Mechanisms of mitophagy

ProgrEss
Mechanisms of mitophagy
Richard J. Youle and Derek P. Narendra
and photodamage-induced autophagy, Lemasters and colleagues10 coined the term mitophagy to describe the engulfment of mitochondria into vesicles that are coated with the autophagosome marker MAP1 light chain 3 (LC3; a homologue of yeast Atg8), a process that can occur within 5 minutes. LC3 (and Atg8) is an ubiquitin-likeprotein that is covalently attached to phosphatidylethanolamine during autophagosome biogenesis, which allows it to integrate into, and sculpt, the growing isolation membrane11 and participate in cargo recruitment 12. Another study found that in neurons cultured with caspase inhibitors to prevent cell dissolution, mitochondria were completely removed by mitophagy following apoptosis induction13. Asmitochondrial outer membrane permeabilization occurs upstream of caspase activation during apoptosis, these results suggest that mitochondrial damage can induce mitophagy. These early studies indicated that mitophagy regulates mitochondrial number to match metabolic demand and might also be a form of quality control to remove damaged mitochondria. In yeast 14 and mammalian cells15 mitophagy ispreceded by mitochondrial fission16, which divides elongated mitochondria into pieces of manageable size for encapsulation and also quality control segregation of damaged mitochondrial material for selective removal by mitophagy. Beyond quality control, mitophagy has been shown to be required for steady-state turnover of mitochondria17, for the adjustment of mitochondrion numbers to changingmetabolic requirements18 and during specialized developmental stages in mammalian cells, such as during red blood cell differentiation19,20. In this Progress article we discuss recently identified pathways that mediate mitophagy in yeast and mammalian cells, including those involving the kinase PTEN-induced putative kinase protein 1 (PINK1) and the E3 ubiquitin ligase parkin (which have no yeasthomologues). We also highlight how defects in mitophagy may contribute to human conditions such as Parkinson’s disease.
vOLUME 12 | jANUARy 2011 | 9 © 2011 Macmillan Publishers Limited. All rights reserved

Abstract | Autophagy not only recycles intracellular components to compensate for nutrient deprivation but also selectively eliminates organelles to regulate their number and maintain qualitycontrol. Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, mediated by autophagy-related 32 (Atg32), and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L). Moreover, mitophagy is regulated in many metazoan cell types by parkin and PTEN-induced putative kinase protein 1 (PINK1), and mutations in thegenes encoding these proteins have been linked to forms of Parkinson’s disease.
Autophagy is the process of catabolism of cellular components, such as the cytosol, organelles and protein aggregates, through their encapsulation by a double-membrane structure known as the autophagosome1,2. In yeast, the autophagosome is thought to develop from a single pre-autophagosomal structure (PAS), possiblythrough the coalescence of smaller vesicles3, whereas in mammalian cells its origin is multifocal. For example, in mammals the autophagosome can develop from a specialized double-membrane extension of the endoplasmic reticulum (ER) known as the omegasome4. Furthermore, recent reports indicate that, in some forms of autophagy, lipid for the autophagosomal membrane can be contributed by the ER (throughcontact with mitochondria, from which the autophagosomal membranes bud5) and the plasma membrane6. The newly formed double-membrane, which is known as an isolation membrane, surrounds cytosolic cargo, and its edges seal to sequester the contents into the autophagosome. This then fuses with a lysosome, allowing degradation of the cargo and the inner bilayer of the double autophagosomal membrane,...