Oxidation of Atg3 and Atg7 mediates inhibition of autophagy

Frudd, Karen; Burgoyne, Thomas; Burgoyne, Joseph R.

doi:10.1038/s41467-017-02352-z

Cited by 165 publications

(132 citation statements)

References 48 publications

(64 reference statements)

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“…Although both dysfunctions are thought to be causally linked, the respective place of mitochondria and lysosomes in mediating this mechanism is challenging to elucidate in view of the interdependence of these organelles. On the one hand, mitochondria can act upstream of lysosomal dysfunction by generating reactive oxygen species (ROS) that can impair autophagy (7) or by reducing ATP production, which is essential for lysosomal vacuolar ATPase (vATPase)-mediated acidification. On the other hand, accumulation of damaged mitochondria can occur downstream to lysosomal dysfunction within the mitochondrial quality control mechanism, which, as we have previously reported, consists of targeting fragmented depolarized mitochondria to autophagy for degradation (8).…”

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confidence: 99%

Nanoparticle‐mediated lysosomal reacidification restores mitochondrial turnover and function in β cells under lipotoxicity

et al. 2018

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Chronic exposure of pancreatic β cells to high concentrations of free fatty acids leads to lipotoxicity (LT)‐mediated suppression of glucose‐stimulated insulin secretion. This effect is in part caused by a decline in mitochondrial function as well as by a reduction in lysosomal acidification. Because both mitochondria and lysosomes can alter one another's function, it remains unclear which initiating dysfunction sets off the detrimental cascade of LT, ultimately leading to β‐cell failure. Here, we investigated the effects of restoring lysosomal acidity on mitochondrial function under LT. Our results show that LT induces a dose‐dependent lysosomal alkalization accompanied by an increase in mitochondrial mass. This increase is due to a reduction in mitochondrial turnover as analyzed by MitoTimer, a fluorescent protein for which the emission is regulated by mitochondrial clearance rate. Mitochondrial oxygen consumption rate, citrate synthase activity, and ATP content are all reduced by LT. Restoration of lysosomal acidity using lysosome‐targeted nanoparticles is accompanied by stimulation of mitochondrial turnover as revealed by mitophagy measurements and the recovery of mitochondrial mass. Remarkably, re‐acidification restores citrate synthase activity and ATP content in an insulin secreting β‐cell line (INS‐1). Furthermore, nanoparticle‐mediated lysosomal reacidification rescues mitochondrial maximal respiratory capacity in both INS‐1 cells and primary mouse islets. Therefore, our results indicate that mitochondrial dysfunction is downstream of lysosomal alkalization under lipotoxic conditions and that recovery of lysosomal acidity is sufficient to restore the bioenergetic defects.—Assali, E. A., Shlomo, D., Zeng, J., Taddeo, E. P., Trudeau, K. M., Erion, K. A., Colby, A. H., Grinstaff, M. W., Liesa, M., Las, G., Shirihai, O. S. Nanoparticle‐mediated lysosomal reacidification restores mitochondrial turnover and function in β cells under lipotoxicity. FASEB J. 33, 4154–4165 (2019). http://www.fasebj.org

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confidence: 99%

Nanoparticle‐mediated lysosomal reacidification restores mitochondrial turnover and function in β cells under lipotoxicity

et al. 2018

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“…For instance, a similar situation has been observed in sepsis, in which the rate of autophagic clearance of damaged organelles was outpaced by the extent of sustained insult to hepatocytes . Conversely, it is possible that the increase in oxidative stress impairs autophagic activity in cells …”

Section: Autophagy In the Ageing Heartmentioning

confidence: 69%

“…37 Conversely, it is possible that the increase in oxidative stress impairs autophagic activity in cells. 38,39 Metabolic and hormonal changes accompanying ageing may contribute to lower levels of autophagy. Age-related activation of autophagy suppressors, in addition to inhibition of autophagy activators, may also play a role here.…”

Section: Autophagy In the Ageing Heartmentioning

confidence: 99%

Autophagy—A key pathway for cardiac health and longevity

Woodall

Gustafsson

2018

Acta Physiologica

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As average life expectancy continues to rise in the developed world, age-associated pathologies are increasing in prevalence. The hallmarks of cardiac ageing include cardiomyocyte loss, fibrosis and hypertrophy, all of which contribute to an increased incidence of cardiac disease. At the molecular level, cellular ageing is characterized by increased ROS production, mitochondrial dysfunction and the accumulation of damaged proteins and organelles. Cardiomyocytes and other senescent cell types rely upon autophagy, a lysosome-mediated degradation pathway, to remove potentially toxic protein aggregates and damaged organelles from the cellular milieu. However, increasing lines of evidence point to an age-associated decrease in cardiomyocyte autophagy, with predictably negative consequences for cardiac function and health. Conversely, stimulation of autophagy has been shown to improve cellular health and cardiac function and to increase lifespan in numerous model organisms. Clearly, autophagy represents a critical pathway for cellular vitality, as well as a promising therapeutic target for the treatment of age-related cardiac pathologies. In this review, we will discuss the mechanism of autophagy and its regulation in the cell, the role of autophagy in the ageing heart, and how the autophagy pathway might be targeted to improve cardiac health.

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“…Furthermore, direct up-regulation of autophagy has been shown to exert health benefits and extend lifespan in a range of model organisms including worms, flies and mice 37–39 . Several components of the autophagy pathway are known to be redox regulated, including Atg3 and Atg7 40 , as well as the focus of our study Atg4 26 . Overall, we have shown that shifting the in vivo redox state of Drosophila through over-expression of catalase extends lifespan and healthspan in females through redox regulation of autophagy via a key redox-regulatory cysteine in Atg4a.…”

Section: Figmentioning

confidence: 99%

Enhancing autophagy by redox regulation extends lifespan inDrosophila

Cochemé

Bjedov

Grönke

et al. 2019

Preprint

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Redox signalling is an important modulator of diverse biological pathways and processes, and 22 operates through specific post-translational modification of redox-sensitive thiols on cysteine 23 residues 1-4 . Critically, redox signalling is distinct from irreversible oxidative damage and 24 functions as a reversible 'redox switch' to regulate target proteins. H2O2 acts as the major 25 effector of redox signalling, both directly and through intracellular thiol redox relays 5,6 . 26 Dysregulation of redox homeostasis has long been implicated in the pathophysiology of many 27 age-related diseases, as well as in the ageing process itself, however the underlying 28 mechanisms remain largely unclear 7,8 . To study redox signalling by H2O2 in vivo and explore 29 its involvement in metabolic health and longevity, we used the fruit fly Drosophila as a model 30 organism, with its tractable lifespan and strong evolutionary conservation with mammals 9 . 31 Here we report that inducing an endogenous redox-shift, by manipulating levels of the H2O2-32 degrading enzyme catalase, improves health and robustly extends lifespan in flies, 33 independently of oxidative stress resistance and dietary restriction. We find that the catalase 34 redox-shifted flies are acutely sensitive to starvation stress, which relies on autophagy as a 35 vital survival mechanism. Importantly, we show that autophagy is essential for the lifespan 36 extension of the catalase flies. Furthermore, using redox-inactive knock-in mutants of Atg4a, 37 a major effector of autophagy, we show that the lifespan extension in response to catalase 38 requires a key redox-regulatory cysteine residue, Cys102 in Atg4a. These findings 39 demonstrate that redox regulation of autophagy can extend lifespan, confirming the 40 importance of redox signalling in ageing and as a potential pro-longevity target. 42To explore the role of endogenous redox signalling in vivo, we used the UAS/GAL4 43 expression system to up-regulate catalase in wild-type (WT) flies. Global up-regulation of catalase 44 under control of the daughterless promoter (da-GAL4>UAS-cat) extended the median and 45 maximum lifespan of female flies (typically by ~10-15%; Fig. 1a). Importantly, for these 46 experiments we used the white Dahomey (w Dah ) background, which is a long-lived and outbred WT, 47 hence we are extending healthy lifespan and not rescuing a short-lived defect. Catalase was over-48 expressed ~5-fold at the mRNA level in whole flies ( Fig. S1a). Lifespan was not extended in males 49 ( Fig. 1a), despite similar catalase over-expression ( Fig. S1a), however interventions modulating 50 nutrient-sensing in Drosophila often show gender-specific effects on survival in females, that are 51 absent or marginal in males 10 . 52The da-GAL4>UAS-cat flies were mildly delayed in eclosing, without affecting the 53 proportion of larvae surviving to adulthood (Fig. S1b). To exclude developmental effects, we 54 showed that the lifespan extension could be fully recapitulated using the inducible GeneSwitc...

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Oxidation of Atg3 and Atg7 mediates inhibition of autophagy

Cited by 165 publications

References 48 publications

Nanoparticle‐mediated lysosomal reacidification restores mitochondrial turnover and function in β cells under lipotoxicity

Nanoparticle‐mediated lysosomal reacidification restores mitochondrial turnover and function in β cells under lipotoxicity

Autophagy—A key pathway for cardiac health and longevity

Enhancing autophagy by redox regulation extends lifespan inDrosophila

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