VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy.
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, VMA21 ... is an essential assembly chaperone of the vacuolar ATPase (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 leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.
Mesh Terms:
Adenosine Triphosphatases, Animals, Autophagy, Cells, Cultured, Humans, Hydrogen-Ion Concentration, Leucine, Lysosomal Storage Diseases, Lysosomes, Male, Mice, Muscle, Skeletal, Muscular Diseases, Mutation, RNA Interference, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Subcellular Fractions, Time Factors, Vacuolar Proton-Translocating ATPases, Vacuoles
Adenosine Triphosphatases, Animals, Autophagy, Cells, Cultured, Humans, Hydrogen-Ion Concentration, Leucine, Lysosomal Storage Diseases, Lysosomes, Male, Mice, Muscle, Skeletal, Muscular Diseases, Mutation, RNA Interference, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Subcellular Fractions, Time Factors, Vacuolar Proton-Translocating ATPases, Vacuoles
Acta Neuropathol.
Date: Mar. 01, 2013
PubMed ID: 23315026
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