Mitochondrial morphology in mitophagy and macroautophagy

Gomes, Lígia C.; Scorrano, Luca

doi:10.1016/j.bbamcr.2012.02.012

Cited by 218 publications

(176 citation statements)

References 128 publications

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“…The mitochondria are dynamic organelles that migrate throughout the cell, fuse, divide and undergo regulated turnover (Chen and Chan, 2009). iASPP depletion affects the balance of these activities by inhibiting the fusion machinery, leading to the formation of numerous small sphere-shaped mitochondria instead of the tubular and branched organelles observed in normal control cells (Gomes and Scorrano, 2013). A similar phenotype has been reported for the mitochondria of quiescent cells, which have been described as containing numerous morphologically and functionally distinct small spheres (Collins et al, 2002).…”

Section: Discussionmentioning

confidence: 82%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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BSTRACTThe protein iASPP (encoded by PPP1R13L) is an evolutionarily conserved p53 inhibitor, the expression of which is often upregulated in human cancers. We have recently shown that iASPP is a crucial regulator of epidermal homeostasis. Here, we report that iASPP also acts as autophagy inhibitor in keratinocytes. Our data show that depletion of iASPP protects keratinocytes from apoptosis by modulating the expression of Noxa (also known as PMAIP1). In our model, iASPP expression can affect the fissionfusion cycle, mass and shape of mitochondria. iASPP-silenced keratinocytes display disorganization of cytosolic compartments and increased metabolic stress caused by deregulation of mTORC1 signaling. Moreover, increased levels of lipidated LC3 protein confirmed the activation of autophagy in iASPP-depleted cells. We have identified a novel mechanism modulating autophagy in keratinocytes that relies upon iASPP expression specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction that is essential for autophagosome formation or maturation. Using organotypic culture, we further explored the link between autophagy and differentiation, and we showed that impairing autophagy affects epidermal terminal differentiation. Our data provide an alternative mechanism to explain how epithelial integrity is maintained against environmental stressors and might also improve the understanding of the etiology of skin diseases that are characterized by defects in differentiation and DNA damage responses.

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Section: Discussionmentioning

confidence: 82%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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“…Thus, it has been suggested that the fragmentation of dysfunctional mitochondria is a crucial step that precedes mitophagy. 63,64 This phenomenon is modulated by a specific ubiquitin ligase, PARK2/parkin 65 and its interaction with the kinase PINK1 (PTEN-induced putative kinase 1). 66 Especially PINK1 undergoes a voltage dependent cleavage in polarized mitochondria and, following Ψ m collapse, an accumulation of PINK1 is observed, with consequent induction of PARK2 stabilization and initiation of mitochondrion engulfment.…”

Section: Discussionmentioning

confidence: 99%

PRKCB/protein kinase C, beta and the mitochondrial axis as key regulators of autophagy

et al. 2013

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autophagy is the major intracellular system of degradation, and it plays an essential role in various biological events. Recent observations indicate that autophagy is modulated in response to the energy status of the mitochondrial compartment. however, the exact signaling mechanism that controls autophagy under these conditions remains unclear. in this study, we report that the activation of protein kinase c β (PRKcB), a member of the classical PRKcs, negatively modulates the mitochondrial energy status and inhibits autophagy. Furthermore, cells treated with a pharmacological PRKcB inhibitor, and prkcb knockout MeFs showed an increase in autophagy both in vitro and in vivo, as well as an increased mitochondrial membrane potential (Ψ m ), suggesting a strong involvement of mitochondrial energy in the modulation of the autophagy machinery. Finally, we show that factors that increase the Ψ m oppose the PRKcB-dependent inhibition of autophagy. altogether, these data underscore the importance of PRKcB in the regulation of autophagy; moreover, the finding that a pharmacological modulation of the Ψ m modifies autophagy levels may be useful in fighting pathologies (including various types of cancer and neurodegenerative disorders) that are characterized by reduced levels of autophagy.

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“…2D and E), although cristae were not readily visible, consistent with the mitochondrial damage described following mitophagy. 24 Electron microscopy images are difficult to quantify, thus to assay the level of mitophagy accurately we used a biochemical method. The delivery of damaged mitochondria to autophagic vacuoles is controlled by the mitochondrial protein PINK1 (PTEN induced putative kinase 1).…”

Section: Mitochondrial Reactive Oxygen Activates the Inflammasome Folmentioning

confidence: 99%

Mitochondrial damage contributes toPseudomonas aeruginosaactivation of the inflammasome and is downregulated by autophagy

Jabir¹,

Hopkins²,

Ritchie³

et al. 2015

Autophagy

142

110

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Abbreviations: Three-MA, 3-methyladenine; AIM2, absent in melanoma 2; ATG, autophagy related; ATPIF1, ATPase inhibitory factor 1; BID, BH3 interacting domain death agonist; BMDM, bone marrow-derived macrophages; BrdU, 5-bromo-2-deoxyuridine; CASP, caspase; GFP, green fluorescent protein; IL1B, interleukin 1, b; LC3B, microtubule-associated protein 1 light chain 3 b; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; Mito-TEMPO, (2-(2, 2, 6, 6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride; MT-CO1, mitochondrially encoded cytochrome c oxidase I; mtDNA, mitochondrial DNA; NAC, N-acetylcysteine; NAIP, NLR family apoptosis inhibitor; NGS, normal goat serum; NLR, nucleotide-binding domain, leucine-rich repeat containing; NLRC4, NLR family, CARD domain containing 4; NLRP3, NLR family, pyrin domain containing 3; PBS, phosphate-buffered saline; PINK1, PTEN induced putative kinase 1; Rn18s, 18S rRNA; T3SS, type III secretion system; TNF, tumor necrosis factor; TUBB5, tubulin, b 5 class I; Vav, vav 1 oncogene.The nucleotide-binding domain, leucine-rich repeat containing family caspase recruitment domain containing 4 (NLRC4) inflammasome can be activated by pathogenic bacteria via products translocated through the microbial type III secretion apparatus (T3SS). Recent work has shown that activation of the NLRP3 inflammasome is downregulated by autophagy, but the influence of autophagy on NLRC4 activation is unclear. We set out to determine how autophagy might influence this process, using the bacterium Pseudomonas aeruginosa, which activates the NLRC4 inflammasome via its T3SS. Infection resulted in T3SS-dependent mitochondrial damage with increased production of reactive oxygen intermediates and release of mitochondrial DNA. Inhibiting mitochondrial reactive oxygen release or degrading intracellular mitochondrial DNA abrogated NLRC4 inflammasome activation. Moreover, macrophages lacking mitochondria failed to activate NLRC4 following infection. Removal of damaged mitochondria by autophagy significantly attenuated NLRC4 inflammasome activation. Mitochondrial DNA bound specifically to NLRC4 immunoprecipitates and transfection of mitochondrial DNA directly activated the NLRC4 inflammasome; oxidation of the DNA enhanced this effect. Manipulation of autophagy altered the degree of inflammasome activation and inflammation in an in vivo model of P. aeruginosa infection. Our results reveal a novel mechanism contributing to NLRC4 activation by P. aeruginosa via mitochondrial damage and release of mitochondrial DNA triggered by the bacterial T3SS that is downregulated by autophagy.

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Mitochondrial morphology in mitophagy and macroautophagy

Cited by 218 publications

References 128 publications

iASPP is a novel autophagy inhibitor in keratinocytes

iASPP is a novel autophagy inhibitor in keratinocytes

PRKCB/protein kinase C, beta and the mitochondrial axis as key regulators of autophagy

Mitochondrial damage contributes toPseudomonas aeruginosaactivation of the inflammasome and is downregulated by autophagy

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