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The Pathways of Mitophagy for Quality Control and Clearance of Mitochondria

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The Pathways of Mitophagy for Quality Control and Clearance of Mitochondria Cell Death and Differentiation (2013) 20, 31–42 & 2013 Macmillan Publishers Limited All rights reserved 1350-9047/13 www.nature.com/cdd Review The pathways of mitophagy for quality control and clearance of mitochondria G Ashrafi1,3 and TL Schwarz*,1,2 Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Cell Death and Differentiation (2013) 20, 31–42; doi:10.1038/cdd.2012.81; published online 29 June 2012 Facts To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyper- Mitophagy mediates clearance of damaged mitochondria, ubiquitinating the mitochondrial surface? and is also involved in the removal of mitochondria from How do PINK1 and Parkin interact with one another and maturing erythrocytes and eliminating sperm-derived mito- with substrates on the mitochondrial surface in causing chondria after fertilization. mitophagy? In yeast, the mitochondrial outer membrane protein In contrast to the remarkable conservation of the core autophagy-related gene 32 (ATG32) recruits the core auto- autophagic machinery, why are mitophagy-specific genes phagic machinery to mitochondria for their selective removal. so little conserved between yeast and mammals? A pathway containing PTEN-induced putative protein How best should mitophagy be triggered by researchers kinase 1 (PINK1) and Parkin responds to loss of probing physiologically relevant pathways? mitochondrial membrane potential by targeting damaged mitochondria for clearance. The mitochondrion is an important actor in the life of a The PINK1/Parkin pathway is triggered when PINK1 is eukaryotic cell, but, like all good actors, a mitochondrion stabilized on the outer membrane of damaged mitochon- needs to exit the stage at the right time. Mitophagy removes dria, where it facilitates recruitment of cytosolic Parkin. mitochondria once they have played their part. This article will Damaged mitochondria are prevented from moving and review the mechanism by which they are cleared and the cues fusing with the mitochondrial reticulum in preparation for that signal their removal. Alongside the critical metabolic their mitophagic clearance. functions of mitochondria in fatty acid oxidation, the Krebs cycle, and oxidative phosphorylation, mitochondria can also potentially damage cells.1 Reactive oxygen species (ROS), in À Open Questions particular superoxide anion (O2 ), hydrogen peroxide (H2O2), and hydroxyl radical (OH) are toxic byproducts of oxidative How distinct are the mitophagy pathways triggered by phosphorylation.2 ROS causes oxidative damage to mito- different stimuli or conditions? chondrial lipids, DNA, and proteins, making mitochondria 1FM Kirby Neurobiology Center, Children’s Hospital Boston, Boston, MA 02115, USA; 2Department of Neurobiology, Harvard Medical School, Cambridge, MA, USA and 3Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA *Corresponding author: TL Schwarz, FM Kirby Neurobiology Center, Children’s Hospital Boston, 3 Blackfan Circle, CLS 12120, Boston, MA 02115, USA. Tel: 617 919 2219; Fax: 617 919 2771; E-mail: [email protected] Keywords: mitochondria; mitophagy; PINK1; Parkin; mitochondrial dynamics; neuron Abbreviations: ROS, reactive oxygen species; LAMP2A, lysosome-associated membrane protein 2A; ATG, autophagy-re;ated gene; TORC1, target of rapamycin complex 1; PI3K, phosphatidyl inositol 3-kinase; LC3, microtubule-associated protein light chain 3; CCCP, carbonyl cyanide m-chlorophenylhydrazone; Drp1, dynain- related protein 1; Opa1, optic atrophy 1; PINK1, PTEN-induced putatieve protein kinase 1; Miro, mitochondria Rho-GTPase Received 01.3.12; revised 14.5.12; accepted 16.5.12; Edited by M Piacentini; published online 29.6.12 The pathways of mitophagy G Ashrafi and TL Schwarz 32 Mitochondrial Quality Control microscopy studies.10,11 Bulk degradation of cellular contents occurs through a regulated process called autophagy Select mitochondrial Unfolded Proteins Entire (reviewed elsewhere in this issue); however, a selective form proteins Mitochondrion of autophagy, termed mitophagy, is chiefly responsible for elimination of damaged or superfluous mitochondria. In this process, mitochondria are sequestered in double- membrane vesicles and delivered to lysosomes for hydrolytic Vesicular transport degradation. In addition, although mitochondrial turnover and AAA Protease complexes Mitophagy to lysosome clearance of damaged mitochondria may be the primary OM functions of mitophagy, there are other specialized cases of mitophagy: the complete removal of mitochondria during 12 IM erythrocyte maturation and the selective destruction of 13,14 Autolysosome sperm-derived mitochondria after oocyte fertilization. Lysosome In this review, we will discuss the general features of mitophagy as a quality control pathway, and also the Figure 1 Three major pathways of mitochondrial quality control. Misfolded activation of specific types of mitophagy in response to mitochondrial membrane proteins can be degraded by two AAA protease complexes with catalytic sites facing both sides of the inner membrane. different physiological triggers. Mitochondrial proteins can also be degraded by being transferred to lysosomes; vesicles budding from mitochondrial tubules sequester selected mitochondrial cargos, and deliver those mitochondrial components to the lysosome for Overview of Autophagy degradation. The third pathway, known as mitophagy, involves sequestration of Autophagy (from Greek, meaning self-eating) is a broad term an entire mitochondrion within a double-membrane vesicle, the autophagosome, referring to different pathways for bulk degradation of followed by fusion with a lysosome cytosolic components and organelles, including mitochondria, through delivery to the lysosome. There are three distinct classes of autophagy: microautophagy, chaperone-mediated further prone to ROS production. In turn, damaged mitochon- autophagy (CMA), and macroautophagy.15 In microauto- dria release high levels of Ca2 þ and cytochrome c to the phagy, invaginations of the lysosomal membrane directly cytosol and thereby trigger apoptosis.3 Thus, like macro- engulf portions of the cytoplasm. In contrast, CMA involves scopic energy sources and power plants, these microscopic the chaperone Hsc70 and its co-chaperones that recognize power supplies are essential but prone to release hazardous and unfold substrate proteins with a KFERQ amino-acid motif. materials, particularly when they have been compromised by The substrates bind to the lysosomal protein LAMP-2A and damage or age. Accordingly, ensuring proper elimination of are translocated across the lysosomal membrane for dysfunctional mitochondria is imperative to cellular survival, degradation.16 and mitochondrial damage has been implicated in aging,4 Macroautophagy is the major type of autophagy and it is diabetes, and neurodegenerative diseases.2 well conserved from yeast to mammals. Non-selective or bulk To prevent cellular damage by preserving a population of autophagy is induced by starvation to provide the cell with healthy mitochondria, several quality control mechanisms essential nutrients. In contrast, selective autophagy occurs to have evolved (Figure 1). Mitochondria have their own clear unwanted or damaged organelles, including mitochon- proteolytic system, two AAA protease complexes in the inner dria. In this process, an isolation membrane (known as membrane, whose function is to degrade unfolded membrane phagophore) surrounds a portion of the cytoplasm or an proteins.5 Cytosolic proteosomes have also been shown to organelle, forming a double membranous structure called the mediate degradation of proteins on the inner and outer autophagosome. The autophagosome then fuses with the mitochondrial membrane.6 In addition to proteolytic and lysosome to form an autolysosome, in which the hydrolytic proteosomal degradation, recent evidence points to a degradation of contents of the autophagosome will occur. lysosomal pathway in which vesicles bud from mitochondrial Mitochondria are removed by a form of macroautophagy tubules, sequester selected mitochondrial cargos, and then (called mitophagy), in which the core machinery of bulk deliver those mitochondrial
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