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 Kalimo; Nicolas Levy; Morris F. Manolson; Cameron A. Ackerley; Berge A. Minassian

doi:10.1016/j.cell.2009.01.054

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 journal › Article › peer-review

56 Scopus citations

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 language	English (US)
Pages (from-to)	235-246
Number of pages	12
Journal	Cell
Volume	137
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2009.01.054
State	Published - Apr 17 2009

Keywords

CELLBIO
HUMDISEASE

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2009.01.054

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Ramachandran, N., Munteanu, I., Wang, P., Aubourg, P., Rilstone, J. J., Israelian, N., Naranian, T., Paroutis, P., Guo, R., Ren, Z. P., Nishino, I., Chabrol, B., Pellissier, J. F., Minetti, C., Udd, B., Fardeau, M., Tailor, C. S., Mahuran, D. J., Kissel, J. T., ... 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

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

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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.}",

note = "Funding Information: I.M. identified the disease gene and characterized the effects of the mutations on the gene product (Figure 1). N.R. designed and performed the functional experiments that resolved the pathogenetic mechanisms of disease (Figures 2–7). Principal funding was from the Canadian Institutes of Health Research. B.A.M. holds the Canada Research Chair in Paediatric Neurogenetics. Additional acknowledgments are available in the Supplemental Data.",

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doi = "10.1016/j.cell.2009.01.054",

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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.

N1 - Funding Information: I.M. identified the disease gene and characterized the effects of the mutations on the gene product (Figure 1). N.R. designed and performed the functional experiments that resolved the pathogenetic mechanisms of disease (Figures 2–7). Principal funding was from the Canadian Institutes of Health Research. B.A.M. holds the Canada Research Chair in Paediatric Neurogenetics. Additional acknowledgments are available in the Supplemental Data.

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.

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KW - HUMDISEASE

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JF - Cell

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ER -

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

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