RETRACTED: VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification (Retracted article. See vol. 142, pg. 984, 2010)

被引：45

作者：

Ramachandran, Nivetha ^{[1
]}

Munteanu, Iulia ^{[1
,5
]}

Wang, Peixiang ^{[1
]}

Aubourg, Pauline ^{[6
]}

Rilstone, Jennifer J. ^{[1
,5
]}

Israelian, Nyrie ^{[1
]}

Naranian, Taline ^{[1
]}

Paroutis, Paul ^{[2
]}

Guo, Ray ^{[1
]}

Ren, Zhi-Ping ^{[1
]}

Nishino, Ichizo ^{[7
]}

Chabrol, Brigitte ^{[8
]}

Pellissier, Jean-Francois ^{[9
]}

Minetti, Carlo ^{[10
,11
]}

Udd, Bjame ^{[12
,13
]}

Fardeau, Michel ^{[14
]}

Tailor, Chetankumar S. ^{[2
]}

Mahuran, Don J. ^{[1
]}

Kissel, John T. ^{[15
]}

Kalimo, Hannu ^{[16
,17
]}

Levy, Nicolas ^{[6
]}

Manolson, Morris F. ^{[18
]}

Ackerley, Cameron A. ^{[3
]}

Minassian, Berge A. ^{[1
,4
,5
]}

机构：

[1] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[2] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada

[3] Hosp Sick Children, Dept Pathol & Lab Med, Toronto, ON M5G 1X8, Canada

[4] Hosp Sick Children, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada

[5] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada

[6] Univ Aix Marseille 2, Fac Med Marseille, INSERM, UMR S910, F-13385 Marseille, France

[7] Natl Ctr Neurol & Psychiat, Dept Neuromuscular Res, Kodaira, Tokyo 1878502, Japan

[8] CHU Timone, Hop Enfants, Unite Med Infantile, F-13385 Marseille, France

[9] Hop La Timone, Lab Anat Pathol & Neuropathol, F-13385 Marseille, France

[10] G Gaslini Inst Children, Muscular & Neurodegenerat Dis Unit, I-16147 Genoa, Italy

[11] Univ Genoa, I-16147 Genoa, Italy

[12] Vaasa Cent Hosp, Dept Neurol, FIN-65130 Vaasa, Finland

[13] Tampere Univ, FIN-65130 Vaasa, Finland

[14] Salpetriere Hosp, Myol Inst, F-75013 Paris, France

[15] Ohio State Univ, Dept Neurol, Columbus, OH 43210 USA

[16] Univ Helsinki, Haartman Inst, Dept Pathol, FIN-00014 Helsinki, Finland

[17] Univ Turku, Dept Pathol & Forens Med, FI-20520 Turku, Finland

[18] Univ Toronto, Fac Dent, Toronto, ON M5G 1G6, Canada

来源：

CELL | 2009年 / 137卷 / 02期

基金：

加拿大健康研究院;

关键词：

X-LINKED MYOPATHY; RENAL TUBULAR-ACIDOSIS; EXCESSIVE AUTOPHAGY; SKELETAL-MUSCLES; SUBUNIT; MUTATIONS; PROTEIN; MICE; CARDIOMYOPATHY; OSTEOPETROSIS;

D O I：

10.1016/j.cell.2009.01.054

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

X-linked myopathy with excessive autophagy (XMEA) is a childhood-onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p it is an essential assembly chaperone of the V-ATPase, the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH, which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids, which upregulates the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge together, and vacuolate the cell. Our results uncover macroautophagic overcompensation leading to cell vacuolation and tissue atrophy as a mechanism of disease.

引用

页码：235 / 246

页数：12

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