones, axons, and synapses. The mechanisms by which old or damaged mitochondria are removed and replaced in neurons remain to be fully understood. Mitophagy has gained considerable interest since the discovery of familial forms of Parkinson’s disease caused by dysfunction of PINK1 and Parkin, two multifunctional proteins cooperating in the regulation of this process. Over the past 10 years, the molecular mechanisms by which PINK1 and Parkin jointly promote the degradation of defective mitochondria by autophagy have been dissected. However, our understanding of the relevance of mitophagy to mitochondrial homeostasis in neurons remains poor. Insight has been recently gained thanks to the development of fluorescent reporter systems for tracking mitochondria in the acidic compartment of the lysosome. Using these tools, mitophagy events have been visualized in primary neurons in culture and in vivo, under basal conditions and in response to toxic insults. Despite these advances, whether PINK1 and Parkin play a major role in promoting neuronal mitophagy under physiological conditions in adult animals and during aging remains a matter of debate. Future studies will have to clarify in how far dysfunction of neuronal mitophagy is central to the pathophysiology of Parkinson’sdisease. Keywords Mitophagy . Parkinson’sdisease . PINK1 and Parkin-dependentmitochondrial quality control . Aging . Mitochondrial stress . Fluorescent mitophagy reporters Introduction Wattiaux 1966; Novikoff 1959; Novikoff and Essner 1962). This phenomenon was interpreted as progressive mitochondrial Mitophagy is a form of cargo-selective autophagy removing degeneration (Novikoff and Essner 1962). However, the term unnecessary mitochondria, or clearing aged or dysfunctional mitophagy was coined more recently with the emergence of mitochondria to protect the cells from their deleterious effects. evidence, initially from yeast, indicating that the autophagy of More than 50 years ago, electron microscopy images revealed mitochondria does not occur at random, but rather reflects a the presence of altered mitochondrial profiles in atypically en- selective program (Kissova et al. 2004;Lemasters2005). The larged lysosomal vesicles in the liver and kidney, under patho- term was then used to describe the autophagy-dependent deg- logical conditions (Ashford and Porter 1962;DeDuveand radation of mitochondria in cultured hepatocytes, following nutrient deprivation or laser-induced photodamage (Kim et al. 2007; Rodriguez-Enriquez et al. 2006). An earlier precursor studyinculturedprimarysympathetic neurons reported com- * Olga Corti plete removal of mitochondria under conditions of apoptosis [email protected] induction in the presence of caspase inhibitors, presumably associated with loss of mitochondrial membrane potential and 1 Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France cytochrome c release (Tolkovsky et al. 2002). These studies highlighted a role for mitophagy in the regulation of mitochon- 2 Inserm, U1127, F-75013 Paris, France drial degradation under conditions of metabolic remodeling or 3 CNRS, UMR 7225, F-75013 Paris, France severe mitochondrial damage. Other types of programmed 4 Sorbonne Universités, F-75013 Paris, France mitophagy were recognized to be central to specific Neurotox Res (2019) 36:292–305 293 developmental programs: during the maturation of erythro- 2017), PINK1/Parkin-dependent mitochondrial clearance is cytes, whereby the cells get rid of their mitochondria to acquire undoubtedly the best characterized. Comparatively, however, the ability to transport oxygen (Sandoval et al. 2008;Schweers our understanding of the relevance of PINK1/Parkin- et al. 2007); following fertilization of the oocyte, a stage marked dependent mitophagy to mitochondrial homeostasis in neu- by the removal of paternal mitochondria, underlying the uni- rons, particularly in those that degenerate in PD, remains poor versal principle of maternal mitochondrial inheritance in ani- (Jang et al. 2018; Palikaras et al. 2018). mals(AlRawietal.2011;SatoandSato2011); during cardio- myocyte maturation in the neonatal period, whereby fetal mi- tochondria are replaced by adult mitochondria to sustain the PINK1/Parkin-Dependent Mitophagy in Brief transition from carbohydrates to fatty acid metabolism (Gong et al. 2015); or during the differentiation of myoblasts into Our current understanding of PINK1/Parkin-dependent mature myotubes, during which a distinct network of mitochon- mitophagy is that it is a program activated by specific stress- dria replaces the old population to support the metabolic switch related stimuli. Its activation depends on mitochondrial protein from glycolysis to oxidative phosphorylation (Sin et al. 2016). import arrest, caused either by toxins leading to mitochondrial It was not until 2008 that mitophagy emerged as a mito- depolarization, such as the protonophore carbonyl cyanide m- chondrial quality control mechanism of potential relevance to chlorophenyl hydrazone (CCCP) (Geisler et al. 2010;Matsuda neuronal cells, with the groundbreaking discovery of the in- et al. 2010; Narendra et al. 2008;Narendraetal.2010), by volvement of the RING-IBR-RING E3 ubiquitin ligase Parkin dysfunction of protein import components or proteases involved in the clearance of severely damaged mitochondria (Narendra in PINK1 processing (Bertolin et al. 2013;Greeneetal.2012; et al. 2008). Parkin is encoded by the PARK2 gene, which Jin et al. 2010), or by unfolded protein stress in the mitochon- carries loss-of-function mutations in autosomal recessive drial matrix (Fiesel et al. 2017; Jin and Youle 2013). These forms of Parkinson’s disease (PD), a common most often spo- conditions interfere with the translocation of PINK1 into the radic movement disorder caused by the progressive degener- organelle; leading to its accumulation in proximity of the ation of the dopaminergic (DA) neurons in a region of the translocase of outer mitochondrial membrane (Bertolin et al. midbrain termed substantia nigra pars compacta (SNc). Why 2013;Hassonetal.2013; Lazarou et al. 2012; Okatsu et al. these neurons die in PD remains a mystery. However, mito- 2012;Okatsuetal.2013); its dimerization and autophosphory- chondrial dysfunction had been suspected to play a role since lation; the phosphorylation of ubiquitin moieties associated with the 1980s, when the mitochondrial neurotoxin MPTP was the outer mitochondrial membrane (Koyano et al. 2014;Kane identified as the cause of Parkinsonism in young people con- et al. 2014; Kazlauskaite et al. 2014;Matsuda2016); the recruit- suming drugs (Corti et al. 2011; Exner et al. 2012;Langston ment and activation of the otherwise inactive Parkin ligase and Ballard 1983; Schapira and Gegg 2011). The discovery of (Riley et al. 2013 Trempe et al. 2013; Wauer and Komander Parkin-dependent mitophagy provided a cellular mechanism 2013), by binding to phospho-ubiquitin; and its stabilization in leading to mitochondrial dysfunction in PD. The role of this an active state through the PINK1-dependent phosphorylation mechanism was strengthened a few years later, when work of its N-terminal ubiquitin-like domain (Byrd and Weissman from several laboratories demonstrated that the product of 2013; Caulfield et al. 2015; Chaugule et al. 2011; Gladkova another gene responsible of autosomal recessive PD, the mi- et al. 2018; Kazlauskaite and Muqit 2015; Kondapalli et al. tochondrial serine/threonine kinase PINK1, was central to the 2012; Ordureau et al. 2015;Ordureauetal.2014; Sauve et al. activation of Parkin and its mitochondrial recruitment during 2018; Shiba-Fukushima et al. 2012;Sprattetal.2014; Yamano mitophagy (Geisler et al. 2010; Matsuda et al. 2010;Narendra et al. 2015). As a consequence, Parkin ubiquitylates a number of et al. 2010). Thanks to an unprecedented collective effort of proteins of the outer mitochondrial membrane by forming dif- the scientific community in the field during the past 10 years, ferent types of ubiquitin chains, which are further phosphorylat- enlightened by recent descriptions of the crystal structure of ed by PINK1, recruiting additional Parkin molecules, and there- Parkin (Byrd and Weissman 2013; Caulfield et al. 2015; by feeding an amplification loop (Okatsu et al. 2015;Ordureau Gladkova et al. 2018; Kumar et al. 2017a; Riley et al. 2013; et al. 2015;Ordureauetal.2014;Sarrafetal. 2013). This pro- Sauve et al. 2018; Seirafi et al. 2015;Sprattetal.2014; cess is negatively regulated by specific deubiquitylases (Bingol Trempe et al. 2013; Wauer and Komander 2013)andPINK1 et al. 2014; Cornelissen et al. 2014;Durcanetal.2014). The (Kumar et al. 2017b;Okatsuetal.2018; Schubert et al. 2017), ubiquitylation of mitochondrial