Autophagy and mitophagy in diabetic cardiomyopathy.

BBADIS-63962; No. of pages: 10; 4C: 2, 4 Biochimica et Biophysica Acta xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta

Review

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Autophagy and mitophagy in diabetic cardiomyopathy☆

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Satoru Kobayashi, Qiangrong Liang ⁎

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Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, USA

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Article history: Received 10 March 2014 Received in revised form 7 May 2014 Accepted 21 May 2014 Available online xxxx

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Keywords: Autophagy Mitochondrion Mitophagy Diabetes Diabetic cardiomyopathy

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Diabetic cardiomyopathy is a heart muscle-specific disease that increases the risk of heart failure and mortality in diabetic patients independent of vascular pathology. Mitochondria are cellular power plants that generate energy for heart contraction and concurrently produce reactive oxygen species that, if unchecked, may damage the mitochondria and the heart. Elimination of damaged mitochondria by autophagy known as mitophagy is an essential process for maintaining normal cardiac function at baseline and in response to various stress and disease conditions. Mitochondrial structural injury and functional impairment have been shown to contribute to diabetic heart disease. Recent studies have demonstrated an inhibited autophagic flux in the hearts of diabetic animals. Surprisingly, the diminished autophagy appears to be an adaptive response that protects against cardiac injury in type 1 diabetes. This raises several questions regarding the relationship between general autophagy and selective mitophagy in the diabetic heart. However, autophagy may play a different role in the hearts of type 2 diabetic animals. In this review, we will summarize current knowledge in this field and discuss the potential functional roles of autophagy and mitophagy in the pathogenesis of diabetic cardiomyopathy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. © 2014 Published by Elsevier B.V.

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Autophagy is an intracellular catabolic pathway in which long-lived proteins and organelles are delivered to and degraded in the lysosomes. Basal level autophagy plays a house-keeping role to maintain cellular homeostasis. In response to starvation and various stresses, autophagy is activated to degrade and recycle cellular materials for energy homeostasis and cell survival. However, unchecked autophagy can result in cell death. General macro-autophagy is believed to be a bulk non-selective process that eliminates cellular components indiscriminately. However,

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1. Introduction

Abbreviations: ROS, reactive oxygen species; p62, sequestosome 1; HDAC6, histone deacetylase 6; BNIP3, BCL2/adenovirus E1B interacting protein 3; NIX/BNIP3L, BNIP3like; FUNDC1, FUN14 domain containing 1; Atg, autophagy-related protein; AVs, autophagic vacuoles; VPS34, vacuolar protein sorting 34; PI3K, phosphatidylinositol 3-kinase; LC3, microtubule-associated protein 1 light chain 3; PE, phosphatidylethanolamine; mTOR, mammalian or mechanistic target of rapamycin; ULK, Unc-51-like kinase; AMPK, AMP-activated protein kinase; STZ, streptozotocin; GFP, green fluorescent protein; RFP, red fluorescent protein; HFD, high fat diet; HO-1, heme oxygenase-1; ALDH2, mitochondrial aldehyde dehydrogenase; Drp1, dynamin-related protein 1; PINK1, phosphatase and tensin homolog-induced putative kinase 1; Mfn1/2, mitofusin 1/2; VDAC1, voltagedependent anion channel 1; Ub, ubiquitin; SMURF1, SMAD-specific E3 ubiquitin protein ligase 1; LAMP1, lysosomal-associated membrane protein 1; GABARAP, gamma-aminobutyric acid receptor-associated protein ☆ This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. ⁎ Corresponding author at: Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Northern Blvd, PO Box 8000, Old Westbury, NY 11568-8000, USA. Tel.: +1 516 686 1331; fax: +1 516 686 3832. E-mail address: [email protected] (Q. Liang).

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autophagic degradation can become very selective when a specific organelle is exclusively targeted and escorted into autophagosomes, the double-membrane vesicles that engulf the destined cargo [1]. When the selective cargo is mitochondria, it is termed mitophagy, meaning the degradation of mitochondria through the autophagic process. How exactly mitophagy achieves its selectivity and specificity is under intense research. Several molecules have been identified to serve as adaptors or receptors that mediate mitophagy such as sequestosome 1 (p62), histone deacetylase 6 (HDAC6), BCL2/adenovirus E1B interacting protein 3 (BNIP3), BNIP3-like (BNIP3L or NIX) [2,3] and FUN14 domain containing 1 (FUNDC1) [4]. The general bulk autophagy and the selective mitophagy can occur under the same conditions but they do not necessarily change together in the same direction [5], suggesting distinct regulatory mechanisms for autophagy and mitophagy. Two-thirds of diabetic patients die from heart disease or stroke, which highlights the importance of understanding and treating cardiovascular complications of diabetes including diabetic cardiomyopathy. Convincing evidence indicates that mitochondrial dysfunction and increased generation of reactive oxygen species (ROS) are critical to diabetic heart damage [6–9]. However, several clinical trials have failed to confirm the ability of antioxidant therapies to reduce heart failure in diabetic patients [10–14]. This may reflect the fact that antioxidants can only scavenge or antagonize existing ROS, but cannot curb continuous ROS generation from aged or injured mitochondria, which are a major source and target of intracellular ROS in diabetes [15–18]. Thus, a more effective treatment strategy for reducing diabetic cardiac injury may be to timely eliminate dysfunctional mitochondria thereby preventing ROS generation. Presumably, this could be achieved by improving

http://dx.doi.org/10.1016/j.bbadis.2014.05.020 0925-4439/© 2014 Published by Elsevier B.V.

Please cite this article as: S. Kobayashi, Q. Liang, Autophagy and mitophagy in diabetic cardiomyopathy, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbadis.2014.05.020

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Autophagy is the major cellular pathway for degrading and recycling long-lived proteins and organelles. It begins with the formation of double-membrane vesicles termed autophagosomes that sequester targeted cell constituents and fuse with the lysosomes to form autolysosomes (Fig. 1). The inner membrane and the contents of the autolysosomes are degraded by the lysosomal enzymes and recycled. More than 30 autophagy-related (Atg) genes encode proteins essential for the generation and maturation of autophagosomes and autolysosomes which are collectively called autophagic vacuoles (AVs). Induction of autophagy is tightly controlled by many positive and negative regulators. Forming a complex with several partners, including Beclin 1/Atg6, Atg14L, UVRAG, Ambra1, vacuolar protein sorting 15 (VPS15), and Bif-1, the class III phosphatidylinositol 3-kinase (PI3K or VPS34) is required for autophagy induction. When autophagy is initiated, the microtubule-associated protein 1 light chain 3 (LC3-I/ Atg8) is conjugated to phosphatidylethanolamine (PE) by Atg7 and Atg3 to form LC3-II. LC3-II is then incorporated into both the inner and the outer membranes of the autophagosomes and remains membranebound until after autolysosomes are formed. LC3-II on the inner membrane is degraded by lysosomal proteases, while LC3-II on the outer membrane is recycled back to the cytosolic pool of free LC3 [33]. The

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Atg12–Atg5–Atg16 complex is essential for the formation of LC3-II and autophagosomes [31]. The mechanistic or mammalian target of rapamycin complex 1 (mTORC1) pathway, activated by insulin, growth factors and many metabolic signals, is well known to inhibit autophagy, presumably through phosphorylating and inactivating autophagyrelated protein kinase 1 (Atg1), whose mammalian homolog is known as Unc-51-like kinase 1 (ULK1) [34]. As an energy sensor, the AMPactivated protein kinase (AMPK) stimulates autophagy through multiple mechanisms. For example, AMPK competes with mTOR to phosphorylate and activate ULK1 [34]. It also phosphorylates tuberous sclerosis complex 2 (TSC2) and regulatory associated protein of mTOR (Raptor) leading to the inhibition of mTORC1 [35,36]. AMPK induces, phosphorylates and activates the FoxO transcription factors that in turn promote autophagy [37–39]. In addition, AMPK can phosphorylate JNK1 [40] and Beclin 1 [41], respectively, resulting in the activation of the Vps34 complex and the induction of autophagy. Autophagy plays an important role in the maintenance of normal heart function and morphology [42–45]. At baseline, autophagy functions as a cytoplasmic quality control mechanism to remove protein aggregates and damaged organelles. Thus, disruption of autophagy by ablating Atg5 gene results in cardiac dysfunction in old mice [46] and worsens pressure overload-induced cardiac remodeling and heart failure [47]. Cardiac specific ablation of the Class III PI3K/vacuolar protein sorting 34 (Vps34), a critical regulator of autophagy, reduces autophagy leading to cardiac hypertrophy and dysfunction [48]. Moreover, autophagic activity declines with aging in rodents and humans, which may contribute to the increased incidence of heart disease with aging [49]. In response to starvation or ischemia, autophagy is activated to allow recycling of metabolic substrates and maintenance of energy generation for myocardial survival [50,51]. Consistently, enhanced autophagy in chronically ischemic myocardium is associated with reduced myocardial apoptosis [52]. Ischemia preconditioning-induced cardioprotection may be partially mediated by autophagy [53]. In addition, haploinsufficiency of the Beclin 1 gene (Beclin 1+/−) accelerates heart failure in desmin-related cardiomyopathy [54] and abolishes rapamycin-conferred cardioprotection against ischemic injury [24]. These observations demonstrate a protective role for autophagy under these conditions. However, under other conditions, dysregulated autophagy appears to be detrimental to the heart, probably due to excessive non-discriminative self-digestion of essential cellular constituents or enzyme leakage from lysosomes or autolysosomes. For instance, diphtheria toxin and the anticancer drug doxorubicin each can induce autophagy, which triggers heart failure rather than protects the heart [55,56]. Also, Beclin 1+/− mice are protected from cardiac damage

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mitochondrial quality control through autophagy, an endogenous cellular mechanism responsible for mitochondrial degradation. Recent studies have demonstrated that autophagy is inhibited in the hearts of type 1 diabetic mice [19–22] and several forms of metabolic syndrome and type 2 diabetic animal models [23–26], suggesting that the inhibition of autophagy may contribute to diabetic cardiomyopathy. However, in the case of type 2 diabetes, studies have not produced consistent results to support a general protective role of autophagy in diabetic cardiac injury. More surprisingly, in type 1 diabetic mouse models, the diminished autophagy appears to be an adaptive response that limits diabetic cardiac injury. This effect may be related to an upregulation of a non-canonical alternative autophagy and a restoration of the selective mitophagy. In this review, we will summarize the available evidence that links autophagy and mitophagy to diabetic cardiac injury and discuss the potential functional roles of these two pathways in the pathogenesis of diabetic cardiomyopathy. This review is not intended to give an exhaustive description of the machinery, detection methods and regulatory mechanisms of autophagy or mitophagy. These topics have been covered by excellent review articles elsewhere [27–32].

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S. Kobayashi, Q. Liang / Biochimica et Biophysica Acta xxx (2014) xxx–xxx

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Fig. 1. Diabetes inhibits cardiac autophagy. Hyperglycemia (type 1 diabetes), hyperinsulinemia (type 2 diabetes) and other metabolic signals inhibit AMPK and activate mTOR leading to the inactivation of ULK1, a kinase essential for autophagy initiation. Autophagy begins with the formation of double-membrane vesicles termed autophagosomes that sequester targeted cell constituents and fuse with the lysosomes to form autolysosomes where the cargos are degraded. Many proteins participate in the formation of autophagosomes such as class III PI3K, Beclin 1, LC3, and Atg12–Atg5–Atg16 complex.


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4. Mitophagy, a selective form of autophagy

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Autophagy is a survival pathway that allows the cell to maintain energy homeostasis in response to starvation or nutrient deprivation. Conversely, autophagy can also trigger cell death upon stimulation by various harmful stresses. Under both scenarios, the induced autophagy has long been thought to be a non-selective bulk degradation pathway that indiscriminately eliminates cellular components including mitochondria. However, autophagy can become highly selective when a specific organelle is exclusively targeted and escorted into autophagosomes which then transport the cargo to the lysosomes for degradation [14]. When the destined cargo is mitochondria, it is termed mitophagy, meaning the degradation of mitochondria through the autophagic process. Although activation of general autophagy may be accompanied by increased mitophagy under certain conditions, it is now very clear that the functional status of general bulk autophagy may not necessarily reflect the activity of the selective mitophagy. For example, mitophagy can be induced under nutrient-rich conditions to remove superfluous or injured mitochondria when general autophagy is not activated or even inhibited [28]. Conversely, starvation activates autophagy in several cell types, including muscle cells. However, mitochondrial degradation is not increased correspondingly. Instead, mitophagy is inhibited during starvation, which is accompanied by increased mitochondrial elongation [5]. Similarly, cyclosporin A can induce general autophagy in rat kidney cells [68] and in mouse muscle cells [69], but it attenuates mitophagy in human fibroblasts. Collectively, these observations suggest that general autophagy and selective mitophagy can change in

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Mitochondria are essential for energy production and metabolism in a cell. Ironically, mitochondria are also critically involved in cell death pathways. Therefore, strict mitochondrial quality control mechanisms exist in the cell to ensure that metabolic functions are efficiently executed and cell death is appropriately orchestrated when needed. Mitochondrial quality control can be performed at multiple points during the mitochondrial life cycle, ranging from biogenesis, ATP production, protein folding, fusion and fission, motility, and degradation. Mitochondrial degradation through autophagy is the important final quality control mechanism for maintaining a healthy and functional mitochondrial network. Altered autophagy is closely associated with mitochondrial dysfunction, suggesting a potential causative relationship between the two. Indeed, autophagic activity declines with aging in rodents and humans [49], which is accompanied by increased mitochondria injury and enhanced ROS generation [62,63]. Mice deficient in Atg5 developed cardiac hypertrophy with impaired left ventricular function at 10 months of age [46] and had worse cardiac remodeling and heart failure in response to pressure overload [47]. The cardiac dysfunction was associated with increased aggregation of abnormal proteins and enlarged or collapsed mitochondria that had diminished mitochondrial respiratory functions. Conversely, caloric restriction is sufficient to accelerate cardiac autophagic flux [64,65] and simultaneously reduce mitochondrial oxidative damage in the heart [49,65–67]. These results suggest that autophagy plays a very important role in maintaining normal mitochondrial structure and function in the heart.

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opposite directions and they are regulated by different signaling pathways [70,71]. How exactly mitophagy achieves its selectivity and specificity is under intense research. Several mechanisms have been identified that confer the selective nature of mitophagy. Mitophagy is closely associated with mitochondrial fission, a process that splits large mitochondria into smaller daughter mitochondria. Controlled mainly by dynamin-related protein 1 (Drp1), mitochondrial fission events segregate damaged segments of mitochondria and facilitate their removal by mitophagy [72]. Inhibition of fission by inactivating Drp1 prevents mitophagy, suggesting that fission may be required for mitophagy [28]. Several pathways have been shown to regulate the initiation of mitophagy (Fig. 2). A common trigger for mitophagy is the mitochondrial depolarization induced by various stimuli. When dysfunctional mitochondria lose their membrane potential ΔΨm, the serine/threonine protein kinase PINK1 (phosphatase and tensin homolog-induced putative kinase 1) becomes activated and stabilized on the mitochondrial outer membrane [73]. The activated PINK1 then phosphorylates specific proteins including mitofusin 2 (Mfn2) that serves as a receptor to recruit Parkin [74], an E3 ubiquitin (Ub) ligase that normally resides in the cytosol. Upon translocation to depolarized mitochondria, Parkin is phosphorylated at serine 65 by PINK1 and becomes activated [75]. Interestingly, the full activation of Parkin requires PINK1 to phosphorylate ubiquitin at serine 65 as well [76]. The activated Parkin then ubiquitinates mitochondrial proteins including voltagedependent anion channel 1 (VDAC1), Mfn1 and Mfn2 [77–84]. These ubiquitinated mitochondria bind p62 and HDAC6 through the ubiquitinbinding domain and are transported along microtubules to cluster in the perinuclear region [85,86]. P62 then recruits autophagosomal membranes via LC3 through its LC3-interacting domain, leading to mitochondrial clearance in the lysosome [86,87]. Another E3 ligase SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) is downstream of Parkin and promotes mitophagy independently of its catalytic activity [88]. In addition, NIX or BNIP3 and FUNDC1 may serve as mitophagy receptors that bridge mitochondria and LC3 to selectively induce mitochondrial degradation [2–4]. NIX or Bnip3 is inserted into the outer mitochondrial membrane through its C-terminal transmembrane domains, and recruits autophagy machinery by directly binding to LC3/GABARAP proteins on the autophagosome via the N-terminal LC3-interacting motifs [89,90]. Also, NIX and BNIP3 may directly trigger mitochondrial depolarization, which by itself has been shown to be sufficient to induce mitophagy [72,91]. Thus far, it remains controversial whether and how NIX/BNIP3 interacts with Parkin to regulate mitophagy. Of note, both NIX and BNIP3 can induce cell death, but it is currently unclear how the pro-death and pro-mitophagy functions of NIX or BNIP3 are coordinated or differentially regulated under normal or disease conditions [3]. Another mitophagy receptor is FUNDC1, a mitochondrial outer-membrane protein that recruits the autophagosome through its typical LC3-binding motif similar to NIX/ BNIP3. FUNDC1-mediated mitophagy is inhibited by its phosphorylation at tyrosine 18 in the LC3 interacting motif by Src kinase [4], but enhanced by its phosphorylation at serine 17 by ULK1 [92]. FUNDC1-induced mitophagy is Atg5 dependent but Beclin 1 independent. It does not seem to require Parkin since FUNDC1 was sufficient to induce mitophagy in HeLa cells that do not express Parkin. Unlike NIX or BNIP3, FUNDC1 does not induce cell death, suggesting a unique functional role for FUNDC1 in mitochondrial quality control that may be harnessed for therapeutic purposes [4]. Mitophagy is a process in which dysfunctional or otherwise depolarized mitochondria are selectively sequestered by autophagic vacuoles and subsequently degraded within the lysosomes (Fig. 2). As such, the occurrence of mitophagy can be determined by the colocalization of a mitochondrial protein with a lysosomal or autophagosomal protein. However, this approach suffers from low resolution and low specificity. Transmission electron microscopy can provide direct evidence for mitophagy but it is hard to quantify. A novel Rosella mitophagy reporter has been described in Yeast that allows direct visualization and quantification of the mitochondria that are degraded through the mitophagic

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induced by reperfusion [50] and pressure overload [57]. Loss of mTORC1 signaling by ablating mTOR [58] or Raptor [59] gene renders mice susceptible to heart failure, which is associated with enhanced autophagy. Cardiac specific deletion of the insulin receptor genes induces excessive autophagy, leading to myocyte loss, heart failure, and premature death [60]. Collectively, these contrasting results underscore the dichotomous nature of autophagy that could be either protective or detrimental depending on the specific context [50,61]. As a result, either activation or inhibition of autophagy can be a viable therapeutic strategy in heart failure of different origins.

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Fig. 2. An illustration of the mitophagic pathways. Damaged and depolarized mitochondrial segments are segregated through Drp1-mediated fission. PINK1 is activated upon mitochondrial depolarization and promotes Parkin translocation from the cytosol to the damaged mitochondria. Parkin ubiquitinates mitochondrial proteins that bind adaptor proteins p62 and HDAC6. The latter two recruit autophagosomal membranes through LC3 triggering mitochondrial clearance. Alternatively, Nix or BNIP3 and FUNDC1 may serve as receptors that bridge mitochondria and LC3 to induce mitophagy independently of Parkin.

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5. Mitophagy and cardiac homeostasis

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Given its importance in maintaining a healthy mitochondrial network, mitophagy has been shown, not surprisingly, to be essential for myocardial protection under both physiological and pathological conditions [96–103]. For instance, overexpression of Parkin is sufficient to induce mitophagy when mitochondria lose their membrane potential [104] and to prevent cardiac dysfunction in aged mice [100]. Conversely, inhibition of mitophagy respectively by Parkin deficiency [101], SMURF1-deficiency [88] or BNIP3 and NIX deficiency [105] leads to an accumulation of abnormal mitochondria in cardiomyocytes. Parkin ablation abolishes the cardioprotective effect of ischemic preconditioning [96] and results in more severe cardiac injury following myocardial infarction [97]. Together, these results demonstrate an indispensable role for mitophagy in maintaining cardiac homeostasis under several

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process [93]. Rosella is a mitochondria-targeted dual-emission biosensor comprising a pH-stable red fluorescent protein (RFP) linked to a pHsensitive green fluorescent protein (GFP). Mitochondria that appear green or yellow on merged fluorescent images are located in the cytosolic compartments, while those who give rise to only red fluorescence are being degraded within the autolysosomes where the pH is low and the GFP is quenched. A similar reporter mCherry-GFP-FIS1 was used to quantify mitophagy in U2OS cells and SH-SY5Y cells [94]. In addition, Keima, a coral-derived acid-stable fluorescent protein, has been used to monitor mitophagy in mouse embryonic fibroblast cells [95]. Keima emits a red fluorescent signal at acidic pH (586 nm) and a green fluorescent signal at higher pH (438 nm). Similar to Rosella and mCherry-GFP-FIS1, Keima-labeled mitochondria that appear red are being degraded within the autolysosomes. It would greatly facilitate mitophagy research at the whole animal level if Rosella, mCherry-GFP-FIS1 or Keima mitophagy reporter mice can be constructed.

conditions. However, it is currently unknown whether excessive mitophagy can cause heart damage in any cardiac or systemic pathologies, despite the fact that ischemia–reperfusion and the deletion of both Mfn 1 and Mfn 2 induce excessive mitochondrial fragmentation and cardiac damage, which may suggest a potential involvement of mitophagy [106,107].

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6. Canonical, non-canonical autophagy and mitophagy

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Canonical autophagy begins with the formation of the autophagosome, the vesicle that engulfs cellular components and delivers them to the lysosome for degradation. A set of autophagyrelated proteins including Atg5 and Atg7 is required for the generation of the autophagosome. However, recent studies have demonstrated the existence of non-canonical forms of autophagy. Dr. Shimizu's group described an Atg5- and Atg7-independent pathway that controls autophagy through the unconventional biogenesis of canonical autophagosomes. This alternative autophagy was regulated by ULK1 and Beclin 1. The formation of the autophagosome depends on the small GTPase Rab9, but not Atg5, which facilitates the fusion of isolation membrane or phagophore with vesicles derived from the trans-Golgi and late endosomes. Interestingly, the Rab9 dependent alternative autophagic pathway is responsible for mitochondrial degradation during erythrocyte differentiation [108], raising the possibility that the Rab9-dependent non-canonical autophagy may also contribute to mitophagy in the heart under certain conditions.

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7. Diabetic heart disease is a major cause of death in diabetic patients 340 Diabetes is a risk factor for the development of various cardiovascu- 341 lar complications, which constitute the leading causes of death in both 342 type 1 and type 2 diabetic populations. The susceptibility of diabetic 343



9. Autophagy is inhibited in the diabetic hearts

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Insulin signaling activates the PI3K–Akt/PKB–mTORC1 pathway not only to stimulate protein synthesis, but also to concurrently inhibit autophagy [123,124]. It was thus hypothesized that insulin deficiency (type 1 diabetes) or insulin resistance (type 2 diabetes) would increase autophagic activity [125]. Consistently, mice deficient in insulin receptor substrates have increased cardiac autophagy [60]. However, diabetes caused by either insulin deficiency or insulin resistance is often accompanied by varying degrees of hyperglycemia, hyperinsulinemia, dyslipidemia and other signaling changes that can also affect the autophagic activity. For example, high levels of glucose can directly inhibit autophagy in cardiomyocytes [126]. Increased palmitic acid can suppress autophagy in hepatocytes [127] but induce autophagy in H9c2 cardiac myoblasts [128]. Accordingly, the ultimate functional status of autophagy in the diabetic heart will reflect a net effect of insulin deficiency or resistance, hyperglycemia and/or other changes associated with diabetes. Indeed, despite insulin deficiency, autophagy is reduced rather than increased in the hearts of OVE26 [19] and streptozotocin (STZ)-induced type 1 diabetic mice [19–21]. Specifically, diabetes reduced the protein levels of LC3-II, a lipidated form of LC3 that is incorporated into the membrane of an autophagic vacuole (AV). The LC3-II levels are a function of both the formation and degradation of the AVs and are proportional to the number of AVs at the time LC3-II is measured [129]. The inhibition of autophagy in both OVE26 and STZ type 1 diabetic hearts was confirmed by the reduced autophagic flux as determined by the difference in LC3-II levels and the GFP-LC3 puncta in the absence and presence of Bafilomycin A1, a lysosomal inhibitor that blocks autophagic degradation [22]. The fact that the mTORC1

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10. The functional role of autophagy in the diabetic hearts

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Previous studies not only have demonstrated an association between altered autophagy and diabetic cardiac injury but also have attempted to address whether the altered autophagy contributes to cardiac injury or promotes myocardial survival. Treatment of OVE26 and STZ diabetic mice with the anti-diabetic drug metformin reduced cardiac injury [19,40]. Similarly, overexpression of heme oxygenase-1 (HO-1) [21] or mitochondrial aldehyde dehydrogenase (ALDH2, this issue: Molecular Basis of Disease Special Issue on: Autophagy & protein quality control) provided cardioprotection in STZ diabetic mice. Metformin, HO-1 and ALDH2 each reversed the inhibited AMPK signaling and autophagy in the diabetic heart. Since AMPK is a critical positive regulator of autophagy, it was suggested that metformin, HO-1 or ALDH2 improved cardiac function in type 1 diabetes through AMPK-mediated upregulation of autophagy. The functional role of autophagy was directly tested in another study using both gain- and loss-of-function mouse

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In diabetes, mitochondria are a predominant source of intracellular reactive oxygen species (ROS) and are themselves a primary target of oxidative injury [17,18]. Damaged mitochondria can further increase ROS production through ROS-induced ROS release [109,110] and may trigger leakage of pro-death factors, setting in motion a vicious cycle to induce cardiomyocyte death [111–115]. Indeed, increased mitochondrial production of ROS and damaged mitochondrial structure and function are commonly seen in the hearts of both type 1 and type 2 diabetic patients and animal models [15,16,115–118]. The causative role of ROS in the pathogenesis of diabetic cardiomyopathy is well established in animal studies by the ability of various antioxidants to reduce diabetic heart injury [9,114,119–122]. However, the efficacy of antioxidant therapy has not been reproduced in diabetic patients thus far [10–14]. The inconsistency between animal studies and clinical trials could result from the heterogeneity of the patient populations and/or the types of antioxidants used. Further research in more homogeneous patients using more robust antioxidants may help resolve this issue. On the other hand, it is possible that antioxidants cannot block continuous formation of ROS despite their ability to scavenge existing ROS. If this is true, a more effective therapeutic strategy for diabetic cardiomyopathy may be to timely eliminate aged and dysfunctional mitochondria which would otherwise constantly generate ROS and release pro-death factors. Presumably, this could be achieved by autophagic sequestration and lysosomal degradation of injured mitochondria, a process termed mitophagy that plays an important role in mitochondrial quality control and cellular homeostasis.

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8. Diabetic cardiomyopathy is closely related to mitochondrial dysfunction and ROS generation

signaling pathway is activated while the AMPK is inhibited in the hearts of type 1 diabetic mice [19–22] provides a mechanistic explanation for the inhibited autophagy (Fig. 1). Cardiac autophagy in type 2 diabetes is reported to be inhibited in a number of studies but it is not as consistent as in type 1 diabetes. For example, cardiac autophagy was inhibited in obesity and metabolic syndrome induced by high fat diet [23–26], but it was activated by fructoseinduced insulin resistance and hyperglycemia [130]. Moreover, a milk fat-based diet was reported to activate autophagy and induce cardiac hypertrophy in mice [131]. Another study reported unchanged cardiac autophagy in mice fed a high fat diet [132]. The different cardiac autophagic responses to diet-induced metabolic changes can be partially explained by the variation in duration of the dietary intervention and the types and relative contents of carbohydrates and lipids in the diets [133]. Of note, not all studies have determined the autophagic flux in the heart, which may contribute to the variation among different reports. Autophagic flux reflects the number of autophagic vacuoles (AVs) that are delivered to and degraded in the lysosome; it can be measured by the difference in the protein levels of the LC3-II or the numbers of AVs in the absence and presence of a lysosomal inhibitor such as chloroquine [134,135] and Bafilomycin A1 [22,136]. The importance of using autophagic flux instead of static levels of LC3-II as a marker for autophagic activity was elegantly demonstrated in a recent study that investigated the protective effects of Akt2 deletion against high fat diet (HFD)induced cardiac dysfunction [26]. Although cardiac LC3-II levels in wild type mice were increased by HFD, they were not an indication of increased autophagic activity. Instead, the accumulated LC3-II was due to an impaired clearance of AVs, as chloroquine did not further elevate cardiac LC3-II levels, suggesting an inhibited autophagic flux in mice fed HFD. However, Akt2 knockout relieved the inhibition and maintained a very high level of autophagic flux as indicated by dramatically increased LC3-II levels by chloroquine [75]. Another useful marker for autophagic activity is p62, a polyubiquitin-binding protein that is degraded by autophagy and its protein levels are inversely related to autophagic activity [47,137,138]. Indeed, HFD inhibited cardiac autophagic flux in mice, which was accompanied by increased p62 protein levels [24–26]. Nevertheless, cardiac p62 levels were increased also in fructose-induced insulin resistance, which was not readily explainable by enhanced autophagy [130]. Measuring autophagic flux may help resolve this issue. Interestingly, the mTORC1 signaling pathway is activated, while the AMPK is inhibited, in the models that do show inhibited cardiac autophagy [24–26], consistent with findings in type 1 diabetic hearts [19,22]. Conversely, fructose-induced cardiac autophagy is associated with reduced phosphorylation of Akt and the mTORC1 downstream target ribosomal protein S6 [130]. Since mTORC1 negatively, while AMPK positively, regulates autophagy, the functional status of cardiac autophagy in diet-induced diabetes may be predicted by the activities of mTORC1 and/or AMPK in the heart (Fig. 1).

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patients to heart damage may result from diabetes-associated risk factors such as obesity, hypercholesterolemia, atherosclerosis and hypertension. However, a heart muscle-specific disease independent of vascular pathology, namely diabetic cardiomyopathy, has been recognized as an important causative factor for the heightened risk of heart failure and mortality in diabetic patients [6,7].

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It is not readily explained why inhibition of cardiac autophagy appears adaptive in type 1 diabetic models but maladaptive in most HFD-induced type 2 diabetes. This may be related to the difference in etiologies and coexisting conditions between type 1 and type 2 diabetes. For example, HFD-induced diabetes, but not STZ or OVE26 diabetes, is accompanied by overt obesity and metabolic syndrome that may contribute to the different natures of the suppressed autophagy in the hearts of type 1 and type 2 diabetic mice. On the other hand, the role of cardiac autophagy in HFD-induced type 2 diabetic mice was tested mostly by using rapamycin or mTOR+/− mice [24,25]. It is possible that the beneficial effects of rapamycin or mTOR deficiency on type 2 diabetic hearts may not be mediated exclusively through autophagy restoration given that rapamycin or mTOR deficiency can activate other signaling pathways such as Akt [58,145,146] that may contribute to cardioprotection. Also, the increased mTOR activity in the hearts of both type 1 and type 2 diabetic mice may be an adaptive response since overexpression of mTOR was shown to protect from cardiac dysfunction in pathological hypertrophy [147]. It will be of interest to investigate if autophagy is inhibited in the mTOR transgenic hearts and if and how diabetic injury will be affected by mTOR overexpression. Should mTOR overexpression turn out to inhibit autophagy and reduce cardiac injury in HFD-induced diabetes, it would suggest that the inhibited autophagy may also be an adaptive response in type 2 diabetes and that the beneficial effects of rapamycin or mTOR deficiency on type 2 diabetic hearts are mediated through mechanisms other than autophagy restoration. Apparently, further research is required to resolve this issue.

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The functional status of general autophagy may not necessarily reflect the activity of the selective mitophagy. Indeed, autophagy is inhibited in the diabetic heart as early as 3 weeks after STZ injection, but mitophagy is not reduced until advanced stages. More intriguingly, mice deficient in Beclin 1 or Atg16 had partially restored mitophagy under overt diabetic conditions [22] as assessed by the expression and mitochondrial localization of PINK1, Parkin, and the lysosomalassociated membrane protein 1 (LAMP1). These results suggest that the restored mitophagy may have accounted for the attenuated diabetic cardiac injury in autophagy-deficient mice, which is supported by the protective role of Parkin-mediated mitophagy in pancreatic β-cell function in diabetes [148]. It is also very clear that mitophagy must be mechanistically separable from general bulk autophagy to ensure the selective nature of mitophagy that eliminates only dysfunctional mitochondria under diabetic conditions. Nevertheless, the functional role of mitophagy and the specific regulatory mechanisms of mitophagy in the diabetic heart remain to be determined. Interestingly, the reduced cardiac autophagy in type 1 diabetes was associated with increased expression of Rab9 [22], a small GTP binding protein implicated in a non-canonical alternative autophagy that requires Rab9 and is responsible for mitochondrial degradation during erythrocyte maturation in the absence of Atg5 [108]. Indeed, the increase in Rab9 protein levels was more pronounced in the mitochondrial fraction, suggesting that Rab9 may be translocated to mitochondria to mediate their degradation in the diabetic heart. Consistently, there is increased colocalization of Rab9 with lysosomes in the diabetic Beclin 1+/− hearts [22]. It is thus possible that when canonical autophagy is inhibited, alternative autophagy is up-regulated, which may trigger mitophagy to protect the diabetic heart (Fig. 3). This attractive hypothesis remains to be directly tested by using Rab9 overexpressing and deficient mice, or more specifically, by disrupting the mitochondrial or lysosomal localization of Rab9. Additionally, the role of other non-canonical autophagic pathways in the diabetic heart remains to be explored such as Beclin 1-independent but Atg7 dependent autophagy as described previously in cancer cells [149]. It is expected that the next few years will see an

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models. Surprisingly, the type 1 diabetes-induced cardiac damage was attenuated in Beclin 1 deficient (Beclin 1+/−) mice and exacerbated by Beclin 1 overexpression [22], suggesting a detrimental role for autophagy in the type 1 diabetic heart. Of note, a recent study questioned the role of Beclin 1 as a positive regulator of autophagy. Specifically, Dr. Diwan's group made an interesting observation that knockdown of Beclin 1 enhanced the clearance of AVs in cultured cardiomyocytes, suggesting that Beclin 1 deficiency may accelerate rather than reduce autophagic flux [91]. However, this possibility was not supported by the fact that diabetes resulted in a greater inhibition of autophagic flux in Beclin 1+/− hearts and did not reduce autophagic flux in Beclin 1 transgenic hearts as compared with wild type controls [22]. Moreover, diabetic cardiac injury was also reduced in mice deficient in Atg16, a component of the Atg12–Atg5–Atg16 protein complex essential for autophagosome formation [22]. This result further supported the conclusion that the diminished autophagy is an adaptive response that limits cardiac injury in type 1 diabetes. The results also suggested that the cardioprotective effects of metformin, HO-1 or ALDH2 on the diabetic heart may not necessarily be mediated by autophagy. Instead, metformin, HO-1 or ALDH2 may protect the diabetic heart through other AMPK-induced signaling and metabolic changes. For example, AMPK inhibits cellular processes that consume ATP and activates ATP-generating pathways. It enhances mitochondrial oxidation of fatty acids [139] and promotes mitochondrial biogenesis [140]. These autophagy-independent effects of AMPK may account for the ability of metformin, HO-1 or ALDH2 to protect the diabetic heart. It is also possible that metformin, HO-1 or ALDH2 may use AMPK-independent mechanisms to confer cardioprotection in diabetes [141]. This hypothesis is supported by a recent study showing that metformin can still robustly protect against pressure overloadinduced pathological cardiac remodeling in mice deficient in AMPK signaling [142]. Apparently, the exact molecular mechanism by which metformin, HO-1 or ALDH2 protects the type 1 diabetic heart remains to be elucidated. In contrast to its adaptive nature in type 1 diabetes, the inhibited cardiac autophagy in most HFD-induced type 2 diabetic models appears to be maladaptive, and thus strategies to enhancing autophagy may be cardioprotective. For example, either cardiac specific haploinsufficiency of mTOR (mTOR+/−) or rapamycin treatment was able to restore cardiac autophagy in mice fed a HFD [24] and concurrently abolish the exaggeration of myocardial infarction triggered by a 3-hour coronary artery ligation. Rapamycin was unable to reduce the infarct size in HFD-fed Beclin-1+/− mice where autophagy could not be restored by rapamycin. Also, Akt2 gene ablation inhibited mTORC1 activation and enhanced cardiac autophagic flux in mice fed a HFD, which was accompanied by reduced cardiac hypertrophy and improved heart function [26]. Furthermore, adiponectin deficiency augmented HFD-induced accumulation of p62 and exacerbated HFD-induced cardiac remodeling and dysfunction. These detrimental effects were abolished by rapamycin treatment [25]. Collectively, these results suggested that autophagy reactivation is responsible for the beneficial effects of mTORC1 inhibition in HFD-fed mice. Rapamycin was also shown to improve cardiac function in genetic type 2 diabetic mice deficient in leptin receptor (db/db) although the protective effects may not involve autophagy [143]. However, some studies reported activated cardiac autophagy in diet-induced diabetes and suggested a harmful role for autophagy under these conditions. For instance, the fructose-induced type 2 diabetes was associated with suppressed survival signaling and increased cardiac pathology [71]. A milk fat-based diet led to adverse cardiac remodeling in mice [131]. These two studies proposed that the enhanced autophagy contributed to cardiac injury in diet-induced diabetes, but this hypothesis remains to be directly tested by using an autophagy deficient mouse model. Nevertheless, by using the autophagy inhibitor 3-methyladenine, increased autophagy was shown to exacerbate ischemic brain injury in a type 2 diabetic mouse model generated by combined administration of STZ and nicotinamide [144].

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and by grants from the National Center for Research Resources (5P20RR017662-10) and the National Institute of General Medical Sciences (8 P20 GM103455-10) from the NIH. SK was supported by an Advanced Postdoctoral Fellowship from the Juvenile Diabetes Research Foundation (JDRF).

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Autophagy is inhibited in the diabetic hearts. Whereas the diminished autophagy appears to contribute to cardiac injury in several type 2 diabetic animal models, it turns out to be cardioprotective in type 1 diabetes, which is linked to non-canonical alternative autophagy and mitophagy (Fig. 3). There are many open questions that remain to be addressed. For example, the functional role of mitophagy or Rab9dependent alternative autophagy has not been directly tested in the diabetic hearts by using either gain- or loss-of-functional models. It is also not clear whether mitophagy uses the core machinery of autophagy or alternative autophagy to perform its function. Given that mitochondria may provide a membrane source for the autophagosome [150], how does the cell determine whether just to contribute some of the mitochondrial membrane to autophagosomal formation or to induce mitophagy altogether? For the same reason, is it possible that mitochondrial membrane can directly fuse with the lysosomes to form mitolysosomes thus triggering mitophagy without the involvement of autophagosomes? How are general autophagy and selective mitophagy differentially regulated? Is it the same mitophagic pathway that mediates the constitutive turnover of mitochondria at baseline and the clearance of injured mitochondria in diabetes? How can mitophagy be specifically upregulated without affecting general autophagy? Under what conditions, if any, does mitophagy become detrimental and contribute to cell death? Answers to these questions will help elucidate the molecular mechanisms that regulate and coordinate these different autophagic pathways so that their therapeutic potential could be harnessed for the treatment of diabetic cardiomyopathy and heart failure.

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The research in QL's laboratory was supported by a Career Development Grant (1-09-CD-09) from the American Diabetes Association

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explosion of studies aiming to understand the molecular mechanisms that regulate these different autophagic or mitophagic pathways.

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Fig. 3. The inhibited autophagy is cardioprotective in type 1 diabetes, which may be explained by the increased Rab9-related alternative autophagy and restored mitophagy.


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Unbreak my heart: targeting mitochondrial autophagy in diabetic cardiomyopathy.

Intracellular pH Modulates Autophagy and Mitophagy.

PINK1 deficiency enhances autophagy and mitophagy induction.

Regulation of autophagy and mitophagy by nutrient availability and acetylation.

Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway.

SIRT5 regulation of ammonia-induced autophagy and mitophagy.

Diabetic cardiomyopathy.

Spatiotemporal dynamics of autophagy receptors in selective mitophagy.

Mir30c Is Involved in Diabetic Cardiomyopathy through Regulation of Cardiac Autophagy via BECN1.

mitophagy in the heart.

Autophagy in diabetic nephropathy.

MicroRNAs in diabetic cardiomyopathy and clinical perspectives.

Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy.

Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy.

Inducing mitophagy in diabetic platelets protects against severe oxidative stress.

Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy.

Dihydromyricetin Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Mice.

Diabetic cardiomyopathy: the preclinical phase.

Diabetic cardiomyopathy: catabolism driving metabolism.

Diabetic Cardiomyopathy: An Immunometabolic Perspective.

Nitric oxide synthases and diabetic cardiomyopathy.

Diagnostic approaches for diabetic cardiomyopathy.

Endothelial cell-cardiomyocyte crosstalk in diabetic cardiomyopathy.

Mitofilin: Key factor in diabetic cardiomyopathy?