Mitochondrial clearance by autophagy in developing erythrocytes: Clearly important, but just how much so?

Mortensen, Monika; Ferguson, David J. P.; Simon, Anna Katharina

doi:10.4161/cc.9.10.11603

Cited by 58 publications

(53 citation statements)

References 48 publications

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“…Autophagy is dramatically upregulated during erythropoiesis, when it contributes to the removal of mitochondria and other organelles from the cytoplasm of the nascent erythrocyte. 18 Recent studies in mice genetically depleted of key autophagy/mitophagy genes (e.g., Ulk1, Atg7, Nix) suggest that the failure to remove mitochondria at the correct stage of erythroid differentiation can cause elevated oxidative stress, reduced reticulocyte viability and chronic anemia. [18][19][20][21][22][23][24][25] Interestingly, sublethal caspase action has been shown to contribute to erythroblast terminal differentiation (e.g., see refs.…”

Section: Resultsmentioning

confidence: 99%

A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress

et al. 2012

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The Atg4 cysteine proteases play crucial roles in the processing of Atg8 proteins during autophagy, but their regulation during cellular stress and differentiation remains poorly understood. We have found that two Atg4 family membersAtg4C and Atg4D-contain cryptic mitochondrial targeting sequences immediately downstream of their canonical (DEVD) caspase cleavage sites. Consequently, caspase-cleaved Atg4D (DN63 Atg4D) localizes to the mitochondrial matrix when expressed in mammalian cells, where it undergoes further processing to a~42 kDa mitochondrial form. Interestingly, caspase cleavage is not needed for Atg4D mitochondrial import, because~42 kDa mitochondrial Atg4D is observed in cells treated with caspase inhibitors and in cells expressing caspase-resistant Atg4D (DEVA 63 ). Using HeLa cell lines stably expressing DN63 Atg4D, we showed that mitochondrial Atg4D sensitizes cells to cell death in the presence of the mitochondrial uncoupler, CCCP, and that mitochondrial cristae are less extensive in these cells. We further showed that the organization of mitochondrial cristae is altered during the mitochondrial clearance phase in differentiating primary human erythroblasts stably expressing DN63 Atg4D, and that these cells have elevated levels of mitochondrial reactive oxygen species (ROS) during late stages of erythropoiesis. Together these data suggest that the import of Atg4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability.

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Section: Resultsmentioning

confidence: 99%

A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress

et al. 2012

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“…[26][27][28] Notably, the differentiation of hematopoietic cells requires intense energy consumption, membrane remodeling and/or organelles elimination, as exemplified for myeloid, megakaryocytic, or erythroid differentiation. 7,11,29,30 Physiological monocyte differentiation triggered by CSF1R engagement requires the formation of a multimolecular complex consisting of FADD, CFLAR/FLIP, CASP8, RIPK1 and other protein partners; and CASP8 acts as the initiatory caspase to induce the cleavage of key protein substrates (such as RIPK1 and NUCLEOPHOSMIN, among others) that orchestrate the differentiation process. 6,31 Accordingly, inhibition of caspase activation with pancaspase inhibitors or by CASP8 silencing is sufficient to dampen the differentiation of human monocytes into macrophages.…”

Section: Discussionmentioning

confidence: 99%

The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML

Obba

Hizir²,

Boyer

et al. 2015

Autophagy

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These authors contributed equally to this work.Keywords: autophagy, CMML, CSF1, differentiation, primary monocyte, PRKAA1/AMPKa1, P2RY6Abbreviations: ACTB actin, b; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2, b; CASP8, caspase 8; apoptosisrelated cysteine peptidase; CFLAR CASP8 and FADD-like apoptosis regulator; CMML chronic myelomonocytic leukemia; CSF1 colony stimulating factor 1 (macrophage); CSF1R colony stimulating factor 1 receptor; DEFA1 defensin a 1; DEFA3 defensin a 3 neutrophil-specific; DRS; dorsomorphin; EMR1 EGF-like module-containing mucin-like hormone receptor-like 1; FADD Fas (TNFRSF6)-associated via death domain; ITGAM integrin a M; MAP1LC3B/LC3B microtubule-associated protein 1 light chain 3 b; P2RY6 pyrimidinergic receptor P2Y; G-protein coupled 6; PLCB3 phospholipase C; b 3 (phosphatidylinositol-specific); PLC phospholipase; PLCG2 phospholipase C gamma 2 (phosphatidylinositol-specific); PRKAA protein kinase AMP-activated; PRKAA1 protein kinase AMP-activated a 1 catalytic subunit; PRKAA2 protein kinase AMP-activated a 2 catalytic subunit; PRKAG1 protein kinase AMP-activated gamma 1 noncatalytic subunit; RIPK1 receptor (TNFRSF)-interacting serine-threonine kinase 1; STK11 serine/ threonine kinase 11; TFRC transferrin receptor; UDP uridine diphosphate; ULK1 unc-51 like autophagy activating kinase 1; WT wild-type.Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1-ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2RY6 to the induction of autophagy, and we decipher the signaling network that links the CSF1 receptor to P2RY6-mediated autophagy and monocyte differentiation. In addition, we show that the physiological P2RY6 ligand UDP and the specific P2RY6 agonist MRS2693 can restore normal monocyte differentiation through reinduction of autophagy in primary myeloid cells from some but not all chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for PRKAA1-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML.

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“…Specific degradation of obsolete mitochondria is also observed in mammalian cells, although Atg32 is not conserved in higher eukaryotes [134][135][136]. Instead, FUNDC1 and BNIP3, BNIP3L/NIX and SQSTM1/p62 function npg as receptors in mammalian mitophagy, depending on the inducing conditions, during hypoxia, erythrocyte maturation or damage-induced mitophagy, respectively [136][137][138].…”

Section: Mitophagymentioning

confidence: 99%

The machinery of macroautophagy

et al. 2013

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Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and energy under stress conditions, to remove superfluous and damaged organelles to adapt to changing nutrient conditions and to maintain cellular homeostasis. In addition, autophagy plays a critical role in cytoprotection by preventing the accumulation of toxic proteins and through its action in various aspects of immunity including the elimination of invasive microbes and its participation in antigen presentation. The most prevalent form of autophagy is macroautophagy, and during this process, the cell forms a double-membrane sequestering compartment termed the phagophore, which matures into an autophagosome. Following delivery to the vacuole or lysosome, the cargo is degraded and the resulting macromolecules are released back into the cytosol for reuse. The past two decades have resulted in a tremendous increase with regard to the molecular studies of autophagy being carried out in yeast and other eukaryotes. Part of the surge in interest in this topic is due to the connection of autophagy with a wide range of human pathophysiologies including cancer, myopathies, diabetes and neurodegenerative disease. However, there are still many aspects of autophagy that remain unclear, including the process of phagophore formation, the regulatory mechanisms that control its induction and the function of most of the autophagy-related proteins. In this review, we focus on macroautophagy, briefly describing the discovery of this process in mammalian cells, discussing the current views concerning the donor membrane that forms the phagophore, and characterizing the autophagy machinery including the available structural information.

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Mitochondrial clearance by autophagy in developing erythrocytes: Clearly important, but just how much so?

Cited by 58 publications

References 48 publications

A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress

A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress

The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML

The machinery of macroautophagy

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