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Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.

Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T - J. Cell Biol. (2005)

Bottom Line: Autophagy is a membrane-trafficking mechanism that delivers cytoplasmic constituents into the lysosome/vacuole for bulk protein degradation.Aberrant autophagy has been reported in several neurodegenerative disorders, hepatitis, and myopathies.Furthermore, Atg7 deficiency led to multiple cellular abnormalities, such as appearance of concentric membranous structure and deformed mitochondria, and accumulation of ubiquitin-positive aggregates.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.

ABSTRACT
Autophagy is a membrane-trafficking mechanism that delivers cytoplasmic constituents into the lysosome/vacuole for bulk protein degradation. This mechanism is involved in the preservation of nutrients under starvation condition as well as the normal turnover of cytoplasmic component. Aberrant autophagy has been reported in several neurodegenerative disorders, hepatitis, and myopathies. Here, we generated conditional knockout mice of Atg7, an essential gene for autophagy in yeast. Atg7 was essential for ATG conjugation systems and autophagosome formation, amino acid supply in neonates, and starvation-induced bulk degradation of proteins and organelles in mice. Furthermore, Atg7 deficiency led to multiple cellular abnormalities, such as appearance of concentric membranous structure and deformed mitochondria, and accumulation of ubiquitin-positive aggregates. Our results indicate the important role of autophagy in starvation response and the quality control of proteins and organelles in quiescent cells.

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Atg7 deficiency in the liver causes hepatomegaly and hepatic cell swelling. (A) The gross anatomical views of representative mice at the indicated day after pIpC injection. (B–E) Histology of representative livers with Atg7 deficiency. Hematoxylin and eosin staining of Atg7F/+:Mx1 (B and C) and Atg7F/F:Mx1 (D and E) liver at 90 d after pIpC injection.
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fig5: Atg7 deficiency in the liver causes hepatomegaly and hepatic cell swelling. (A) The gross anatomical views of representative mice at the indicated day after pIpC injection. (B–E) Histology of representative livers with Atg7 deficiency. Hematoxylin and eosin staining of Atg7F/+:Mx1 (B and C) and Atg7F/F:Mx1 (D and E) liver at 90 d after pIpC injection.

Mentions: We further chased the phenotypes of the mutant mice for up to 90 d after pIpC injection. Gross anatomy revealed severe enlargement of the liver, filling up most of the abdominal cavity (Fig. 5 A). Other major organs were normal histologically (Fig. S3, available at http://www.jcb.org/cgi/content/full/jcb.200412022/DC1). The mean liver weights of control and mutant mice at 90 d after pIpC injection were 1.39 ± 0.24 and 6.10 ± 2.06 g, respectively (n = 5 each). Histological analysis revealed disorganized hepatic lobules and cell swelling in the mutant liver (Fig. 5, D and E). No hepatocellular proliferation or regeneration was detected (unpublished data). Vacuolated hepatic cells were occasionally observed and those were associated with hepatic cell death, which is consistent with the leakage of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase in the mutant mice sera (Fig. S4, available at http://www.jcb.org/cgi/content/full/jcb.200412022/DC1).


Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.

Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T - J. Cell Biol. (2005)

Atg7 deficiency in the liver causes hepatomegaly and hepatic cell swelling. (A) The gross anatomical views of representative mice at the indicated day after pIpC injection. (B–E) Histology of representative livers with Atg7 deficiency. Hematoxylin and eosin staining of Atg7F/+:Mx1 (B and C) and Atg7F/F:Mx1 (D and E) liver at 90 d after pIpC injection.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171928&req=5

fig5: Atg7 deficiency in the liver causes hepatomegaly and hepatic cell swelling. (A) The gross anatomical views of representative mice at the indicated day after pIpC injection. (B–E) Histology of representative livers with Atg7 deficiency. Hematoxylin and eosin staining of Atg7F/+:Mx1 (B and C) and Atg7F/F:Mx1 (D and E) liver at 90 d after pIpC injection.
Mentions: We further chased the phenotypes of the mutant mice for up to 90 d after pIpC injection. Gross anatomy revealed severe enlargement of the liver, filling up most of the abdominal cavity (Fig. 5 A). Other major organs were normal histologically (Fig. S3, available at http://www.jcb.org/cgi/content/full/jcb.200412022/DC1). The mean liver weights of control and mutant mice at 90 d after pIpC injection were 1.39 ± 0.24 and 6.10 ± 2.06 g, respectively (n = 5 each). Histological analysis revealed disorganized hepatic lobules and cell swelling in the mutant liver (Fig. 5, D and E). No hepatocellular proliferation or regeneration was detected (unpublished data). Vacuolated hepatic cells were occasionally observed and those were associated with hepatic cell death, which is consistent with the leakage of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase in the mutant mice sera (Fig. S4, available at http://www.jcb.org/cgi/content/full/jcb.200412022/DC1).

Bottom Line: Autophagy is a membrane-trafficking mechanism that delivers cytoplasmic constituents into the lysosome/vacuole for bulk protein degradation.Aberrant autophagy has been reported in several neurodegenerative disorders, hepatitis, and myopathies.Furthermore, Atg7 deficiency led to multiple cellular abnormalities, such as appearance of concentric membranous structure and deformed mitochondria, and accumulation of ubiquitin-positive aggregates.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.

ABSTRACT
Autophagy is a membrane-trafficking mechanism that delivers cytoplasmic constituents into the lysosome/vacuole for bulk protein degradation. This mechanism is involved in the preservation of nutrients under starvation condition as well as the normal turnover of cytoplasmic component. Aberrant autophagy has been reported in several neurodegenerative disorders, hepatitis, and myopathies. Here, we generated conditional knockout mice of Atg7, an essential gene for autophagy in yeast. Atg7 was essential for ATG conjugation systems and autophagosome formation, amino acid supply in neonates, and starvation-induced bulk degradation of proteins and organelles in mice. Furthermore, Atg7 deficiency led to multiple cellular abnormalities, such as appearance of concentric membranous structure and deformed mitochondria, and accumulation of ubiquitin-positive aggregates. Our results indicate the important role of autophagy in starvation response and the quality control of proteins and organelles in quiescent cells.

Show MeSH
Related in: MedlinePlus