Mitochondria and autophagy: Critical interplay between the two homeostats

Biochimica et Biophysica Acta 1820 (2012) 595–600

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a g e n

Review

Mitochondria and autophagy: Critical interplay between the two homeostats☆ Koji Okamoto ⁎, Noriko Kondo-Okamoto Laboratory of Mitochondrial Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan

a r t i c l e

i n f o

Article history: Received 24 June 2011 Accepted 1 August 2011 Available online 7 August 2011 Keywords: Biogenesis Degradation Fission Fusion Quality control Reactive oxygen species

a b s t r a c t Background: Mitochondria are dynamic organelles that frequently change their number, size, shape, and distribution in response to intra- and extracellular cues. After proliferated from pre-existing ones, fresh mitochondria enter constant cycles of fission and fusion that organize them into two distinct states — “individual state” and “network state”. When compromised with various injuries, solitary mitochondria are subjected to organelle degradation. This clearance pathway relies on autophagy, a self-eating process that plays key roles in manifold cell activities. Recent studies reveal that defects in autophagic degradation selective for mitochondria (mitophagy) are associated with neurodegenerative diseases, highlighting the physiological relevance to cellular functions. Scope of review: Here we review recent progress regarding a link between mitochondria and autophagy in yeast and multicellular eukaryotes. In particular, fundamental principles underlying mitophagy, and mitochondrial quality control are emphasized. Accumulating evidence also implicates nonselective autophagy in the management of mitochondrial fitness. Conversely, mitochondria are suggested to serve as signaling platforms vital for regulating autophagy. These interdependent relationships are likely to coordinate metabolic plasticity in the cell. Major conclusions: Mitochondria and autophagy are elaborately linked homeostatic elements that act in response to changes in cellular environment such as energy, nutrient, and stress. How cells integrate these double membrane-bound systems still remains elusive. General significance: Interplay between mitochondria and autophagy seems to be evolutionarily conserved. Defects in one of these elements could simultaneously impair the other, resulting in risk increments for various human diseases. This article is part of a Special Issue entitled Biochemistry of Mitochondria. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Mitochondria are major intracellular compartments bound by two lipid bilayer membranes, playing important roles in numerous metabolic reactions and signaling pathways [1,2]. One of the hallmarks, which define this organelle as “the life of a cell”, is that mitochondria possess their own genome, and frequently change their morphologies [3]. Such dynamic membrane remodeling takes place in a manner that is not random but rather purposive to optimize their structure and function for cellular needs [4]. In addition, degradation of damaged or excess mitochondria is thought to occur constitutively and inducibly, which is critical for mitochondrial quality and quantity control [5–10]. Since the late 1960's, pioneering studies on mitochondrial biogenesis have long been central in the research field [11], followed by outstanding advance made in understanding mitochondrial dynamics, particularly, fission and fusion, in the last one and a

half decade [12,13]. Very recently, much attention has been paid to the milestone discovery that Parkin, an E3 ubiquitin ligase whose defects are associated with a form of autosomal recessive juvenile Parkinson's disease, plays a pivotal role in autophagy-dependent degradation of depolarized mitochondria in mammalian cells [14]. Concurrent studies also reveal NIX (NIP3-like protein X)/BNIP3L (BCL2/adenovirus E1B 19 kDa interacting protein 3-like), and Atg32 (autophagy-related protein 32), membrane-anchored landmark proteins critical for mitochondria-specific autophagy (mitophagy) in reticulocytes and yeast, respectively [15–18]. Furthermore, there is an emerging body of evidence suggesting a regulatory alliance between mitochondrial function and nonselective autophagy [19,20]. In this short review, we discuss these ongoing issues in relation with the mechanisms by which cells coordinate the two homeostatic elements — mitochondria and autophagy, and hope to delineate how disturbance in one of them contributes to malfunction of the other, which may be commonly linked to aging, cancer, and neurodegeneration. 2. The mitochondrial life cycle

☆ This article is part of a Special Issue entitled Biochemistry of Mitochondria. ⁎ Corresponding author. Tel./fax: + 81 6 6879 7970. E-mail address: [email protected] (K. Okamoto). 0304-4165/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2011.08.001

Fission and fusion are two opposing processes that control mitochondrial number, size, shape, and distribution. In addition, these

596

K. Okamoto, N. Kondo-Okamoto / Biochimica et Biophysica Acta 1820 (2012) 595–600

events allow mitochondria to shuttle between two distinct states — “individual state” and “network state” (Fig. 1). For example, one mitochondrion is divided into two mitochondria by the Dnm1 (dynamin-related protein 1)/Drp1 (dynamin-related protein 1) fission GTPase complex [21]. In some cases, this event results in generation of heterogeneous individuals: healthy and unhealthy mitochondria. The former one subsequently fuses to another healthy mitochondrion via the Fzo1 (fuzzy onions homolog protein 1)/Mfn1&2 (mitofusin 1&2) and Mgm1 (mitochondrial genome maintenance protein 1)/OPA1 (optic atrophy 1) fusion GTPase complexes [22]. The latter one might contain little or no mitochondrial DNA (mtDNA), low respiratory activity, or reduced inner membrane electrical potential (Δψm). Importantly, mitochondrial fusion requires intact Δψm [23–25]. When such sick mitochondrion eventually becomes depolarized, it cannot fuse to the other, thereby leaving the fission–fusion cycle [26,27]. It should be noted that, in this cycle, fission occurs in a nonselective manner, whereas fusion is a process with a certain threshold of Δψm that selects healthy (and also slightly impaired) mitochondria, and generates homogeneous networks by mixing and exchanging intraorganellar components [28–30]. Hence, the fission– fusion cycle could contribute to the segregation and complementation of dysfunctional and functional mitochondria, respectively. Additional processes that define the life of mitochondria are biogenesis (birth) and degradation (death) (Fig. 1). Since mitochondria cannot be synthesized de novo, they must be proliferated from preexisting ones. Their biogenesis seems to be regulated through multiple processes including protein and lipid import, oxidative phosphorylation, and mtDNA replication. PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator 1α) functions as a master transcriptional regulator for mitochondrial biogenesis in vertebrates, and its upstream signaling events and downstream target genes have been reported [31– 33]. Fresh mitochondria then undergo either fission or fusion to enter the life cycle. Eventually, solitary mitochondria are generated by fission events, and unhealthy individuals are excluded from healthy populations. Thereafter, depolarized mitochondria are selectively surrounded and sequestered by newly formed structures called isolation membranes, which ultimately results in the formation of autophagosomes [34,35]. Finally, the double membrane-bound vesicles fuse to lysosomes, and the cargoes (depolarized mitochondria) are degraded by hydrolytic enzymes. Thus, biogenesis and degradation could serve to decrease the dysfunctional/functional ratio of mitochondria. 3. Mitochondrial shaping and mitophagy In the mitochondrial life cycle, autophagy selectively targets to depolarized mitochondria that are generated via fission events. It is

therefore conceivable that the number of depolarized mitochondria correlates with the fission efficiency, which in turn affects the degree of mitophagy. Consistent with this idea, expression of a dominantnegative variant of the fission GTPase Drp1 in INS1 (rat insulinomaderived β-cell line) cells resulted in the formation of elongated mitochondrial tubules and reduction of mitophagy [26]. In addition, Parkin-mediated degradation of depolarized mitochondria was strongly suppressed in DRP1 −/− MEFs [36]. How do cells specifically prevent disordered individuals from fusion to others? A primary process is that dissipation of Δψm causes proteolytic processing or degradation of the OPA1 long isoforms, leading to inhibition of mitochondrial fusion [37–40]. Another process could be that the fusion GTPases Mfn1 and Mfn2 in depolarized mitochondria are ubiquitinated by Parkin, and degraded in a proteasome-dependent manner [36,41–44], which is in agreement with studies in Drosophila [45,46]. These Δψm-linked inactivation mechanisms for the OPA1- and Mfn1&2-mediated fusion pathways are likely to ensure effective mitophagy. Nutrient starvation induces massive autophagy that promotes nonselective sequestration of proteins and organelles in the cytoplasm. On the other hand, excess degradation of healthy mitochondria should be avoided in order to maintain ATP levels adequate for cell survival. Indeed, mitochondria become elongated upon nutrient deprivation, and escape from autophagic turnover in mammalian cells [47,48]. Intriguingly, the fission GTPase Drp1 is a key target to promote this protection process. During starvation, cellular cyclic AMP levels increase, resulting in activation of PKA (protein kinase A) that phosphorylates Drp1. This posttranslational modification leads to reduction of Drp1-mediated fission events, thereby shifting the fission/fusion balance towards fusion. Moreover, activation of ATP synthase and promotion of cristae formation occur concomitantly with mitochondrial elongation in starved cells [47]. Consequently, mitochondria in the “network state” are poor substrates for autophagy, but vigorous factories for bioenergetic reactions. In contrast to the relevance of fission for mitochondrial degradation in mammals, there are conflicting reports about the fissiondegradation relationship in yeast. Cells lacking Mdm38, an inner membrane protein whose human ortholog LETM1 (leucine zipper-EFhand containing transmembrane protein 1) is implicated in Wolf– Hirschhorn syndrome, has been shown to display fragmentation and degradation of mitochondria [49]. Mitochondria were converted from fragments to giant spheres, and their clearance was blocked in the mdm38 dnm1 double-deletion mutant. It seems probable that such giant mitochondria cannot be surrounded by isolation membranes. In addition, another study revealed that cells lacking Dnm1 exhibit severe defects in mitochondrial degradation [50]. Contrary to these

Fission complex

Individual

(Dnm1/Drp1 GTPase)

Network

Biogenesis

Stress

(Birth)

m

Fusion complexes (Fzo1/Mfn1&2, Mgm1/OPA1 GTPases)

Degradation (death)

Mitophagy

BALANCED Fig. 1. The mitochondrial life cycle. See text for details.

K. Okamoto, N. Kondo-Okamoto / Biochimica et Biophysica Acta 1820 (2012) 595–600

findings, two reports provided data suggesting that this fission GTPase is dispensable for mitophagy [17,51]. Although the reason for this discrepancy is not entirely clear, it could be due to different strain backgrounds, growth conditions, and assays. Further analyses are necessary to clarify this issue, since it still remains possible that fission upon yeast mitophagy might be catalyzed by unknown mechanisms, as seen in a previous finding that mitochondria fragment during sporulation in the absence of Dnm1 [52].

4. Autophagy for mitochondria Accumulating evidence supports the notion that mitophagy is a surveillance mechanism directly and selectively targeted to mitochondria. Based on the previous findings that bulk, nonselective autophagy is critical for cellular homeostasis, it is not unreasonable to assume that loss of this self-eating process also indirectly compromises mitochondrial integrity. A study using conditional Atg7 knockout mice revealed that, when this core autophagy gene was disrupted in the adult body, degradation of mitochondria in response to food deprivation was impaired in the mutant liver [53]. In addition, mitochondrial morphology was altered in the mutant hepatocytes. Similarly, liver-specific Atg7 knockout and systematically mosaic Atg5-deficient mice displayed hepatocellular tumorigenesis accompanied by mitochondrial swelling and decreased respiration [54,55]. Yeast cells lacking core ATG genes have also been shown to exhibit reduced mitochondrial activity, lowered Δψm, increased reactive oxygen species (ROS) levels, and high mtDNA instability [56]. Thus, although an Atg5/Atg7-independent mechanism has also been detected during embryogenesis and erythroid maturation [57], mitochondria appear to be the intracellular constituents that predominantly require autophagy for their maintenance. Yet, whether mitochondrial malfunction in the ATG knockout mutants results from loss of mitophagy and/or bulk autophagy remains uncertain. A recent study in yeast elucidated that autophagy-dependent recycling is vital for maintenance of mitochondria during starvation [20]. In the yeast Saccharomyces cerevisiae, disruption of core ATG genes leads to reduced cell viability under nitrogen deprivation [58]. This cell death phenotype is due to the lowered extracellular pH below 3.0, and almost completely suppressed by buffering of the starvation medium to pH 5.0–6.0. Remarkably, during this “buffered” starvation, viable core atg mutant cells displayed respiration deficiency and mtDNA loss. Additional data indicated high levels of ROS, and low expression of ROS scavenging enzymes and oxidative phosphorylation components in the absence of autophagy, which seem to cause mtDNA instability. Similar to core atg mutants, cells lacking Atg15, a protein required for intravacuolar degradation of autophagic bodies, also exhibited respiratory defects under the same conditions, suggesting that nutrient recycling is crucial for mitochondrial function. Importantly, respiration activity was only slightly affected in cells lacking Atg32, excluding the possibility that mitophagy contributes to mitochondrial homeostasis during nitrogen starvation. Together, these findings for the first time unambiguously implicate nonselective autophagy in regulation of mitochondrial integrity. In yeast and various multicellular eukaryotes, reduced signaling of TOR (target of rapamycin), an evolutionarily conserved protein kinase, has been suggested to extend life span [59]. Notably, deletion of the TOR1 gene in yeast causes increased respiration and mtDNAencoded gene expression via mitochondrial ROS, which ultimately leads to prolonged chronological life span [60,61]. In addition, TORdeficient nematodes exhibit life span extension that is suppressed by the reduction of autophagy [62]. How TOR signaling modulates mitochondria is still poorly understood, however, it could control the electron transport chain activity in an autophagy-independent manner. Alternatively, considering that TOR negatively regulates both mitochondrial function and autophagy, it remains conceivable

597

that autophagy induced by TOR inhibition directly or indirectly activates mitochondria. An intimate link between autophagy and mitochondrial function exists in innate immune responses [63,64]. In macrophages, the NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome is a heterooligomeric protein complex that mediates maturation and secretion of the cytokines IL-1β (interleukin-1β) and IL-18 [65]. Interestingly, excess amounts of these proinflammatory cytokines are produced by autophagy-deficient macrophages [66]. Although ROS signaling has been suggested as a positive regulator for the NLRP3 inflammasome [67], where NLRP3-related ROS are generated, and how activation of this inflammasome takes place has remained obscure. Two new studies now reveal that defects in autophagic degradation cause accumulation of damaged, ROS-generating mitochondria, which in turn activates the NLRP3 inflammasome [63,64]. Surprisingly, mtDNA translocates from the mitochondrial matrix to the cytosol, and contributes to the secretion of IL-1β and IL-18 [63]. These findings raise the possibility that autophagy negatively modulates NLRP3mediated innate immunity through sustaining mitochondrial fitness. Whether mitophagy, not autophagy, serves to control the host defense systems is an open issue. Independently of their central roles in autophagosome formation, an Atg–Atg pair may atypically commit to the mitochondrial life cycle [68]. Atg12 is a ubiquitin-like modifier that is conjugated to Atg5 [69]. The covalently linked Atg12–Atg5 complex functions as an E3-like enzyme required for efficient lipidation of Atg8 to phosphatidylethanolamine (PE) [70,71]. A recent study in mammalian cells demonstrated that Atg12 also modifies Atg3, an E2-like enzyme for Atg8–PE formation, and that this conjugate is dispensable for autophagy under starvation conditions [68]. In the absence of Atg12–Atg3, mitochondria fragmented due to reduced fusion, and their mass was increased. It remains unknown whether the function of this previously unappreciated protein conjugate is physiologically relevant in vivo, and conserved in other eukaryotes.

5. Mitochondria for autophagy Emerging data unveil a new face of mitochondria that, as multitasking platforms, they may play key roles in regulation of nonselective autophagy. One of the responsible elements is ROS signaling that induces autophagic degradation in mammalian cells [72]. Specifically, H2O2 accumulates in mitochondria under starvation conditions, and negatively modulates the activity of Atg4, a cysteine protease that mediates both processing (initial step required for PE conjugation) and delipidation of the mammalian Atg8 homologs, LC3 and GATE-16 [73]. One possibility is that Atg4 in close proximity to mitochondria is locally inactivated, thereby preventing delipidation of LC3–PE and GATE-16–PE, and then promoting autophagosome formation without compromising the overall lipidation–delipidation cycle. Consistent with this ROS-dependent mechanism, a recent study showed that the early and late autophagosomal markers Atg5 and LC3, respectively, localize as puncta on mitochondria in mammalian cells during nutrient deprivation [74]. Additional data indicate that the LC3-positive puncta overlap with outer membrane markers, but not inner membrane and matrix markers, excluding involvement of mitophagy. Hence, mitochondrial outer membrane can be a source of autophagosomes formed under starvation conditions. It is, however, noteworthy that since the discovery of autophagy in 1950s there has been a long-standing debate on where the autophagosomal membrane is derived from, including recent findings in yeast and mammalian cells suggesting the endoplasmic reticulum (ER), Golgi, and plasma membrane as the origin of this double membrane-bound vesicle [34,75]. This issue needs to await detailed functional analyses.

598

K. Okamoto, N. Kondo-Okamoto / Biochimica et Biophysica Acta 1820 (2012) 595–600

Regardless of the membranous enigma, proteins on the surface of mitochondria seem to regulate autophagy [76]. In mammals, Beclin 1 (Atg6 in yeast), a component of the class III phosphatidylinositol 3-kinase, localizes to mitochondria and the ER [77,78]. AMBRA1 (activating molecule in beclin 1-regulated autophagy) and the antiapoptotic factor Bcl-2 control Beclin 1 in a positive and negative fashion, respectively [79]. Under nutrient-rich conditions, Bcl-2 interacts with AMBRA1 at the mitochondrial surface, and Beclin 1 at the ER to inhibit autophagy [76]. Upon starvation, AMBRA1 dissociates from Bcl-2, and associates with Beclin 1 at the ER and mitochondrial surface to stimulate autophagy [76]. AMBRA1 dissociation from mitochondrial Bcl-2 also occurs during apoptosis [76]. As is evident from the pivotal role for programmed cell death, mitochondria may serve as integrated circuits to coordinate autophagy and apoptosis. Based on the fact that human diseases such as aging, cancer, and neurodegeneration are commonly associated with defects in mitochondrial function and autophagy [80–85], it can be anticipated that the two distinct processes crosstalk interdependently. A recent study smashed out a clean hit that such interplay is also conserved in yeast [19]. Under amino acid starvation, autophagy is likely to require intact Δψm, which negatively controls PKA, a nutrient-sensing regulator that suppresses autophagic flux [86,87]. For example, cells lacking mtDNA are autophagy-deficient. Specific inhibition of PKA led to induction of autophagic flux even in respiration-deficient cells, indicating that mitochondrial activity per se is not required for autophagy [19]. These findings raise the possibility that defects in either mitochondrial function or autophagy could concomitantly disrupt the other, leading to elevation of risks for various human disorders [19]. It should be noted that, upon starvation, this cAMP-dependent kinase becomes inactive in yeast, but active in mammals, representing the diversity of PKA signaling. Nevertheless, the close relationship between mitochondrial function and autophagy might be beneficial to orchestrate numerous metabolic pathways in the cell. 6. Autophagic and proteasomal degradation on mitochondria It is well established that autophagy and the ubiquitin–proteasome system (UPS) cooperatively act in protein quality control [88,89]. In addition, growing evidence underscores the importance of the UPS for mitochondrial dynamics and function [90,91]. This organelle-linked UPS appears to rely on various ubiquitin E3 ligases either peripherally associated with, or membrane-integrated to the mitochondrial surface. Parkin is one of such E3 ligases that selectively targets to depolarized mitochondria and promotes mitophagy [14]. Intriguingly, Parkin mediates degradation of outer membrane proteins in a manner dependent on the UPS, but independent on mitophagy [92]. A further surprise is that Parkin also facilitates outer membrane rupture in cooperation with the UPS [92]. These two processes are not essential for degradation of depolarized mitochondria [92], and thus the physiological significance remains to be investigated. A possible scenario could be that Parkin serves as a damage dose–dependent regulator that, according to the functional state of mitochondria (Δψm, ROS, ATP, Ca 2+, etc.), removes dysfunctional outer membrane proteins, inhibits fusion, and ultimately promotes mitophagy. Strikingly, a tight collaboration between autophagy and the proteasome for mitochondrial maintenance exists in fission yeast starved for nitrogen [93]. In vegetatively growing cells, the proteasome is mainly located in the nucleus. When fission yeast left the cell cycle and entered G0 phase (quiescent state), the nuclear proteasome decreased, and instead the cytosolic one increased [93]. In addition, proteasome activity is essential for G0 cell viability, and the ROS levels are elevated in proteasome-deficient mutants [93]. Moreover, loss of proteasome function resulted in dramatic autophagy-dependent degradation of mitochondria in quiescent cells [93]. How much mitochondria-targeted proteasome and autophagy contribute to G0 cell survival is not entirely certain, although it seems likely that both

catabolic processes synergistically regulate mitochondrial homeostasis and turnover in quiescent state. 7. Conclusions In eukaryotic cells, mitophagy is crucial for degradation of surplus or injured mitochondria in order to ensure the sustainability of the multitasking organelles. Prior to this process, mitochondrial dynamics plays regulatory roles in modulating the levels of mitophagy both positively and negatively. In addition, autophagy contributes to the maintenance of mitochondria, which may also be relevant to controlling higher-order biological processes. Reciprocally, mitochondria act as structural and functional platforms to activate autophagy. Hence, the evolutionarily conserved interplay between mitochondria and autophagy is a fundamental mechanism underlying energy and metabolic homeostasis in eukaryotic cells. Acknowledgments This work was supported in part by grant-in-aid from the Ministry of Education, Culture, Science and Technology of Japan for Young Scientists (B) (22770124) (N.K.-O.), Scientific Research on Priority Areas (22020012) (K.O.), Scientific Research on Innovative Areas (23113717) (K.O.), Challenging Exploratory Research (23657090) (K.O.), and Special Coordination Funds from Osaka University Life Science Young Independent Researcher Support Program to Disseminate Tenure Tracking System (K.O.), and by grants from the Mochida Memorial Foundation for Medical and Pharmaceutical Research (K.O.), and the Sumitomo Foundation (K.O.). References [1] E. Braschi, H.M. McBride, Mitochondria and the culture of the Borg: understanding the integration of mitochondrial function within the reticulum, the cell, and the organism, Bioessays 32 (2010) 958–966. [2] V. Soubannier, H.M. McBride, Positioning mitochondrial plasticity within cellular signaling cascades, Biochimica et Biophysica Acta 1793 (2009) 154–170. [3] C.S. Palmer, L.D. Osellame, D. Stojanovski, M.T. Ryan, The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery, Cellular Signalling 23 (2011) 1534–1545. [4] A.Y. Seo, A.M. Joseph, D. Dutta, J.C. Hwang, J.P. Aris, C. Leeuwenburgh, New insights into the role of mitochondria in aging: mitochondrial dynamics and more, Journal of Cell Science 123 (2010) 2533–2542. [5] R.J. Youle, D.P. Narendra, Mechanisms of mitophagy, nature reviews, Nature Reviews Molecular Cell Biology 12 (2011) 9–14. [6] J. Zhang, P.A. Ney, Mechanisms and biology of B-cell leukemia/lymphoma 2/adenovirus E1B interacting protein 3 and Nip-like protein X, Antioxidants & Redox Signaling 14 (2011) 1959–1969. [7] T. Kanki, D.J. Klionsky, K. Okamoto, Mitochondria autophagy in yeast, Antioxidants & Redox Signaling 14 (2011) 1989–2001. [8] C. Vives-Bauza, S. Przedborski, Mitophagy: the latest problem for Parkinson's disease, Trends in Molecular Medicine 17 (2011) 158–165. [9] D.P. Narendra, R.J. Youle, Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control, Antioxidants & Redox Signaling 14 (2011) 1929–1938. [10] A. Tanaka, Parkin-mediated selective mitochondrial autophagy, mitophagy: Parkin purges damaged organelles from the vital mitochondrial network, FEBS Letters 584 (2010) 1386–1392. [11] O. Schmidt, N. Pfanner, C. Meisinger, Mitochondrial protein import: from proteomics to functional mechanisms, nature reviews, Nature Reviews Molecular Cell Biology 11 (2010) 655–667. [12] B. Westermann, Mitochondrial fusion and fission in cell life and death, nature reviews, Nature Reviews Molecular Cell Biology 11 (2010) 872–884. [13] H. Otera, K. Mihara, Molecular mechanisms and physiologic functions of mitochondrial dynamics, Journal of Biochemistry 149 (2011) 241–251. [14] D. Narendra, A. Tanaka, D.F. Suen, R.J. Youle, Parkin is recruited selectively to impaired mitochondria and promotes their autophagy, The Journal of Cell Biology 183 (2008) 795–803. [15] H. Sandoval, P. Thiagarajan, S.K. Dasgupta, A. Schumacher, J.T. Prchal, M. Chen, J. Wang, Essential role for Nix in autophagic maturation of erythroid cells, Nature 454 (2008) 232–235. [16] R.L. Schweers, J. Zhang, M.S. Randall, M.R. Loyd, W. Li, F.C. Dorsey, M. Kundu, J.T. Opferman, J.L. Cleveland, J.L. Miller, P.A. Ney, NIX is required for programmed mitochondrial clearance during reticulocyte maturation, Proceedings of the National Academy of Sciences of the United States of America 104 (2007) 19500–19505.

K. Okamoto, N. Kondo-Okamoto / Biochimica et Biophysica Acta 1820 (2012) 595–600 [17] K. Okamoto, N. Kondo-Okamoto, Y. Ohsumi, Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy, Developmental Cell 17 (2009) 87–97. [18] T. Kanki, K. Wang, Y. Cao, M. Baba, D.J. Klionsky, Atg32 is a mitochondrial protein that confers selectivity during mitophagy, Developmental Cell 17 (2009) 98–109. [19] M. Graef, J. Nunnari, Mitochondria regulate autophagy by conserved signalling pathways, The EMBO Journal 30 (2011) 2101–2114. [20] S.W. Suzuki, J. Onodera, Y. Ohsumi, Starvation induced cell death in autophagydefective yeast mutants is caused by mitochondria dysfunction, PLoS One 6 (2011) e17412. [21] L.L. Lackner, J.M. Nunnari, The molecular mechanism and cellular functions of mitochondrial division, Biochimica et Biophysica Acta 1792 (2009) 1138–1144. [22] S. Hoppins, J. Nunnari, The molecular mechanism of mitochondrial fusion, Biochimica et Biophysica Acta 1793 (2009) 20–26. [23] S. Meeusen, J.M. McCaffery, J. Nunnari, Mitochondrial fusion intermediates revealed in vitro, Science 305 (2004) 1747–1752. [24] F. Legros, A. Lombes, P. Frachon, M. Rojo, Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins, Molecular Biology of the Cell 13 (2002) 4343–4354. [25] N. Ishihara, A. Jofuku, Y. Eura, K. Mihara, Regulation of mitochondrial morphology by membrane potential, and DRP1-dependent division and FZO1-dependent fusion reaction in mammalian cells, Biochemical and Biophysical Research Communications 301 (2003) 891–898. [26] G. Twig, A. Elorza, A.J. Molina, H. Mohamed, J.D. Wikstrom, G. Walzer, L. Stiles, S.E. Haigh, S. Katz, G. Las, J. Alroy, M. Wu, B.F. Py, J. Yuan, J.T. Deeney, B.E. Corkey, O.S. Shirihai, Fission and selective fusion govern mitochondrial segregation and elimination by autophagy, The EMBO Journal 27 (2008) 433–446. [27] P.K. Mouli, G. Twig, O.S. Shirihai, Frequency and selectivity of mitochondrial fusion are key to its quality maintenance function, Biophysical Journal 96 (2009) 3509–3518. [28] B.B. Hyde, G. Twig, O.S. Shirihai, Organellar vs cellular control of mitochondrial dynamics, Seminars in Cell & Developmental Biology 21 (2010) 575–581. [29] G. Twig, O.S. Shirihai, The interplay between mitochondrial dynamics and mitophagy, Antioxidants & Redox Signaling 14 (2011) 1939–1951. [30] G. Twig, B. Hyde, O.S. Shirihai, Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view, Biochimica et Biophysica Acta 1777 (2008) 1092–1097. [31] T. Wenz, Mitochondria and PGC-1alpha in aging and age-associated diseases, J Aging Res 2011 (2011) 810619. [32] R. Ventura-Clapier, A. Garnier, V. Veksler, Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha, Cardiovascular Research 79 (2008) 208–217. [33] J. Lin, C. Handschin, B.M. Spiegelman, Metabolic control through the PGC-1 family of transcription coactivators, Cell Metabolism 1 (2005) 361–370. [34] H. Weidberg, E. Shvets, Z. Elazar, Biogenesis and cargo selectivity of autophagosomes, Annual Review of Biochemistry 80 (2011) 125–156. [35] Z. Yang, D.J. Klionsky, Eaten alive: a history of macroautophagy, Nature Cell Biology 12 (2010) 814–822. [36] A. Tanaka, M.M. Cleland, S. Xu, D.P. Narendra, D.F. Suen, M. Karbowski, R.J. Youle, Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin, The Journal of Cell Biology 191 (2010) 1367–1380. [37] N. Ishihara, Y. Fujita, T. Oka, K. Mihara, Regulation of mitochondrial morphology through proteolytic cleavage of OPA1, The EMBO Journal 25 (2006) 2966–2977. [38] L. Griparic, T. Kanazawa, A.M. van der Bliek, Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage, The Journal of Cell Biology 178 (2007) 757–764. [39] S. Duvezin-Caubet, R. Jagasia, J. Wagener, S. Hofmann, A. Trifunovic, A. Hansson, A. Chomyn, M.F. Bauer, G. Attardi, N.G. Larsson, W. Neupert, A.S. Reichert, Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology, The Journal of Biological Chemistry 281 (2006) 37972–37979. [40] Z. Song, H. Chen, M. Fiket, C. Alexander, D.C. Chan, OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L, The Journal of Cell Biology 178 (2007) 749–755. [41] L. Glauser, S. Sonnay, K. Stafa, D.J. Moore, Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1, Journal of Neurochemistry 118 (2011) 636–645. [42] A. Rakovic, A. Grunewald, J. Kottwitz, N. Bruggemann, P.P. Pramstaller, K. Lohmann, C. Klein, Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts, PLoS One 6 (2011) e16746. [43] M.E. Gegg, J.M. Cooper, K.Y. Chau, M. Rojo, A.H. Schapira, J.W. Taanman, Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy, Human Molecular Genetics 19 (2010) 4861–4870. [44] N.C. Chan, A.M. Salazar, A.H. Pham, M.J. Sweredoski, N.J. Kolawa, R.L. Graham, S. Hess, D.C. Chan, Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy, Human Molecular Genetics 20 (2011) 1726–1737. [45] A.C. Poole, R.E. Thomas, S. Yu, E.S. Vincow, L. Pallanck, The mitochondrial fusionpromoting factor mitofusin is a substrate of the PINK1/parkin pathway, PLoS One 5 (2010) e10054. [46] E. Ziviani, R.N. Tao, A.J. Whitworth, Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin, Proceedings of the National Academy of Sciences of the United States of America 107 (2010) 5018–5023. [47] L.C. Gomes, G. Di Benedetto, L. Scorrano, During autophagy mitochondria elongate, are spared from degradation and sustain cell viability, Nature Cell Biology 13 (2011) 589–598. [48] A.S. Rambold, B. Kostelecky, N. Elia, J. Lippincott-Schwartz, Tubular network formation protects mitochondria from autophagosomal degradation during

[49]

[50]

[51]

[52] [53]

[54]

[55]

[56]

[57]

[58] [59]

[60]

[61]

[62]

[63]

[64] [65] [66]

[67]

[68]

[69]

[70]

[71]

[72] [73]

[74]

[75] [76]

[77]

599

nutrient starvation, Proceedings of the National Academy of Sciences of the United States of America 108 (2011) 10190–10195. K. Nowikovsky, S. Reipert, R.J. Devenish, R.J. Schweyen, Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy, Cell Death and Differentiation 14 (2007) 1647–1656. T. Kanki, K. Wang, M. Baba, C.R. Bartholomew, M.A. Lynch-Day, Z. Du, J. Geng, K. Mao, Z. Yang, W.L. Yen, D.J. Klionsky, A genomic screen for yeast mutants defective in selective mitochondria autophagy, Molecular Biology of the Cell 20 (2009) 4730–4738. N. Mendl, A. Occhipinti, M. Muller, P. Wild, I. Dikic, A.S. Reichert, Mitophagy in yeast is independent of mitochondrial fission and requires the stress response gene WHI2, Journal of Cell Science 124 (2011) 1339–1350. S.W. Gorsich, J.M. Shaw, Importance of mitochondrial dynamics during meiosis and sporulation, Molecular Biology of the Cell 15 (2004) 4369–4381. M. Komatsu, S. Waguri, T. Ueno, J. Iwata, S. Murata, I. Tanida, J. Ezaki, N. Mizushima, Y. Ohsumi, Y. Uchiyama, E. Kominami, K. Tanaka, T. Chiba, Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice, The Journal of Cell Biology 169 (2005) 425–434. Y. Inami, S. Waguri, A. Sakamoto, T. Kouno, K. Nakada, O. Hino, S. Watanabe, J. Ando, M. Iwadate, M. Yamamoto, M.S. Lee, K. Tanaka, M. Komatsu, Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells, The Journal of Cell Biology 193 (2011) 275–284. A. Takamura, M. Komatsu, T. Hara, A. Sakamoto, C. Kishi, S. Waguri, Y. Eishi, O. Hino, K. Tanaka, N. Mizushima, Autophagy-deficient mice develop multiple liver tumors, Genes & Development 25 (2011) 795–800. Y. Zhang, H. Qi, R. Taylor, W. Xu, L.F. Liu, S. Jin, The role of autophagy in mitochondria maintenance: characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains, Autophagy 3 (2007) 337–346. Y. Nishida, S. Arakawa, K. Fujitani, H. Yamaguchi, T. Mizuta, T. Kanaseki, M. Komatsu, K. Otsu, Y. Tsujimoto, S. Shimizu, Discovery of Atg5/Atg7-independent alternative macroautophagy, Nature 461 (2009) 654–658. M. Tsukada, Y. Ohsumi, Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae, FEBS Letters 333 (1993) 169–174. P. Kapahi, D. Chen, A.N. Rogers, S.D. Katewa, P.W. Li, E.L. Thomas, L. Kockel, With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging, Cell Metabolism 11 (2010) 453–465. N.D. Bonawitz, M. Chatenay-Lapointe, Y. Pan, G.S. Shadel, Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression, Cell Metabolism 5 (2007) 265–277. Y. Pan, E.A. Schroeder, A. Ocampo, A. Barrientos, G.S. Shadel, Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling, Cell Metabolism 13 (2011) 668–678. M.L. Toth, T. Sigmond, E. Borsos, J. Barna, P. Erdelyi, K. Takacs-Vellai, L. Orosz, A.L. Kovacs, G. Csikos, M. Sass, T. Vellai, Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans, Autophagy 4 (2008) 330–338. K. Nakahira, J.A. Haspel, V.A. Rathinam, S.J. Lee, T. Dolinay, H.C. Lam, J.A. Englert, M. Rabinovitch, M. Cernadas, H.P. Kim, K.A. Fitzgerald, S.W. Ryter, A.M. Choi, Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome, Nature Immunology 12 (2011) 222–230. R. Zhou, A.S. Yazdi, P. Menu, J. Tschopp, A role for mitochondria in NLRP3 inflammasome activation, Nature 469 (2011) 221–225. K. Schroder, J. Tschopp, The inflammasomes, Cell 140 (2010) 821–832. T. Saitoh, N. Fujita, M.H. Jang, S. Uematsu, B.G. Yang, T. Satoh, H. Omori, T. Noda, N. Yamamoto, M. Komatsu, K. Tanaka, T. Kawai, T. Tsujimura, O. Takeuchi, T. Yoshimori, S. Akira, Loss of the autophagy protein Atg16L1 enhances endotoxininduced IL-1beta production, Nature 456 (2008) 264–268. J. Tschopp, K. Schroder, NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nature Reviews Immunology 10 (2010) 210–215. L. Radoshevich, L. Murrow, N. Chen, E. Fernandez, S. Roy, C. Fung, J. Debnath, ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death, Cell 142 (2010) 590–600. J. Geng, D.J. Klionsky, The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series, EMBO Reports 9 (2008) 859–864. T. Hanada, N.N. Noda, Y. Satomi, Y. Ichimura, Y. Fujioka, T. Takao, F. Inagaki, Y. Ohsumi, The Atg12–Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy, The Journal of Biological Chemistry 282 (2007) 37298–37302. N. Fujita, T. Itoh, H. Omori, M. Fukuda, T. Noda, T. Yoshimori, The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy, Molecular Biology of the Cell 19 (2008) 2092–2100. R. Scherz-Shouval, Z. Elazar, Regulation of autophagy by ROS: physiology and pathology, Trends in Biochemical Sciences 36 (2011) 30–38. R. Scherz-Shouval, E. Shvets, E. Fass, H. Shorer, L. Gil, Z. Elazar, Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4, The EMBO Journal 26 (2007) 1749–1760. D.W. Hailey, A.S. Rambold, P. Satpute-Krishnan, K. Mitra, R. Sougrat, P.K. Kim, J. Lippincott-Schwartz, Mitochondria supply membranes for autophagosome biogenesis during starvation, Cell 141 (2010) 656–667. S.A. Tooze, T. Yoshimori, The origin of the autophagosomal membrane, Nature Cell Biology 12 (2010) 831–835. F. Strappazzon, M. Vietri-Rudan, S. Campello, F. Nazio, F. Florenzano, G.M. Fimia, M. Piacentini, B. Levine, F. Cecconi, Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy, The EMBO Journal 30 (2011) 1195–1208. S.F. Funderburk, Q.J. Wang, Z. Yue, The Beclin 1-VPS34 complex — at the crossroads of autophagy and beyond, Trends in Cell Biology 20 (2010) 355–362.

600

K. Okamoto, N. Kondo-Okamoto / Biochimica et Biophysica Acta 1820 (2012) 595–600

[78] C. He, B. Levine, The Beclin 1 interactome, Current Opinion in Cell Biology 22 (2010) 140–149. [79] F. Cecconi, B. Levine, The role of autophagy in mammalian development: cell makeover rather than cell death, Developmental Cell 15 (2008) 344–357. [80] M.H. Vendelbo, K.S. Nair, Mitochondrial longevity pathways, Biochimica et Biophysica Acta 1813 (2011) 634–644. [81] L. Galluzzi, E. Morselli, O. Kepp, I. Vitale, A. Rigoni, E. Vacchelli, M. Michaud, H. Zischka, M. Castedo, G. Kroemer, Mitochondrial gateways to cancer, Molecular Aspects of Medicine 31 (2010) 1–20. [82] E.A. Schon, S. Przedborski, Mitochondria: the next (neurode)generation, Neuron 70 (2011) 1033–1053. [83] T. Vellai, K. Takacs-Vellai, M. Sass, D.J. Klionsky, The regulation of aging: does autophagy underlie longevity? Trends in Cell Biology 19 (2009) 487–494. [84] R. Mathew, E. White, Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night, Current Opinion in Genetics and Development 21 (2011) 113–119. [85] E. Wong, A.M. Cuervo, Autophagy gone awry in neurodegenerative diseases, Nature Neuroscience 13 (2010) 805–811. [86] J.S. Stephan, Y.Y. Yeh, V. Ramachandran, S.J. Deminoff, P.K. Herman, The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase

[87] [88] [89] [90] [91] [92]

[93]

complex to control autophagy, Proceedings of the National Academy of Sciences of the United States of America 106 (2009) 17049–17054. C. He, D.J. Klionsky, Regulation mechanisms and signaling pathways of autophagy, Annual Review of Genetics 43 (2009) 67–93. T. Lamark, T. Johansen, Autophagy: links with the proteasome, Current Opinion in Cell Biology 22 (2010) 192–198. E. Wong, A.M. Cuervo, Integration of clearance mechanisms: the proteasome and autophagy, Cold Spring Harbor Perspectives in Biology 2 (2010) a006734. N. Livnat-Levanon, M.H. Glickman, Ubiquitin–proteasome system and mitochondria — reciprocity, Biochimica et Biophysica Acta 1809 (2011) 80–87. J.M. Heo, J. Rutter, Ubiquitin-dependent mitochondrial protein degradation, The International Journal of Biochemistry & Cell Biology 43 (2011) 1422–1426. S.R. Yoshii, C. Kishi, N. Ishihara, N. Mizushima, Parkin mediates proteasomedependent protein degradation and rupture of the outer mitochondrial membrane, The Journal of Biological Chemistry 286 (2011) 19630–19640. K. Takeda, T. Yoshida, S. Kikuchi, K. Nagao, A. Kokubu, T. Pluskal, A. Villar-Briones, T. Nakamura, M. Yanagida, Synergistic roles of the proteasome and autophagy for mitochondrial maintenance and chronological lifespan in fission yeast, Proceedings of the National Academy of Sciences of the United States of America 107 (2010) 3540–3545.