Autophagy is a catabolic process through which eukaryotic cells degrade disposable, ectopic or damaged cytoplasmic material.
The inhibition or hyperactivation of autophagy has been linked to the pathogenesis of a wide range of clinically relevant conditions that affect all organs, including neurodegeneration, cardiac disorders and cancer.
Pharmacological or nutritional interventions that activate or inhibit autophagy are expected to mediate beneficial effects in multiple clinical settings.
The development of clinically viable modulators of autophagy has been hampered by specificity issues, technical problems and murine models that suffer from multiple limitations.
Overcoming these obstacles is key to obtaining further insights into autophagy and its intricate relationship with other cellular processes, and hence to unlocking the full therapeutic potential of autophagy modulators.
Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.
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Noda, N. N. & Inagaki, F. Mechanisms of autophagy. Annu. Rev. Biophys. 44, 101–122 (2015). This comprehensive review describes the molecular mechanisms that control autophagic responses and their regulation.
Li, W. W., Li, J. & Bao, J. K. Microautophagy: lesser-known self-eating. Cell. Mol. Life Sci. 69, 1125–1136 (2012).
Cuervo, A. M. & Wong, E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 24, 92–104 (2014).
Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).
Sica, V. et al. Organelle-specific initiation of autophagy. Mol. Cell 59, 522–539 (2015).
Green, D. R. & Levine, B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell 157, 65–75 (2014).
He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).
Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011). This article demonstrates that autophagy is strictly required for mouse cancer cells that succumb to some chemotherapeutics to release danger signals and hence alert the immune system of a threatening situation.
Galluzzi, L., Bravo- San Pedro, J. M., Blomgren, K. & Kroemer, G. Autophagy in acute brain injury. Nat. Rev. Neurosci. 17, 467–484 (2016).
Martinez, J. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17, 893–906 (2015). This is the first identification of molecules that are specifically required for LAP but dispensable for canonical autophagy, including RUBCN.
Kenific, C. M., Wittmann, T. & Debnath, J. Autophagy in adhesion and migration. J. Cell Sci. 129, 3685–3693 (2016).
Ponpuak, M. et al. Secretory autophagy. Curr. Opin. Cell Biol. 35, 106–116 (2015).
Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).
Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).
Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).
Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003). References 15 and 16 provide the first demonstration that the Becn1−/− genotype is embryonically lethal and that Becn1+/− mice are more susceptible to spontaneous carcinogenesis than their wild-type littermates.
Yoshii, S. R. et al. Systemic analysis of Atg5-null mice rescued from neonatal lethality by transgenic ATG5 expression in neurons. Dev. Cell 39, 116–130 (2016).
Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006). References 18 and 19 were the first to demonstrate that neuron-specific deletion of Atg5 or Atg7 causes a progressive neurodegenerative disorder that is associated with premature mortality.
Ross, C. A. & Poirier, M. A. Opinion: what is the role of protein aggregation in neurodegeneration? Nat. Rev. Mol. Cell Biol. 6, 891–898 (2005).
Menzies, F. M., Fleming, A. & Rubinsztein, D. C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16, 345–357 (2015).
Crews, L. et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of α-synucleinopathy. PLoS ONE 5, e9313 (2010).
Bang, Y., Kim, K. S., Seol, W. & Choi, H. J. LRRK2 interferes with aggresome formation for autophagic clearance. Mol. Cell. Neurosci. 75, 71–80 (2016).
Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).
Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010).
Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).
Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).
Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).
Aguado, C. et al. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum. Mol. Genet. 19, 2867–2876 (2010).
Saitsu, H. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat. Genet. 45, 445–449 (2013).
Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PLoS ONE 5, e9979 (2010).
Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: effects on cognitive impairments. J. Biol. Chem. 285, 13107–13120 (2010).
Vingtdeux, V. et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J. Biol. Chem. 285, 9100–9113 (2010).
Yang, D. S. et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 134, 258–277 (2011).
Sun, B. et al. Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron 60, 247–257 (2008).
Spencer, B. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in α-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29, 13578–13588 (2009).
Decressac, M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc. Natl Acad. Sci. USA 110, E1817–E1826 (2013).
Siddiqui, A. et al. Mitochondrial quality control via the PGC1α-TFEB signaling pathway is compromised by parkin Q311X mutation but independently restored by rapamycin. J. Neurosci. 35, 12833–12844 (2015).
Rodriguez-Navarro, J. A. et al. Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol. Dis. 39, 423–438 (2010).
Liu, K., Shi, N., Sun, Y., Zhang, T. & Sun, X. Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. Neurochem. Res. 38, 201–207 (2013).
Dehay, B. et al. Pathogenic lysosomal depletion in Parkinson's disease. J. Neurosci. 30, 12535–12544 (2010).
Li, X. Z. et al. Therapeutic effects of valproate combined with lithium carbonate on MPTP-induced parkinsonism in mice: possible mediation through enhanced autophagy. Int. J. Neurosci. 123, 73–79 (2013).
Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S. & Greene, L. A. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J. Neurosci. 30, 1166–1175 (2010).
Jiang, J., Jiang, J., Zuo, Y. & Gu, Z. Rapamycin protects the mitochondria against oxidative stress and apoptosis in a rat model of Parkinson's disease. Int. J. Mol. Med. 31, 825–832 (2013).
Pan, T. et al. Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol. Dis. 32, 16–25 (2008).
Tain, L. S. et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat. Neurosci. 12, 1129–1135 (2009).
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
Ejlerskov, P. et al. Lack of neuronal IFN-β-IFNAR causes lewy body- and Parkinson's disease-like dementia. Cell 163, 324–339 (2015). This article demonstrates that defective type I interferon signalling promotes parkinsonism in mice, as it imposes an autophagic defect that is accompanied by the accumulation of senescent mitochondria.
Xilouri, M. et al. Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats. Autophagy 12, 2230–2247 (2016).
Sarkar, S. et al. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum. Mol. Genet. 17, 170–178 (2008).
Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).
Lee, J. H. et al. Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85, 303–315 (2015).
Castillo, K. et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9, 1308–1320 (2013).
Zhang, K. et al. Food restriction-induced autophagy modulates degradation of mutant SOD1 in an amyotrophic lateral sclerosis mouse model. Brain Res. 1519, 112–119 (2013).
Feng, H. L. et al. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155, 567–572 (2008).
Zhang, X. et al. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7, 412–425 (2011).
Nassif, M. et al. Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy 10, 1256–1271 (2014).
Guha, P., Harraz, M. M. & Snyder, S. H. Cocaine elicits autophagic cytotoxicity via a nitric oxide-GAPDH signaling cascade. Proc. Natl Acad. Sci. USA 113, 1417–1422 (2016).
Sutton, L. P. & Caron, M. G. Essential role of D1R in the regulation of mTOR complex1 signaling induced by cocaine. Neuropharmacology 99, 610–619 (2015).
Wu, J., McCallum, S. E., Glick, S. D. & Huang, Y. Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization. Neuroscience 172, 104–109 (2011).
Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R. & Sharma, P. L. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur. J. Pharmacol. 698, 6–18 (2013).
Stamoula, E. et al. Low dose administration of glutamate triggers a non-apoptotic, autophagic response in PC12 cells. Cell. Physiol. Biochem. 37, 1750–1758 (2015).
Wang, Y. et al. An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid. Autophagy 4, 214–226 (2008).
Perez-Carrion, M. D. et al. Dendrimer-mediated siRNA delivery knocks down Beclin 1 and potentiates NMDA-mediated toxicity in rat cortical neurons. J. Neurochem. 120, 259–268 (2012).
Kulbe, J. R., Mulcahy Levy, J. M., Coultrap, S. J., Thorburn, A. & Bayer, K. U. Excitotoxic glutamate insults block autophagic flux in hippocampal neurons. Brain Res. 1542, 12–19 (2014).
Giorgi, F. S., Biagioni, F., Lenzi, P., Frati, A. & Fornai, F. The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations. J. Neural Transm. (Vienna) 122, 849–862 (2015).
McMahon, J. et al. Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. J. Neurosci. 32, 15704–15714 (2012).
Zeng, L. H., Xu, L., Gutmann, D. H. & Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63, 444–453 (2008).
Zhou, J. et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773–1783 (2009).
Zeng, L. H. et al. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum. Mol. Genet. 20, 445–454 (2011).
Chang, C. F. et al. Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α-synuclein aggregation. J. Pineal Res. 52, 312–321 (2012).
Ginet, V. et al. Involvement of autophagy in hypoxic-excitotoxic neuronal death. Autophagy 10, 846–860 (2014).
Zheng, Y. et al. Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats. J. Pharmacol. Sci. 124, 354–364 (2014).
Papadakis, M. et al. Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nat. Med. 19, 351–357 (2013).
Wang, P. et al. Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate-activated kinase pathway. Ann. Neurol. 69, 360–374 (2011).
Zhang, X. et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy 9, 1321–1333 (2013).
Buckley, K. M. et al. Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp. Transl Stroke Med. 6, 8 (2014).
Zhang, X. et al. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: involvement of PARK2-dependent mitophagy. Autophagy 10, 1801–1813 (2014).
Sheng, R. et al. Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning. Autophagy 6, 482–494 (2010).
Su, J., Zhang, T., Wang, K., Zhu, T. & Li, X. Autophagy activation contributes to the neuroprotection of remote ischemic perconditioning against focal cerebral ischemia in rats. Neurochem. Res. 39, 2068–2077 (2014).
Jiang, T. et al. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br. J. Pharmacol. 171, 3146–3157 (2014).
Jiang, T. et al. Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. Mol. Neurobiol. 51, 220–229 (2015).
Zheng, Y. Q., Liu, J. X., Li, X. Z., Xu, L. & Xu, Y. G. RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats. Acta Pharmacol. Sin. 30, 919–927 (2009).
Cui, D. R. et al. Propofol prevents cerebral ischemia-triggered autophagy activation and cell death in the rat hippocampus through the NF-κB/p53 signaling pathway. Neuroscience 246, 117–132 (2013).
Zheng, C. et al. NAD+ administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia. Neurosci. Lett. 512, 67–71 (2012).
Wen, Y. D. et al. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 4, 762–769 (2008).
Kubota, C. et al. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J. Biol. Chem. 285, 667–674 (2010).
Xin, X. Y. et al. 2-Methoxyestradiol attenuates autophagy activation after global ischemia. Can. J. Neurol. Sci. 38, 631–638 (2011).
Liu, N., Shang, J., Tian, F., Nishi, H. & Abe, K. In vivo optical imaging for evaluating the efficacy of edaravone after transient cerebral ischemia in mice. Brain Res. 1397, 66–75 (2011).
Carloni, S., Buonocore, G. & Balduini, W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol. Dis. 32, 329–339 (2008).
Koike, M. et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am. J. Pathol. 172, 454–469 (2008).
Xie, C. et al. Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury. Autophagy 12, 410–423 (2016). This report provides compelling evidence in support of the concept that efficient autophagic responses in the neurons of newborns contribute to the aetiology of neonatal asphyxia.
Puyal, J., Vaslin, A., Mottier, V. & Clarke, P. G. Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann. Neurol. 66, 378–389 (2009).
Liu, Y. et al. Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc. Natl Acad. Sci. USA 110, 20364–20371 (2013). This is the first description of the mechanisms and pathophysiological relevance of autosis, which is an instance of autophagic cell death that also relies on the plasma membrane Na+/K+-ATPase and hence can be inhibited by cardiac glycosides.
Wang, Z. Y., Liu, W. G., Muharram, A., Wu, Z. Y. & Lin, J. H. Neuroprotective effects of autophagy induced by rapamycin in rat acute spinal cord injury model. Neuroimmunomodulation 21, 257–267 (2014).
Jing, C. H. et al. Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. Neuroscience 213, 144–153 (2012).
Chen, J. et al. Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. J. Pineal Res. 56, 12–19 (2014).
Shao, A. et al. Enhancement of autophagy by histone deacetylase inhibitor Trichostatin A ameliorates neuronal apoptosis after subarachnoid hemorrhage in rats. Mol. Neurobiol. 53, 18–27 (2016).
Zhao, H. et al. Role of autophagy in early brain injury after subarachnoid hemorrhage in rats. Mol. Biol. Rep. 40, 819–827 (2013).
Zhou, Y. et al. Retinoic acid prevents disruption of blood-spinal cord barrier by Iinducing autophagic flux after spinal cord injury. Neurochem. Res. 41, 813–825 (2015).
Erlich, S., Alexandrovich, A., Shohami, E. & Pinkas-Kramarski, R. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26, 86–93 (2007).
Song, Q., Xie, D., Pan, S. & Xu, W. Rapamycin protects neurons from brain contusioninduced inflammatory reaction via modulation of microglial activation. Mol. Med. Rep. 12, 7203–7210 (2015).
Viscomi, M. T. et al. Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage. Autophagy 8, 222–235 (2012).
Cui, C. M. et al. Chloroquine exerts neuroprotection following traumatic brain injury via suppression of inflammation and neuronal autophagic death. Mol. Med. Rep. 12, 2323–2328 (2015).
Luo, C. L. et al. Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice. Neuroscience 184, 54–63 (2011).
Martinet, W., Knaapen, M. W., Kockx, M. M. & De Meyer, G. R. Autophagy in cardiovascular disease. Trends Mol. Med. 13, 482–491 (2007).
Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902–906 (2000).
Nishino, I. et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910 (2000).
Nakai, A. et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat. Med. 13, 619–624 (2007).
Huang, C. et al. Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS ONE 6, e20975 (2011).
Liao, X. et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545–553 (2012).
Oka, T. et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485, 251–255 (2012).
Tannous, P. et al. Autophagy is an adaptive response in desmin-related cardiomyopathy. Proc. Natl Acad. Sci. USA 105, 9745–9750 (2008).
Bhuiyan, M. S. et al. Enhanced autophagy ameliorates cardiac proteinopathy. J. Clin. Invest. 123, 5284–5297 (2013).
Xie, M. et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 129, 1139–1151 (2014).
Sala-Mercado, J. A. et al. Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation 122, S179–S184 (2010).
Sciarretta, S. et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 125, 1134–1146 (2012).
Finckenberg, P. et al. Caloric restriction ameliorates angiotensin II-induced mitochondrial remodeling and cardiac hypertrophy. Hypertension 59, 76–84 (2012).
Bostrom, P. et al. C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143, 1072–1083 (2010).
Shirakabe, A. et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation 133, 1249–1263 (2016).
Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016). This paper shows that the CRM spermidine extends lifespan in mice as it mediates autophagy-dependent cardioprotective effects, and that a spermidine-rich diet is associated with a lower incidence of cardiovascular disorders in humans.
Garg, S., Bourantas, C. & Serruys, P. W. New concepts in the design of drug-eluting coronary stents. Nat. Rev. Cardiol. 10, 248–260 (2013).
Marx, S. O. & Marks, A. R. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 104, 852–855 (2001).
Zhu, H. et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J. Clin. Invest. 117, 1782–1793 (2007).
Matsui, Y. et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 100, 914–922 (2007).
Xu, X. et al. Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J. Biol. Chem. 288, 18077–18092 (2013).
Schneider, J. L. & Cuervo, A. M. Liver autophagy: much more than just taking out the trash. Nat. Rev. Gastroenterol. Hepatol. 11, 187–200 (2014).
Sequea, D. A., Sharma, N., Arias, E. B. & Cartee, G. D. Calorie restriction enhances insulin-stimulated glucose uptake and Akt phosphorylation in both fast-twitch and slow-twitch skeletal muscle of 24-month-old rats. J. Gerontol. A Biol. Sci. Med. Sci. 67, 1279–1285 (2012).
Marcinko, K. et al. High intensity interval training improves liver and adipose tissue insulin sensitivity. Mol. Metab. 4, 903–915 (2015).
Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).
Hatori, M. et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 15, 848–860 (2012).
Leontieva, O. V., Paszkiewicz, G., Demidenko, Z. N. & Blagosklonny, M. V. Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high fat diet. Cell Death Dis. 4, e472 (2013).
Sun, L. et al. Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am. J. Physiol. Endocrinol. Metab. 309, E925–E935 (2015).
Lin, C. W. et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J. Hepatol. 58, 993–999 (2013).
Kim, K. E. et al. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism. Sci. Rep. 6, 30111 (2016).
Song, Y. M. et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy 11, 46–59 (2015).
Hidvegi, T. et al. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229–232 (2010).
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
Schreiber, K. H. et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14, 265–273 (2015).
Mottillo, E. P. et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 24, 118–129 (2016).
Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467–478 (2010).
Ding, W. X. et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology 139, 1740–1752 (2010).
Ni, H. M., Du, K., You, M. & Ding, W. X. Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am. J. Pathol. 183, 1815–1825 (2013).
Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).
Lee, H. Y. et al. Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis. Autophagy 12, 1390–1403 (2016).
Sakaguchi, M. et al. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem. Biophys. Res. Commun. 340, 296–301 (2006).
Ding, D. F. et al. Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am. J. Nephrol. 31, 363–374 (2010).
Tikoo, K., Tripathi, D. N., Kabra, D. G., Sharma, V. & Gaikwad, A. B. Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53. FEBS Lett. 581, 1071–1078 (2007).
Jung, H. S. et al. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318–324 (2008).
Goginashvili, A. et al. Insulin granules. Insulin secretory granules control autophagy in pancreatic beta cells. Science 347, 878–882 (2015). This article provides compelling evidence in support of the concept that insulin granules are degraded by autophagy in pancreatic β -cells as a mechanism that negatively regulates insulin secretion under fasting conditions.
Altshuler-Keylin, S. et al. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 24, 402–419 (2016). This article shows that efficient autophagic responses are required for the beige-to-white fat transition, which is generally coupled to HFD-induced obesity and insulin resistance.
Galluzzi, L. et al. Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856–880 (2015).
Takamura, A. et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795–800 (2011).
Rao, S. et al. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5, 3056 (2014).
Strohecker, A. M. et al. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 3, 1272–1285 (2013).
Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013). References 154–156 provide solid genetic data demonstrating that autophagy inhibits malignant transformation but accelerates tumour progression in the setting of KRAS-driven or BRAF-driven pulmonary or pancreatic carcinogenesis.
Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).
Wei, Y. et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154, 1269–1284 (2013).
Maiuri, M. C. et al. Autophagy regulation by p53. Curr. Opin. Cell Biol. 22, 181–185 (2010).
Wang, R. C. et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956–959 (2012).
Galluzzi, L., Bravo- San Pedro, J. M., Demaria, S., Formenti, S. C. & Kroemer, G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol. 14, 247–258 (2016). This recent review summarizes preclinical and clinical data indicating that autophagy activators, rather than inhibitors, may potentiate the therapeutic effects of anticancer agents that promote, or at least are compatible with, tumour-targeting immune responses.
Guo, J. Y., Xia, B. & White, E. Autophagy-mediated tumor promotion. Cell 155, 1216–1219 (2013).
Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).
Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).
Ladoire, S. et al. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy 11, 1878–1890 (2015).
Puleston, D. J. et al. Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3, e03706 (2014).
Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N. & He, Y. W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204, 25–31 (2007).
Thurston, T. L., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10, 1215–1221 (2009).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).
Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55–62 (2010).
Py, B. F., Lipinski, M. M. & Yuan, J. Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3, 117–125 (2007).
Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).
Shahnazari, S., Namolovan, A., Mogridge, J., Kim, P. K. & Brumell, J. H. Bacterial toxins can inhibit host cell autophagy through cAMP generation. Autophagy 7, 957–965 (2011).
Tattoli, I. et al. Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11, 563–575 (2012).
Choy, A. et al. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338, 1072–1076 (2012). This paper identifies a protein from L. pneumophila that operates as a virulence factor by inhibiting autophagy in host cells upon LC3 deconjugation.
Dong, N. et al. Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1 inactivation to counteract host defenses. Cell 150, 1029–1041 (2012).
Yoshikawa, Y. et al. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat. Cell Biol. 11, 1233–1240 (2009).
Kim, J. J. et al. Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. Cell Host Microbe 11, 457–468 (2012).
Kuo, S. Y. et al. Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics. Proc. Natl Acad. Sci. USA 112, E4281–E4287 (2015).
Lapaquette, P., Bringer, M. A. & Darfeuille-Michaud, A. Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response. Cell. Microbiol. 14, 791–807 (2012).
Miao, Y., Li, G., Zhang, X., Xu, H. & Abraham, S. N. A. TRP channel senses lysosome neutralization by pathogens to trigger their expulsion. Cell 161, 1306–1319 (2015).
Lee, S. et al. Carbon monoxide confers protection in sepsis by enhancing beclin 1-dependent autophagy and phagocytosis. Antioxid. Redox Signal. 20, 432–442 (2014).
Gong, L. et al. The Burkholderia pseudomallei type III secretion system and BopA are required for evasion of LC3-associated phagocytosis. PLoS ONE 6, e17852 (2011).
Lam, G. Y., Cemma, M., Muise, A. M., Higgins, D. E. & Brumell, J. H. Host and bacterial factors that regulate LC3 recruitment to Listeria monocytogenes during the early stages of macrophage infection. Autophagy 9, 985–995 (2013).
Manzanillo, P. S. et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501, 512–516 (2013).
Kimmey, J. M. et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 528, 565–569 (2015). This report demonstrates that ATG5, but not several other components of the canonical autophagic machinery, in monocytes is required for mice to normally control M. tuberculosis infection.
Renna, M. et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 121, 3554–3563 (2011).
Gutierrez, M. G. et al. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell. Microbiol. 7, 981–993 (2005).
Niu, H., Xiong, Q., Yamamoto, A., Hayashi-Nishino, M. & Rikihisa, Y. Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection. Proc. Natl Acad. Sci. USA 109, 20800–20807 (2012). This study provides robust evidence in support of the notion that A. phagocytophilum actively promotes BECN1-dependent autophagic responses in host cells to acquire nutrients for growth.
Raoult, D. et al. Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch. Intern. Med. 159, 167–173 (1999).
Orvedahl, A. et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480, 113–117 (2011).
Liang, X. H. et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 72, 8586–8596 (1998).
Sumpter, R. Jr. et al. Fanconi anemia proteins function in mitophagy and immunity. Cell 165, 867–881 (2016). This is the first demonstration that members of the FANC protein family participate not only in the DNA damage response but also in virophagy and mitophagy.
Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).
Shelly, S., Lukinova, N., Bambina, S., Berman, A. & Cherry, S. Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus. Immunity 30, 588–598 (2009).
Roy, J., Paquette, J. S., Fortin, J. F. & Tremblay, M. J. The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication. Antimicrob. Agents Chemother. 46, 3447–3455 (2002).
Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).
Nicoletti, F. et al. Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin. Clin. Exp. Immunol. 155, 28–34 (2009).
Alirezaei, M., Flynn, C. T., Wood, M. R. & Whitton, J. L. Pancreatic acinar cell-specific autophagy disruption reduces coxsackievirus replication and pathogenesis in vivo. Cell Host Microbe 11, 298–305 (2012).
Nicola, A. M. et al. Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans. Infect. Immun. 80, 3065–3076 (2012).
Kanayama, M. et al. Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity. Nat. Commun. 6, 5779 (2015).
Akoumianaki, T. et al. Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19, 79–90 (2016).
Zhao, Z. et al. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4, 458–469 (2008).
Choi, J. et al. The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40, 924–935 (2014).
Selleck, E. M. et al. A noncanonical autophagy pathway restricts Toxoplasma gondii growth in a strain-specific manner in IFN-γ-activated human cells. mBio 6, e01157–15 (2015).
Flannery, E. L., Chatterjee, A. K. & Winzeler, E. A. Antimalarial drug discovery — approaches and progress towards new medicines. Nat. Rev. Microbiol. 11, 849–862 (2013).
Sullivan, D. J. Jr, Gluzman, I. Y., Russell, D. G. & Goldberg, D. E. On the molecular mechanism of chloroquine's antimalarial action. Proc. Natl Acad. Sci. USA 93, 11865–11870 (1996).
Roetzer, A., Gratz, N., Kovarik, P. & Schuller, C. Autophagy supports Candida glabrata survival during phagocytosis. Cell. Microbiol. 12, 199–216 (2010).
Deretic, V., Saitoh, T. & Akira, S. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13, 722–737 (2013).
Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).
Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).
Dang, J. et al. Gene–gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus. Int. J. Rheum. Dis. 19, 1284–1293 (2016).
Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115–119 (2016). This report elegantly proves that LAP defects, but not defects in canonical autophagy, are associated with impaired efferocytosis, secretion of pro-inflammatory cytokines and spontaneous onset of an SLE-like disorder in mice.
Remijsen, Q. et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res. 21, 290–304 (2011).
Lee, S. J., Silverman, E. & Bargman, J. M. The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat. Rev. Nephrol. 7, 718–729 (2011).
Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).
Henckaerts, L. et al. Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease. Inflamm. Bowel Dis. 17, 1392–1397 (2011).
Kaul, A. et al. Systemic lupus erythematosus. Nat. Rev. Dis. Primers 2, 16039 (2016).
Matsuda, C. et al. Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis. Clin. Exp. Immunol. 148, 348–359 (2007).
Dumortier, J. et al. Everolimus for refractory Crohn's disease: a case report. Inflamm. Bowel Dis. 14, 874–877 (2008).
Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).
van Loosdregt, J. et al. Increased autophagy in CD4+ T cells of rheumatoid arthritis patients results in T-cell hyperactivation and apoptosis resistance. Eur. J. Immunol. 46, 2862–2870 (2016).
Yoshizaki, A. et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 62, 2476–2487 (2010).
Bhattacharya, A., Parillon, X., Zeng, S., Han, S. & Eissa, N. T. Deficiency of autophagy in dendritic cells protects against experimental autoimmune encephalomyelitis. J. Biol. Chem. 289, 26525–26532 (2014).
Prevel, N., Allenbach, Y., Klatzmann, D., Salomon, B. & Benveniste, O. Beneficial role of rapamycin in experimental autoimmune myositis. PLoS ONE 8, e74450 (2013).
Esposito, M. et al. Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation. J. Neuroimmunol. 220, 52–63 (2010).
Zhang, Z. et al. Low dose rapamycin exacerbates autoimmune experimental uveitis. PLoS ONE 7, e36589 (2012).
Teachey, D. T. et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br. J. Haematol. 145, 101–106 (2009).
Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).
Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).
Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).
Lapierre, L. R. et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267 (2013).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This is the first demonstration that administering rapamycin late in life extends the lifespan of mice independently of their genetic background.
Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).
Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).
Colman, R. J. et al. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 5, 3557 (2014).
Madeo, F., Zimmermann, A., Maiuri, M. C. & Kroemer, G. Essential role for autophagy in life span extension. J. Clin. Invest. 125, 85–93 (2015).
Lopez-Otin, C., Galluzzi, L., Freije, J. M., Madeo, F. & Kroemer, G. Metabolic control of longevity. Cell 166, 802–821 (2016). This recent review dissects the intimate relationship between metabolism and ageing, highlighting several points of intervention at which strategies that support metabolic fitness may extend healthy lifespan in humans.
Yang, L. et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 14, 422–428 (2016).
Patel, A. S. et al. Autophagy in idiopathic pulmonary fibrosis. PLoS ONE 7, e41394 (2012).
Lee, S. J. et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension. Am. J. Respir. Crit. Care Med. 183, 649–658 (2011).
Luciani, A. et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat. Cell Biol. 12, 863–875 (2010).
Chung, E. J. et al. Mammalian target of rapamycin inhibition with rapamycin mitigates radiation-induced pulmonary fibrosis in a murine model. Int. J. Radiat. Oncol. Biol. Phys. 96, 857–866 (2016).
Wang, W. et al. mTORC1 is involved in hypoxia-induced pulmonary hypertension through the activation of Notch3. J. Cell. Physiol. 229, 2117–2125 (2014).
Sureshbabu, A. et al. Inhibition of regulatory-associated protein of mechanistic target of rapamycin prevents hyperoxia-induced lung injury by enhancing autophagy and reducing apoptosis in neonatal mice. Am. J. Respir. Cell Mol. Biol. 55, 722–735 (2016).
Hu, Y. et al. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury. Autophagy 12, 2286–2299 (2016).
Chen, Z. H. et al. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc. Natl Acad. Sci. USA 107, 18880–18885 (2010).
Lam, H. C. et al. Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction. J. Clin. Invest. 123, 5212–5230 (2013).
Mizumura, K. et al. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003 (2014). This paper shows that mitophagic responses participate in the pathogenesis of COPD.
Chen, Z. H. et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS ONE 3, e3316 (2008).
Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010).
Kawakami, T. et al. Deficient autophagy results in mitochondrial dysfunction and FSGS. J. Am. Soc. Nephrol. 26, 1040–1052 (2015).
Oliva Trejo, J. A. et al. Transient increase in proteinuria, poly-ubiquitylated proteins and ER stress markers in podocyte-specific autophagy-deficient mice following unilateral nephrectomy. Biochem. Biophys. Res. Commun. 446, 1190–1196 (2014).
Zeng, C. et al. Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies. J. Pathol. 234, 203–213 (2014).
Cinque, L. et al. FGF signalling regulates bone growth through autophagy. Nature 528, 272–275 (2015).
Chen, J. & Long, F. mTORC1 signaling controls mammalian skeletal growth through stimulation of protein synthesis. Development 141, 2848–2854 (2014).
Yang, G. E. et al. Rapamycin-induced autophagy activity promotes bone fracture healing in rats. Exp. Ther. Med. 10, 1327–1333 (2015).
Alvarez-Garcia, O. et al. Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate. Kidney Int. 78, 561–568 (2010).
Holstein, J. H. et al. Rapamycin affects early fracture healing in mice. Br. J. Pharmacol. 154, 1055–1062 (2008).
Futerman, A. H. & van Meer, G. The cell biology of lysosomal storage disorders. Nat. Rev. Mol. Cell Biol. 5, 554–565 (2004).
Raben, N. et al. Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder — murine Pompe disease. Autophagy 6, 1078–1089 (2010).
Raben, N. et al. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum. Mol. Genet. 17, 3897–3908 (2008).
Awad, O. et al. Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells. Hum. Mol. Genet. 24, 5775–5788 (2015).
Maetzel, D. et al. Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann–Pick Type C patient-specific iPS cells. Stem Cell Rep. 2, 866–880 (2014).
Zhou, Z. et al. Autophagy supports color vision. Autophagy 11, 1821–1832 (2015).
Rodriguez-Muela, N. et al. Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa. Cell Death Differ. 22, 476–487 (2015).
Kim, J. Y. et al. Noncanonical autophagy promotes the visual cycle. Cell 154, 365–376 (2013). This article was the first to demonstrate that LAP is essential for the degradation of photoreceptor outer segments phagocytosed by the retinal epithelium in the course of the visual cycle.
Santeford, A. et al. Impaired autophagy in macrophages promotes inflammatory eye disease. Autophagy 12, 1876–1885 (2016).
Selmi, C. Diagnosis and classification of autoimmune uveitis. Autoimmun. Rev. 13, 591–594 (2014).
Rezaie, T. et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295, 1077–1079 (2002).
Fingert, J. H. et al. Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum. Mol. Genet. 20, 2482–2494 (2011).
Chi, Z. L. et al. Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice. Hum. Mol. Genet. 19, 2606–2615 (2010).
Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1–222 (2016).
Lee, I. H. et al. Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science 336, 225–228 (2012). This study characterizes one of the autophagy-independent functions of ATG7, namely, the regulation of p53 activity in the course of metabolic stress.
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Rodriguez-Boulan, E., Kreitzer, G. & Musch, A. Organization of vesicular trafficking in epithelia. Nat. Rev. Mol. Cell Biol. 6, 233–247 (2005).
Calne, R. Y. et al. Rapamycin for immunosuppression in organ allografting. Lancet 2, 227 (1989).
Taherian, E., Rao, A., Malemud, C. J. & Askari, A. D. The biological and clinical activity of anti-malarial drugs in autoimmune disorders. Curr. Rheumatol. Rev. 9, 45–62 (2013).
Maes, H. et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26, 190–206 (2014). This report elegantly demonstrates that chloroquine exerts robust anticancer effects through its ability to promote tumour vessel normalization independent of autophagy.
Eng, C. H. et al. Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. Proc. Natl Acad. Sci. USA 113, 182–187 (2016).
Niso-Santano, M. et al. Unsaturated fatty acids induce non-canonical autophagy. EMBO J. 34, 1025–1041 (2015).
Kaizuka, T. et al. An autophagic flux probe that releases an internal control. Mol. Cell 64, 835–849 (2016).
Cabrera, S. et al. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis. Autophagy 9, 1188–1200 (2013).
Barinaga, M. Knockout mice: round two. Science 265, 26–28 (1994).
Blaney Davidson, E. N., van de Loo, F. A., van den Berg, W. B. & van der Kraan, P. M. How to build an inducible cartilage-specific transgenic mouse. Arthritis Res. Ther. 16, 210 (2014).
Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 (2009).
Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73 (2015).
Berry, D. L. & Baehrecke, E. H. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131, 1137–1148 (2007).
Tsuboyama, K. et al. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354, 1036–1041 (2016).
Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263–1276 (2014).
Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658 (2009). This was the first characterization of a non-canonical, ATG5-independent and ATG7-independent autophagic response in mouse cells.
McAfee, Q. et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc. Natl Acad. Sci. USA 109, 8253–8258 (2012).
Ronan, B. et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol. 10, 1013–1019 (2014).
Bago, R. et al. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem. J. 463, 413–427 (2014).
Akin, D. et al. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10, 2021–2035 (2014).
Egan, D. F. et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol. Cell 59, 285–297 (2015).
Petherick, K. J. et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J. Biol. Chem. 290, 11376–11383 (2015).
Yap, T. A., Sandhu, S. K., Workman, P. & de Bono, J. S. Envisioning the future of early anticancer drug development. Nat. Rev. Cancer 10, 514–523 (2010).
Owing to space limitations, the authors apologize to the authors of several high-quality articles in the field for not being able to discuss and cite their work. L.G. is supported by the Department of Radiation Oncology of Weill Cornell Medical College (intramural funds) and Sotio a.c. J.M.B.-S.P. and G.K. are supported by the French Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR), Projets blancs; ANR under the frame of the programme E-Rare-2, the European Research Area (ERA)-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno-Oncology; the Site de Recherche Intégrée sur le Cancer (SIRIC) Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). B.L. is supported by the National Institutes of Health, Cancer Prevention Research Institute of Texas, and the LeDucq Foundation. D.R.G. is supported by the National Institutes of Health and the American Lebanese Syrian Associated Charities (ALSAC).
The authors declare no competing financial interests.
- Autophagic cell death
A variant of regulated cell death (RCD) that is precipitated by the autophagic machinery and hence can be retarded with pharmacological or genetic inhibitors of autophagy.
- Regulated cell death
(RCD). A form of cell death that relies on the activation of genetically encoded machinery and hence can be retarded or accelerated with specific pharmacological or genetic interventions.
Autophagic response that is specific for depolarized or otherwise damaged mitochondria.
Autophagic response that is specific for intracellular protein aggregates, which often are highly ubiquitylated.
- Presenilin 1
(PSEN1). Component of the γ-secretase complex that contributes to the accumulation of amyloid plaques in the brain of patients with Alzheimer disease (AD).
- Autophagic adaptor
A protein that directs autophagic substrates to forming autophagosomes through its capacity to bind ubiquitylated structures and lipidated Atg8 family members.
- Amyloid-β precursor protein
(APP). A protein that — upon cleavage — accounts for the majority of amyloid plaques in the brain of patients with Alzheimer disease (AD).
- Caloric restriction mimetic
(CRM). A molecule that mimics the biochemical and cellular effects of fasting, including autophagy activation and cytosolic acetyl-CoA depletion, but does not provoke a sizeable weight loss.
A natural α-linked disaccharide that potently activates autophagy through poorly characterized mechanisms.
A widely used antiepileptic drug that induces autophagy by affecting myo-inositol-1,4,5-trisphosphate levels.
An antidepressant that promotes autophagic responses by altering myo-inositol-1,4,5-trisphosphate levels.
- Locomotor sensitization
Long-lasting exacerbation of a psychostimulant-induced locomotor response, which is brought about by repeated intermittent administration of the same psychoactive agent.
- Ischaemic preconditioning
An experimental technique for increasing the resistance of neurons or cardiomyocytes to prolonged, severe ischaemia based on the repeated administration of short, mild ischaemic episodes.
- Cardiac glycoside
A natural compound that exerts positive inotropic effects and retards some forms of autophagic cell death as it inhibits the plasma membrane Na+/K+-ATPase.
The removal of dying or dead cells by professional phagocytes.
A natural polyamine that potently activates autophagy by operating as a caloric restriction mimetic (CRM).
- Coronary angioplasty
A minimally invasive surgical procedure for the treatment of narrowed or weakened arteries, which consists of the insertion of a small mesh tube (stent) through the femoral artery.
An antidiabetic agent with pleiotropic effects, including the capacity to trigger autophagy by acting as a caloric restriction mimetic (CRM).
- db/db mice
Mice homozygous for the spontaneous db (for diabetes) mutation in leptin receptor (Lepr), which causes limited leptin signalling. These animals are commonly used as models for type 2 diabetes and metabolic syndrome.
- ob/ob mice
Mice homozygous for the spontaneous ob (for obesity) mutation in leptin receptor (Lepr), which causes absent leptin signalling. These animals are commonly used as models for obesity and metabolic syndrome.
A widely used antiepileptic drug that induces autophagy by altering myo-inositol-1,4,5-triphosphate levels.
- α1-antitrypsin deficiency
A genetic disease that causes the defective production of serpin family A member 1 (SERPINA1; also known as α1-antitrypsin) in the lungs and liver, which results in pulmonary disorders that are often associated with hepatic symptoms.
A naturally occurring toxin that is commonly used to generate rodent models of type 1 diabetes owing to its pronounced selectivity for pancreatic β-cells.
- Malignant transformation
The conversion of a healthy, normal cell into a neoplastic cell precursor. Malignant transformation is insufficient to drive tumorigenesis.
- Oncosuppressor genes
Genes mutated or silenced in familial or sporadic forms of cancer. Many of these genes encode proteins that are involved in the maintenance of cellular homeostasis or in the activation of regulated cell death (RCD).
Genes overexpressed or hyperactivated in familial or sporadic forms of cancer. Many of these genes encode positive regulators of cellular proliferation or proteins that inhibit regulated cell death (RCD).
- Tumour progression
A process through which a neoplastic cell precursor acquires additional genetic or epigenetic alterations that allow it to escape cell-intrinsic and cell-extrinsic control mechanisms and form aggressive tumours.
A process in which the immune system recognizes and eliminates a potentially dangerous entity, including invading pathogens as well as pre-malignant and malignant cells.
Supramolecular platforms that support caspase 1 activation, hence allowing for the proteolytic maturation and secretion of pro-inflammatory interleukin-1β (IL-1β) and IL-18.
- Neutrophil extracellular traps
(NETs). Chromatin-based and granule protein-containing fibres that are released by neutrophils to immobilize and kill invading microorganisms.
- Cellular senescence
A permanent proliferative arrest that is generally associated with specific morphological and biochemical features, including the secretion of multiple cytokines and other biologically active factors.
- Chronic obstructive pulmonary disease
(COPD). A progressive lung disease that is characterized by long-term limited airflow, which is often caused or aggravated by tobacco smoke.
- Focal segmental glomerulosclerosis
A leading cause of kidney failure in adults that is characterized by the degeneration of sections of the glomerulus with a focal (as opposed to diffuse) intrarenal distribution.
A sphingolipid that accumulates in patients with Gaucher disease (mostly in the macrophages) as a result of mutations in glucosylceramidase beta (GBA).
- Retinitis pigmentosa
An inherited, degenerative eye disease that causes severe vision impairment owing to the progressive degeneration of the rod photoreceptor cells.
Rapamycin derivatives with improved pharmacodynamic and pharmacokinetic properties.
- Canonical autophagy
A term commonly used to refer to an autophagic response that is dependent on autophagy-related 5 (ATG5), ATG7, beclin 1 (BECN1) and phosphatidylinositol-3-phosphate (PtdIns3P) production.
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Galluzzi, L., Bravo-San Pedro, J., Levine, B. et al. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16, 487–511 (2017). https://doi.org/10.1038/nrd.2017.22
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