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Commentary

On the relevance of precision autophagy flux control in vivo – Points of departure for clinical translation

ORCID Icon, ORCID Icon, & ORCID Icon
Pages 750-762 | Received 14 Jan 2019, Accepted 28 Oct 2019, Published online: 11 Nov 2019

References

  • Feng Y, He D, Yao Z, et al. The machinery of macroautophagy. Cell Res. 2014;24:24–41.
  • Carroll B, Korolchuk VI, Sarkar S. Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis. Amino Acids. 2015;47:2065–2088.
  • Schellens JP, Vreeling-Sindelárová H, Plomp PJ, et al. Hepatic autophagy and intracellular ATP a morphometric study. Exp Cell Res. 1988;177:103–108.
  • Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132.
  • He C, Bassik MC, Moresi V, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481:511.
  • Loos B, Engelbrecht AM, Lockshin RA, et al. The variability of autophagy and cell death susceptibility: unanswered questions. Autophagy. 2013;9:1270–1285.
  • Jiang P, Mizushima N. Autophagy and human diseases. Cell Res. 2014;24:69.
  • Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov. 2012;11:709.
  • Galluzzi L, Bravo-San Pedro JM, Levine B, et al. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017;16:487.
  • Ohsumi Y. Historical landmarks of autophagy research. Cell Res. 2014;24:9.
  • Kaizuka T, Morishita H, Hama Y, et al. An autophagic flux probe that releases an internal control. Mol Cell. 2016;17:835–849.
  • Du Toit A, Hofmeyr JH, Gniadek TJ, et al. Measuring autophagosome flux. Autophagy. 2018;14:1060–1071.
  • Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2016;12:1–222.
  • Galluzzi L, Baehrecke EH, Ballabio A, et al. Molecular definitions of autophagy and related processes. Embo J. 2017;36:1811–1836.
  • Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy. 2014;10:1391–1402.
  • Galluzzi L, Bravo-San Pedro JM, Kroemer G. Autophagy mediates tumor suppression via cellular senescence. Trends Cell Biol. 2016;26:1–3.
  • Mortimore GE, Schworer CM. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature. 1977;270:174.
  • Seglen PO, Gordon PB. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Nat Acad Sci. 1982;79:1889–1892.
  • Mortimore GE, Pösö AR. Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu Rev Nutr. 1987;7:539–568.
  • Tanida I, Minematsu-Ikeguchi N, Ueno T, et al. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy. 2005;1:84–91.
  • Nair U, Thumm M, Klionsky DJ, et al. GFP-Atg8 protease protection as a tool to monitor autophagosome biogenesis. Autophagy. 2011;7:1546–1550.
  • Kanki T, Kang D, Klionsky DJ. Monitoring mitophagy in yeast: the Om45-GFP processing assay. Autophagy. 2009;5:1186–1189.
  • Noda T, Klionsky DJ. The quantitative Pho8Delta60 assay of nonspecific autophagy. Methods Enzymol. 2008;451:33–42.
  • Xie Z, Nair U, Klionsky DJ. Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell. 2008;19:3290–3298.
  • Jin M, He D, Backues SK, et al. Transcriptional regulation by Pho23 modulates the frequency of autophagosome formation. Curr Biol. 2014;24:1314–1322.
  • Ligeon LA, Barois N, Werkmeister E, et al. Structured illumination microscopy and correlative microscopy to study autophagy. Methods. 2015;75:61–68.
  • Guo S, Liang Y, Murphy SF, et al. A rapid and high content assay that measures cyto-ID-stained autophagic compartments and estimates autophagy flux with potential clinical applications. Autophagy. 2015;11:560–572.
  • Chauhan S, Ahmed Z, Bradfute SB, et al. Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential. Nat Commun. 2015;6:8620.
  • Kuo SY, Castoreno AB, Aldrich LN, et al. Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics. Proc Nat Acad Sci. 2015;112:E4281–7.
  • Katayama H, Kogure T, Mizushima N, et al. A sensitive and quantitative technique for detecting autophagic events based on lysosomal delivery. Chem Biol. 2011;18:1042–1052.
  • Loos B, Toit AD, Hofmeyr JH. Defining and measuring autophagosome flux—concept and reality. Autophagy. 2014;10:2087–2096.
  • Kacser H, Burns JA, Fell DA. The control of flux: 21 years on. Biochem Soc Trans. 1995;23:341–366.
  • Hofmeyr JH, Cornish-Bowden A. Regulating the cellular economy of supply and demand. FEBS Lett. 2000;476:47–51.
  • Meijer AJ. Autophagy research: lessons from metabolism. Autophagy. 2009;5(1):3–5.
  • Koga H, Martinez-Vicente M, Macian F, Verkusha VV, Cuervo AM. A photoconvertible fluorescent reporter to track chaperone-mediated autophagy. Nat Commun. 2011;2:386.
  • Tsvetkov AS, Arrasate M, Barmada S, et al. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat Chem Biol. 2013;9:586.
  • Mizushima N, Yamamoto A, Matsui M, et al. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004;15:1101–1111.
  • Iwai-Kanai E, Yuan H, Huang C, et al. A method to measure cardiac autophagic flux in vivo. Autophagy. 2008;4:322–329.
  • Perry CN, Kyoi S, Hariharan N, et al. Novel methods for measuring cardiac autophagy in vivo. Methods Enzymol. 2009;453:325–342.
  • Ju JS, Varadhachary AS, Miller SE, et al. Quantitation of “Autophagic flux” in mature skeletal muscle. Autophagy. 2010;6:929–935.
  • Esteban-Martínez L, Boya P. Autophagic flux determination in vivo and ex vivo. Methods. 2015;75:79–86.
  • Zois CE, Giatromanolaki A, Sivridis E, et al. “Autophagic flux” in normal mouse tissues: focus on endogenous LC3A processing. Autophagy. 2011;7:1371–1378.
  • Haspel J, Shaik RS, Ifedigbo E, et al. Characterization of macroautophagic flux in vivo using a leupeptin-based assay. Autophagy. 2011;7:629–642.
  • Castillo K, Valenzuela V, Matus S, et al. Measurement of autophagy flux in the nervous system in vivo. Cell Death Dis. 2013;4:e917.
  • Lee JH, Rao MV, Yang DS, et al. Transgenic expression of a ratiometric autophagy probe specifically in neurons enables the interrogation of brain autophagy in vivo. Autophagy. 2019;15:543–557.
  • Li L, Wang ZV, Hill JA, et al. New autophagy reporter mice reveal dynamics of proximal tubular autophagy. J Am Soc Nephrol. 2014;25:305–315.
  • castillo N, Zhai P, Sadoshima J. Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal. 2011;14:2179–2190.
  • Sun N, Yun J, Liu J, et al. Measuring in vivo mitophagy. Mol Cell. 2015;60:685–696.
  • McWilliams TG, Prescott AR, Allen GF, et al. mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol. 2016;214:333–345.
  • McWilliams TG, Prescott AR, Montava-Garriga L, et al. Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab. 2018;27:439–449.
  • Pampaloni F, Ansari N, Stelzer EH. High-resolution deep imaging of live cellular spheroids with light-sheet-based fluorescence microscopy. Cell Tissue Res. 2013;352:161–177.
  • Power RM, Huisken J. A guide to light-sheet fluorescence microscopy for multiscale imaging. Nat Methods. 2017;4:360.
  • Stelzer EH. Light sheet microscopy revolutionizes dynamic multi-dimensional light microscopy of three-dimensional specimens (Conference Presentation). In High-Speed Biomedical Imaging and Spectroscopy III: Toward Big Data Instrumentation and Management Vol. 10505; Mar 15; 2018. p. 105050H. San Francisco (CA): International Society for Optics and Photonics.
  • Pampaloni F, Mayer B, Kabat Vel-Job K, et al. novel cellular spheroid-based autophagy screen applying live fluorescence microscopy identifies nonactin as a strong inducer of autophagosomal turnover. Slas Discovery: Advancing Life Sci R&D. 2017;5:558–570.
  • Ansari N, Hardung S, Hötte K, et al. Quantifying the autophagy-triggering effects of drugs in cell spheroids with live fluorescence microscopy. In Cancer Cell Signaling. 2014;1165:19–29. Humana Press, New York, NY.
  • Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441:885.
  • Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;7095:880.
  • Liang CC, Wang C, Peng X, et al. Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J Biol Chem. 2010;285:3499–3509.
  • Joo JH, Wang B, Frankel E, et al. The noncanonical role of ULK/ATG1 in ER-to-Golgi trafficking is essential for cellular homeostasis. Mol Cell. 2016;62:491–506.
  • Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 2010;13:805.
  • Lumkwana D, Du Toit A, Kinnear C, et al. Autophagic flux control in neurodegeneration: progress and precision targeting—where do we stand? Prog Neurobiol. 2017;153:64–85.
  • Mitra S, Tsvetkov AS, Finkbeiner S. Single neuron ubiquitin-proteasome dynamics accompanying inclusion body formation in huntington disease. J Biol Chem. 2009;284:4398–4403.
  • Barmada SJ, Serio A, Arjun A, et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014;10:677.
  • Nixon RA, Yang DS. Autophagy failure in Alzheimer’s disease—locating the primary defect. Neurobiol Dis. 2011;43:38–45.
  • Loos B, Klionsky DJ, Wong E. Augmenting brain metabolism to increase macro-and chaperone-mediated autophagy for decreasing neuronal proteotoxicity and aging. Prog Neurobiol. 2017;156:90–106.
  • Moruno-Manchon JF, Uzor NE, Ambati CR, et al. Sphingosine kinase 1-associated autophagy differs between neurons and astrocytes. Cell Death Dis. 2018;9:521.
  • Rose C, Menzies FM, Renna M, et al. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Gen. 2010;19:2144–2153.
  • Ntsapi C, Lumkwana D, Swart C, et al. New insights into autophagy dysfunction related to amyloid beta toxicity and neuropathology in Alzheimer’s disease. Int Rev Cell Mol Biol. 2018;336:321–361.
  • Caccamo A, Majumder S, Richardson A, et al. Molecular interplay between mTOR, Aβ and tau: effects on cognitive impairments. J Biol Chem. 2010;285(16):13107–13120.
  • Spilman P, Podlutskaya N, Hart MJ, 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. 2010;Apr 5:e9979.
  • Lashuel HA, Overk CR, Oueslati A, et al. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;1:38.
  • Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017;25:1037–1043.
  • Rybstein MD, Bravo-San Pedro JM, Kroemer G, et al. The autophagic network and cancer. Nat Cell Biol. 2018;3:243.
  • Xie X, White EP, Mehnert JM. Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PLoS One. 2013;8:e55096.
  • Noguera-Ortega E, Amaravadi RK. Autophagy in the tumor or in the host: which plays a greater supportive role? Cancer Discov. 2018;8:266–268.
  • Bhat P, Kriel J, Priya BS, et al. Modulating autophagy in cancer therapy: advancements and challenges for cancer cell death sensitization. Biochem Pharmacol. 2018;147:170–182.
  • Kriel J, Müller-Nedebock K, Maarman G, et al. Coordinated autophagy modulation overcomes glioblastoma chemoresistance through disruption of mitochondrial bioenergetics. Sci Rep. 2018;8:10348.
  • Rangwala R, Leone R, Chang YC, et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy. 2014;10:1369–1379.
  • Rosenfeld MR, Ye X, Supko JG, et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014;10:1359–1368.
  • Alirezaei M, Kiosses WB, Fox HS. Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity. Autophagy. 2008;4:963–966.
  • Cho SJ, Lim HJ, Jo C, et al. Plasma ATG5 is increased in Alzheimer’s disease. Sci Rep. 2019;9:4741.
  • Wu G, Wei G, Huang J, et al. Decreased gene expression of LC3 in peripheral leucocytes of patients with coronary artery disease. Eur J Clin Invest. 2011;4:958–963.
  • Zhao K, Xu XS, Meng X, et al. Autophagy of monocytes attenuates the vulnerability of coronary atherosclerotic plaques. Coron Artery Dis. 2013;24:651–656.
  • Bernard A, Jin M, Xu Z, et al. A large-scale analysis of autophagy-related gene expression identifies new regulators of autophagy. Autophagy. 2015;11:2114–2122.
  • Kramer MH, Farre JC, Mitra K, et al. Active interaction mapping reveals the hierarchical organization of autophagy. Mol Cell. 2017;65:761–774.
  • Behrends C, Sowa ME, Gygi SP, et al. Network organization of the human autophagy system. Nature. 2010;466:68.
  • Martinez-Vicente M, Talloczy Z, Wong E, et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci. 2010;13:567.
  • Wong YC, Holzbaur EL. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci. 2014 Jan 22;34(4):1293–1305.
  • Weidberg H, Shvets E, Elazar Z. “Biogenesis and cargo selectivity of autophagosomes.”. Annu Rev Biochem. 2011;80:125–156.
  • Lamark T, Kirkin V, Dikic I, et al. NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle. 2009;8:1986–1990.
  • Jiang P, Mizushima N. LC3-and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods. 2015;75:13–18.
  • Toledo M, Batista-Gonzalez A, Merheb E, et al. Autophagy regulates the liver clock and glucose metabolism by degrading CRY1. Cell Metab. 2018;28:268–281.
  • Green DR, Galluzzi L, Kroemer G. Metabolic control of cell death. Science. 2014;345:1250256.
  • Lockshin RA. Programmed cell death 50 (and beyond). Cell Death Differ. 2016;23:10.
  • Han K, Kim J, Choi MY. Quantitative indices of autophagy activity from minimal models. Theor Biol Med Model. 2014;11:31.
  • Roth DM, Balch WE. Modeling general proteostasis: proteome balance in health and disease. Curr Opin Cell Biol. 2011;23:126–134.
  • Han K, Kim J, Choi M. Autophagy mediates phase transitions from cell death to life. Heliyon. 2015;1:e00027.
  • Cornish-Bowden A, Hofmeyr JH. Determination of control coefficients in intact metabolic systems. Biochem J. 1994;298:367–375.
  • Jager KJ, Van Dijk PC, Zoccali C, et al. The analysis of survival data: the Kaplan–meier method. Kidney Int. 2008;74:560–565.
  • Lopez A, Fleming A, Rubinsztein DC. Seeing is believing: methods to monitor vertebrate autophagy in vivo. Open Biol. 2018;8:180106.
  • Siddiqi FH, Menzies FM, Lopez A, et al. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat Commun. 2019;10:1817.

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