VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy

Acta Neuropathol. 2013 Mar;125(3):439-57. doi: 10.1007/s00401-012-1073-6. Epub 2013 Jan 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Autophagy / genetics*
  • Cells, Cultured
  • Humans
  • Hydrogen-Ion Concentration
  • Leucine / metabolism
  • Lysosomal Storage Diseases / genetics*
  • Lysosomal Storage Diseases / pathology
  • Lysosomal Storage Diseases / prevention & control*
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Male
  • Mice
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / ultrastructure
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology
  • Muscular Diseases / prevention & control*
  • Mutation / genetics
  • RNA Interference / physiology
  • RNA, Messenger / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Subcellular Fractions / metabolism
  • Subcellular Fractions / pathology
  • Time Factors
  • Vacuolar Proton-Translocating ATPases / deficiency*
  • Vacuolar Proton-Translocating ATPases / genetics*
  • Vacuoles / metabolism

Substances

  • RNA, Messenger
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphatases
  • VMA21 protein, human
  • Vacuolar Proton-Translocating ATPases
  • Leucine

Supplementary concepts

  • Vacuolar myopathy