Autophagy is required for necrotic cell death in Caenorhabditis elegans

Abstract

Autophagy is the main process for bulk protein and organelle recycling in cells under extracellular or intracellular stress. Deregulation of autophagy has been associated with pathological conditions such as cancer, muscular disorders and neurodegeneration. Necrotic cell death underlies extensive neuronal loss in acute neurodegenerative episodes such as ischemic stroke. We find that excessive autophagosome formation is induced early during necrotic cell death in C. elegans. In addition, autophagy is required for necrotic cell death. Impairment of autophagy by genetic inactivation of autophagy genes or by pharmacological treatment suppresses necrosis. Autophagy synergizes with lysosomal catabolic mechanisms to facilitate cell death. Our findings demonstrate that autophagy contributes to cellular destruction during necrosis. Thus, interfering with the autophagic process may protect neurons against necrotic damage in humans.

Death Associated Protein Kinase (DAPK) -mediated neurodegenerative mechanisms in nematode excitotoxicity

“…We noticed only a moderate effect for these two factors, evident in some developmental stages (Figure 4 A and B). Such a moderate effect is in line with the reported effect of unc-51 on nuIs5 alone [ 60 ] (see discussion). We then used an independent set of experiments and epistasis analysis to determine if this moderate effect works independently of dapk-1 or in the same pathway.…”

Death Associated Protein Kinase (DAPK) -mediated neurodegenerative mechanisms in nematode excitotoxicity

“…We noticed only a moderate effect for these two factors, evident in some developmental stages (Figure 4 A and B). Such a moderate effect is in line with the reported effect of unc-51 on nuIs5 alone [ 60 ] (see discussion). We then used an independent set of experiments and epistasis analysis to determine if this moderate effect works independently of dapk-1 or in the same pathway.…”

Calcium ions trigger the exposure of phosphatidylserine on the surface of necrotic cells

“…Consistent with previous reports [57,58], we observed a significant and sizable reduction (25%) in the number of necrotic PLM neurons in newly hatched ced-1(e1735); unc-51(e369); mec-4(e1611) L1 larvae comparing to that observed in ced-1(e1735); mec-4(e1611) L1 larvae (Fig 7A). Remarkably, PS is detected on 27.4% of the PLM neurons (labeled with P mec-7 GFP) that appear live and display a relative normal and non-swelling morphology under the DIC microscope in ced-1(e1735); unc-51(e369); mec-4(e1611) L1 larvae (Fig 7 B-C), whereas in ced-1(e1735); unc-51(+); mec-4(+) L1 larvae in which all PLM neurons are alive, 0% of living PLM neurons expose PS (Fig 7 B-C and [19]).…”

Cell Death Induction by the Indirubin Derivative 7BIO and the BH3 Mimetic Drugs ABT-737 and GX15-070 in Medullary Thyroid Carcinoma Cells

“…In RMS rhabdomyosarcoma cells, necroptosis and autophagy without signs of apoptosis were reported to be induced by GX15-070 [56]. These results fit well with our findings in TT medullary thyroid carcinoma cells and furthermore are in accordance with data published by other that all kinds of cell death can occur independently of each other but can also occur simultaneously which results in a combined cell death phenotype depicting a mix of apoptotic, necrotic and autophagic elements [57,58]. Regarding the mechanism of action of GX15-070, one would expect cell death by activating apoptosis according to its effect as BH3 mimetic.…”

Death Associated Protein Kinase (DAPK) -mediated neurodegenerative mechanisms in nematode excitotoxicity

“…We noticed only a moderate effect for these two factors, evident in some developmental stages (Figure 4 A and B). Such a moderate effect is in line with the reported effect of unc-51 on nuIs5 alone [ 60 ] (see discussion). We then used an independent set of experiments and epistasis analysis to determine if this moderate effect works independently of dapk-1 or in the same pathway.…”

Calcium ions trigger the exposure of phosphatidylserine on the surface of necrotic cells

“…Consistent with previous reports [57,58], we observed a significant and sizable reduction (25%) in the number of necrotic PLM neurons in newly hatched ced-1(e1735); unc-51(e369); mec-4(e1611) L1 larvae comparing to that observed in ced-1(e1735); mec-4(e1611) L1 larvae (Fig 7A). Remarkably, PS is detected on 27.4% of the PLM neurons (labeled with P mec-7 GFP) that appear live and display a relative normal and non-swelling morphology under the DIC microscope in ced-1(e1735); unc-51(e369); mec-4(e1611) L1 larvae (Fig 7 B-C), whereas in ced-1(e1735); unc-51(+); mec-4(+) L1 larvae in which all PLM neurons are alive, 0% of living PLM neurons expose PS (Fig 7 B-C and [19]).…”

Cell Death Induction by the Indirubin Derivative 7BIO and the BH3 Mimetic Drugs ABT-737 and GX15-070 in Medullary Thyroid Carcinoma Cells

“…In RMS rhabdomyosarcoma cells, necroptosis and autophagy without signs of apoptosis were reported to be induced by GX15-070 [56]. These results fit well with our findings in TT medullary thyroid carcinoma cells and furthermore are in accordance with data published by other that all kinds of cell death can occur independently of each other but can also occur simultaneously which results in a combined cell death phenotype depicting a mix of apoptotic, necrotic and autophagic elements [57,58]. Regarding the mechanism of action of GX15-070, one would expect cell death by activating apoptosis according to its effect as BH3 mimetic.…”

Death Associated Protein Kinase (DAPK) -mediated neurodegenerative mechanisms in nematode excitotoxicity

“…We noticed only a moderate effect for these two factors, evident in some developmental stages (Figure 4 A and B). Such a moderate effect is in line with the reported effect of unc-51 on nuIs5 alone [ 60 ] (see discussion). We then used an independent set of experiments and epistasis analysis to determine if this moderate effect works independently of dapk-1 or in the same pathway.…”

Calcium ions trigger the exposure of phosphatidylserine on the surface of necrotic cells

“…Consistent with previous reports [57,58], we observed a significant and sizable reduction (25%) in the number of necrotic PLM neurons in newly hatched ced-1(e1735); unc-51(e369); mec-4(e1611) L1 larvae comparing to that observed in ced-1(e1735); mec-4(e1611) L1 larvae (Fig 7A). Remarkably, PS is detected on 27.4% of the PLM neurons (labeled with P mec-7 GFP) that appear live and display a relative normal and non-swelling morphology under the DIC microscope in ced-1(e1735); unc-51(e369); mec-4(e1611) L1 larvae (Fig 7 B-C), whereas in ced-1(e1735); unc-51(+); mec-4(+) L1 larvae in which all PLM neurons are alive, 0% of living PLM neurons expose PS (Fig 7 B-C and [19]).…”

Cell Death Induction by the Indirubin Derivative 7BIO and the BH3 Mimetic Drugs ABT-737 and GX15-070 in Medullary Thyroid Carcinoma Cells

“…In RMS rhabdomyosarcoma cells, necroptosis and autophagy without signs of apoptosis were reported to be induced by GX15-070 [56]. These results fit well with our findings in TT medullary thyroid carcinoma cells and furthermore are in accordance with data published by other that all kinds of cell death can occur independently of each other but can also occur simultaneously which results in a combined cell death phenotype depicting a mix of apoptotic, necrotic and autophagic elements [57,58]. Regarding the mechanism of action of GX15-070, one would expect cell death by activating apoptosis according to its effect as BH3 mimetic.…”