2. Academic Validation
  3. VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification

VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification

  • Cell. 2009 Apr 17;137(2):235-46. doi: 10.1016/j.cell.2009.01.054.
Nivetha Ramachandran 1,  Iulia Munteanu,  Peixiang Wang,  Pauline Aubourg,  Jennifer J Rilstone,  Nyrie Israelian,  Taline Naranian,  Paul Paroutis,  Ray Guo,  Zhi-Ping Ren,  Ichizo Nishino,  Brigitte Chabrol,  Jean-Francois Pellissier,  Carlo Minetti,  Bjarne Udd,  Michel Fardeau,  Chetankumar S Tailor,  Don J Mahuran,  John T Kissel,  Hannu Kalimo,  Nicolas Levy,  Morris F Manolson,  Cameron A Ackerley,  Berge A Minassian
Affiliations

Affiliation

  • 1 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
PMID: 19379691 DOI: 10.1016/j.cell.2009.01.054
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 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.

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