Autophagy Is a Protective Mechanism for Human Melanoma Cells under Acidic Stress

Marino, Maria Lucia; Pellegrini, Paola; Lernia, Giuseppe Di; Djavaheri-Mergny, Mojgan; Brnjic, Slavica; Zhang, Xiaonan; Hägg, Maria; Linder, Stig; Fais, Stefano; Codogno, Patrice; Milito, Angelo De

doi:10.1074/jbc.m112.339127

Cited by 160 publications

(151 citation statements)

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“…Intracellular pH changes are typical for many processes, such as starvation (12) and ischemia (13), and importantly many of them are known to be activators of mitophagy (17).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, other physiological processes that induce mitophagy, such as hypoxia and starvation, also induce mild acidification of the cytosol (12-16). Changes in intracellular pH activates autophagy (17,18).To investigate the effect of the cytosolic changes on mitophagy we investigated the effect of FCCP and nigericin on pH cyt and how these changes promote the mitochondrial translocation to lysosomes. We found that acidification of cytosol caused by nigericin can trigger autophagy and mitophagy.…”

mentioning

confidence: 99%

“…Importantly, other physiological processes that induce mitophagy, such as hypoxia and starvation, also induce mild acidification of the cytosol (12)(13)(14)(15)(16). Changes in intracellular pH activates autophagy (17,18).…”

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confidence: 99%

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Intracellular pH Modulates Autophagy and Mitophagy

Berezhnov

Soutar

Fedotova

et al. 2016

Journal of Biological Chemistry

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The specific autophagic elimination of mitochondria (mitophagy) plays the role of quality control for this organelle. Deregulation of mitophagy leads to an increased number of damaged mitochondria and triggers cell death. The deterioration of mitophagy has been hypothesized to underlie the pathogenesis of several neurodegenerative diseases, most notably Parkinson disease. Although some of the biochemical and molecular mechanisms of mitochondrial quality control are described in detail, physiological or pathological triggers of mitophagy are still not fully characterized. Here we show that the induction of mitophagy by the mitochondrial uncoupler FCCP is independent of the effect of mitochondrial membrane potential but dependent on acidification of the cytosol by FCCP. The ionophore nigericin also reduces cytosolic pH and induces PINK1/PARKIN-dependent and -independent mitophagy. The increase of intracellular pH with monensin suppresses the effects of FCCP and nigericin on mitochondrial degradation. Thus, a change in intracellular pH is a regulator of mitochondrial quality control.Continuous ATP production is essential for cell survival. Mitochondria are the major ATP producers in the cell; these are distributed throughout different tissues in varying amounts depending on energy demand. The number of mitochondria within cells is regulated by the balance between mitochondrial biogenesis (1) and the removal of damaged mitochondria. Furthermore, mitochondria also regulate cell death, which is triggered by release of intramitochondrial proteins (2). Considering this, the removal of dysfunctional mitochondria is an important process for ensuring cell survival.Damaged mitochondria, as well as other impaired organelles and proteins in cells are degraded by specific autophagy. Mitochondrial autophagy (mitophagy) 2 plays a role in the quality control of this organelle, whereas dysfunction in mitophagy can lead to an increase in the number of damaged mitochondria that can trigger the activation of cell death pathways (3, 4). Over the last several years, a number of studies have provided substantial evidence showing the PINK1-Parkin pathway (familial forms of Parkinson disease caused by mutations in the genes encoding the PTEN (phosphatase and tensin homolog)-induced putative kinase-1 (PINK1) and Parkin E3 ubiquitin ligase) promotes mitophagy. PINK1 accumulates at the outer mitochondrial membrane of depolarized mitochondria, which recruits cytoplasmic Parkin to the damaged organelle. This results in the ubiquitination of mitofusins (Mfns) by Parkin, the engulfment of the dysfunctional mitochondria by autophagosomes, and subsequent mitophagy (5-8). In recent years, abnormal autophagy and mitophagy has been shown for toxininjured dopaminergic neurons as well as in all the major genetic models of Parkinson disease (PD), including ␣-synuclein, leucine-rich repeat kinase 2 (LRRK2), parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 (9, 10). Historically, mitophagy research focuses on the biochemical and molecular mechanisms of PD; ...

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“…Intracellular pH changes are typical for many processes, such as starvation (12) and ischemia (13), and importantly many of them are known to be activators of mitophagy (17).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Intracellular pH Modulates Autophagy and Mitophagy

Berezhnov

Soutar

Fedotova

et al. 2016

Journal of Biological Chemistry

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“…28,45,59 Briefly, following IL13 treatment of hTEC cultured at the air-liquid interface, cells were incubated with 50 mM of chloroquine or 100 mM of bafilomycin A 1 for 3 h in the absence or presence of IL13. Subsequently, immunoblot analysis was used to quantify the change in LC3-II to actin ratio, and in parallel samples cells were fixed for LC3 puncta immunostaining.…”

Section: Autophagy Flux Assaymentioning

confidence: 99%

IL13 activates autophagy to regulate secretion in airway epithelial cells

et al. 2016

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Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagyrelated 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

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“…Indeed, a body of evidence suggests that autophagy is induced in cancer cells by microenvironmental stresses including growth factor withdrawal (through MTORC1 inhibition), hypoxia (through hypoxia inducible factor stabilization), oxidative stress (through ROS), and acidic pH (through AMPK activation and MTORC1 inhibition). 69,108,109 The tumor cell microenvironment influences the regulation of autophagy and energy metabolism not only in cancer cells but also in stromal cells. Thus, the accumulation of ROS in the microenvironment of the tumor cell promotes autophagy in surrounding stromal cells, leading to an influx of nutrients (including glutamine) from stromal cells to cancer cells.…”

Section: Regulation and Role Of Autophagy In Cancer Cellsmentioning

confidence: 99%