Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum

Mijaljica, Dalibor; Prescott, Mark; Devenish, Rodney J.

doi:10.4161/auto.7.7.14733

Cited by 461 publications

(356 citation statements)

References 65 publications

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“…In addition, we did not observe any obvious effect of intermittent fasting or LAMP2 ablation on microautophagy 62 in the ultrastructural studies, but definitive studies on its role will require development of tools to modulate this pathway.…”

Section: Discussionmentioning

confidence: 93%

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

et al. 2015

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(2015) Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemiareperfusion injury, Autophagy, 11:9, 1537-1560, DOI: 10.1080/15548627.2015 Keywords: autophagy, fasting, ischemia-reperfusion, lysosome, myocardial infarctionAbbreviations: CMA, chaperone-mediated autophagy; CQ, chloroquine; GFP, green fluorescent protein; LAD, left anterior descending; LAMP2, lysosomal-associated membrane protein 2; MOI, multiplicity of infection; NRCMs, neonatal rat ventricular cardiac myocytes; q4D, quaque qutra die/every fourth day; qOD, quaque otra die/every other day; TFEB, transcription factor EB; MAP1LC3B (also abbreviated as LC3), microtubule-associated protein 1 light chain 3, isoform B; TTC, triphenyl tetrazolium chloride; LV, left ventricle; AAR, area at risk; WT, wild type.Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from invivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEBmediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fastinginduced autophagy in myocardial ischemia-reperfusion injury.

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Section: Discussionmentioning

confidence: 93%

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

et al. 2015

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“…One form, microautophagy, occurs through invagination of the vacuolar membrane to form single membrane vesicles that enter the vacuole for degradation. 72 Microautophagy has been reported during plant senescence and development, but little is known about its role in plant cell homeostasis. 48,50,[73][74][75] It is possible that ATG5 is involved in a microautophagy-like or other novel mechanism that does not require ATG9 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evidence for autophagy-dependent pathways of rRNA turnover inArabidopsis

et al. 2015

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Ribosomes account for a majority of the cell's RNA and much of its protein and represent a significant investment of cellular resources. The turnover and degradation of ribosomes has been proposed to play a role in homeostasis and during stress conditions. Mechanisms for the turnover of rRNA and ribosomal proteins have not been fully elucidated. We show here that the RNS2 ribonuclease and autophagy participate in RNA turnover in Arabidopsis thaliana under normal growth conditions. An increase in autophagosome formation was seen in an rns2-2 mutant, and this increase was dependent on the core autophagy genes ATG9 and ATG5. Autophagosomes and autophagic bodies in rns2-2 mutants contain RNA and ribosomes, suggesting that autophagy is activated as an attempt to compensate for loss of rRNA degradation. Total RNA accumulates in rns2-2, atg9-4, atg5-1, rns2-2 atg9-4, and rns2-2 atg5-1 mutants, suggesting a parallel role for autophagy and RNS2 in RNA turnover. rRNA accumulates in the vacuole in rns2-2 mutants. Vacuolar accumulation of rRNA was blocked by disrupting autophagy via an rns2-2 atg5-1 double mutant but not by an rns2-2 atg9-4 double mutant, indicating that ATG5 and ATG9 function differently in this process. Our results suggest that autophagy and RNS2 are both involved in homeostatic degradation of rRNA in the vacuole.

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“…2) (152). Direct intake of degradable material into lysosomes is called microautophagy (115). In contrast, macroautophagy describes the inclusion of organelles and soluble proteins, first into double-membrane structures (phagophores), generating double-membrane vesicles, called autophagosomes, which afterward merge with the lysosomes (65,76).…”

Section: Repair and Degradation Of Oxidized Proteinsmentioning

confidence: 99%

Protein Oxidation in Aging: Does It Play a Role in Aging Progression?

Reeg

Grune

2015

Antioxidants & Redox Signaling

166

134

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Significance: A constant accumulation of oxidized proteins takes place during aging. Oxidation of proteins leads to a partial unfolding and, therefore, to aggregation. Protein aggregates impair the activity of cellular proteolytic systems (proteasomes, lysosomes), resulting in further accumulation of oxidized proteins. In addition, the accumulation of highly crosslinked protein aggregates leads to further oxidant formation, damage to macromolecules, and, finally, to apoptotic cell death. Furthermore, protein oxidation seems to play a role in the development of various age-related diseases, for example, neurodegenerative diseases. Recent Advances: The highly oxidized lipofuscin accumulates during aging. Lipofuscin formation might cause impaired lysosomal and proteasomal degradation, metal ion accumulation, increased reactive oxygen species formation, and apoptosis. Critical Issues: It is still unclear to which extent protein oxidation is involved in the progression of aging and in the development of some age-related diseases. Future Directions: An extensive knowledge of the effects of protein oxidation on the aging process and its contribution to the development of age-related diseases could enable further strategies to reduce age-related impairments. Strategies aimed at lowering aggregate formation might be a straightforward intervention to reduce age-related malfunctions of organs. Antioxid. Redox Signal. 23, 239-255.

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Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum

Cited by 461 publications

References 65 publications

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

Evidence for autophagy-dependent pathways of rRNA turnover inArabidopsis

Protein Oxidation in Aging: Does It Play a Role in Aging Progression?

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