VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification

Nivetha Ramachandran, 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 KalimoNicolas Levy, Morris F. Manolson, Cameron A. Ackerley, Berge A. Minassian

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)235-246
Number of pages12
JournalCell
Volume137
Issue number2
DOIs
Publication statusPublished - Apr 17 2009

Fingerprint

Acidification
Autophagy
Muscular Diseases
Atrophy
Adenosine Triphosphatases
Proton Pumps
Fungal Proteins
Muscle
Cytoplasm
Skeletal Muscle
Up-Regulation
Genes
Alleles
Tissue
Amino Acids
Myopathy, X-Linked, with Excessive Autophagy

Keywords

  • CELLBIO
  • HUMDISEASE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ramachandran, N., Munteanu, I., Wang, P., Aubourg, P., Rilstone, J. J., Israelian, N., ... Minassian, B. A. (2009). VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification. Cell, 137(2), 235-246. https://doi.org/10.1016/j.cell.2009.01.054

VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification. / Ramachandran, Nivetha; Munteanu, Iulia; Wang, Peixiang; Aubourg, Pauline; Rilstone, Jennifer J.; Israelian, Nyrie; Naranian, Taline; Paroutis, Paul; Guo, Ray; Ren, Zhi Ping; Nishino, Ichizo; Chabrol, Brigitte; Pellissier, Jean Francois; Minetti, Carlo; Udd, Bjarne; Fardeau, Michel; Tailor, Chetankumar S.; Mahuran, Don J.; Kissel, John T.; Kalimo, Hannu; Levy, Nicolas; Manolson, Morris F.; Ackerley, Cameron A.; Minassian, Berge A.

In: Cell, Vol. 137, No. 2, 17.04.2009, p. 235-246.

Research output: Contribution to journalArticle

Ramachandran, N, Munteanu, I, Wang, P, Aubourg, P, Rilstone, JJ, Israelian, N, Naranian, T, Paroutis, P, Guo, R, Ren, ZP, Nishino, I, Chabrol, B, Pellissier, JF, Minetti, C, Udd, B, Fardeau, M, Tailor, CS, Mahuran, DJ, Kissel, JT, Kalimo, H, Levy, N, Manolson, MF, Ackerley, CA & Minassian, BA 2009, 'VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification', Cell, vol. 137, no. 2, pp. 235-246. https://doi.org/10.1016/j.cell.2009.01.054
Ramachandran N, Munteanu I, Wang P, Aubourg P, Rilstone JJ, Israelian N et al. VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification. Cell. 2009 Apr 17;137(2):235-246. https://doi.org/10.1016/j.cell.2009.01.054
Ramachandran, Nivetha ; Munteanu, Iulia ; Wang, Peixiang ; Aubourg, Pauline ; Rilstone, Jennifer J. ; Israelian, Nyrie ; Naranian, Taline ; Paroutis, Paul ; Guo, Ray ; Ren, Zhi Ping ; Nishino, Ichizo ; Chabrol, Brigitte ; Pellissier, Jean Francois ; Minetti, Carlo ; Udd, Bjarne ; Fardeau, Michel ; Tailor, Chetankumar S. ; Mahuran, Don J. ; Kissel, John T. ; Kalimo, Hannu ; Levy, Nicolas ; Manolson, Morris F. ; Ackerley, Cameron A. ; Minassian, Berge A. / VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification. In: Cell. 2009 ; Vol. 137, No. 2. pp. 235-246.
@article{382cb050f1004e7e81b030b6af0c6f61,
title = "VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification",
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.",
keywords = "CELLBIO, HUMDISEASE",
author = "Nivetha Ramachandran and Iulia Munteanu and Peixiang Wang and Pauline Aubourg and Rilstone, {Jennifer J.} and Nyrie Israelian and Taline Naranian and Paul Paroutis and Ray Guo and Ren, {Zhi Ping} and Ichizo Nishino and Brigitte Chabrol and Pellissier, {Jean Francois} and Carlo Minetti and Bjarne Udd and Michel Fardeau and Tailor, {Chetankumar S.} and Mahuran, {Don J.} and Kissel, {John T.} and Hannu Kalimo and Nicolas Levy and Manolson, {Morris F.} and Ackerley, {Cameron A.} and Minassian, {Berge A.}",
year = "2009",
month = "4",
day = "17",
doi = "10.1016/j.cell.2009.01.054",
language = "English",
volume = "137",
pages = "235--246",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - VMA21 Deficiency Causes an Autophagic Myopathy by Compromising V-ATPase Activity and Lysosomal Acidification

AU - Ramachandran, Nivetha

AU - Munteanu, Iulia

AU - Wang, Peixiang

AU - Aubourg, Pauline

AU - Rilstone, Jennifer J.

AU - Israelian, Nyrie

AU - Naranian, Taline

AU - Paroutis, Paul

AU - Guo, Ray

AU - Ren, Zhi Ping

AU - Nishino, Ichizo

AU - Chabrol, Brigitte

AU - Pellissier, Jean Francois

AU - Minetti, Carlo

AU - Udd, Bjarne

AU - Fardeau, Michel

AU - Tailor, Chetankumar S.

AU - Mahuran, Don J.

AU - Kissel, John T.

AU - Kalimo, Hannu

AU - Levy, Nicolas

AU - Manolson, Morris F.

AU - Ackerley, Cameron A.

AU - Minassian, Berge A.

PY - 2009/4/17

Y1 - 2009/4/17

N2 - 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.

AB - 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.

KW - CELLBIO

KW - HUMDISEASE

UR - http://www.scopus.com/inward/record.url?scp=64249134706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=64249134706&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2009.01.054

DO - 10.1016/j.cell.2009.01.054

M3 - Article

C2 - 19379691

AN - SCOPUS:64249134706

VL - 137

SP - 235

EP - 246

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

ER -