Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the gene MFN2 and is one of the most common inherited peripheral neuropathies. Mfn2 is one of two mammalian mitofusin GTPases that promote mitochondrial fusion and maintain organelle integrity. It is not known how mitofusin mutations cause axonal degeneration and CMT2A disease. We used the conserved yeast mitofusin FZO1 to study the molecular consequences of CMT2A mutations on Fzo1 function in vivo and in vitro. One mutation (analogous to the CMT2A I213T substitution in the GTPase domain of Mfn2) not only abolishes GTP hydrolysis and mitochondrial membrane fusion but also reduces Mdm30-mediated ubiquitylation and degradation of the mutant protein. Importantly, complexes of wild type and the mutant Fzo1 protein are GTPase active and restore ubiquitylation and degradation of the latter. These studies identify diverse and unexpected effects of CMT2A mutations, including a possible role for mitofusin ubiquitylation and degradation in CMT2A pathogenesis, and provide evidence for a novel link between Fzo1 GTP hydrolysis, ubiquitylation, and mitochondrial fusion.
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Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Amiott, Elizabeth A.
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Lott, Paul
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Univ Utah, Sch Med, Dept Neurol Human Genet Pathol & Pediat, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Lott, Paul
;
Soto, Jamie
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机构:Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Soto, Jamie
;
Kang, Peter B.
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Harvard Univ, Sch Med, Boston, MA 02115 USA
Childrens Hosp, Dept Neurol, Boston, MA 02115 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Kang, Peter B.
;
McCaffery, J. Michael
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Johns Hopkins Univ, Dept Biol, Integrated Imaging Ctr, Baltimore, MD 21218 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
McCaffery, J. Michael
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DiMauro, Salvatore
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Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
DiMauro, Salvatore
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Abel, E. Dale
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机构:Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Abel, E. Dale
;
Flanigan, Kevin M.
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Univ Utah, Sch Med, Dept Neurol Human Genet Pathol & Pediat, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Flanigan, Kevin M.
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Lawson, Victoria H.
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Univ Utah, Sch Med, Dept Neurol Human Genet Pathol & Pediat, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Lawson, Victoria H.
;
Shaw, Janet M.
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Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
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Washington Univ, Hope Ctr Neurol Disorders, Dept Neurol, St Louis, MO 63110 USAWashington Univ, Hope Ctr Neurol Disorders, Dept Neurol, St Louis, MO 63110 USA
机构:
Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Amiott, Elizabeth A.
;
Lott, Paul
论文数: 0引用数: 0
h-index: 0
机构:
Univ Utah, Sch Med, Dept Neurol Human Genet Pathol & Pediat, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Lott, Paul
;
Soto, Jamie
论文数: 0引用数: 0
h-index: 0
机构:Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Soto, Jamie
;
Kang, Peter B.
论文数: 0引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Boston, MA 02115 USA
Childrens Hosp, Dept Neurol, Boston, MA 02115 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Kang, Peter B.
;
McCaffery, J. Michael
论文数: 0引用数: 0
h-index: 0
机构:
Johns Hopkins Univ, Dept Biol, Integrated Imaging Ctr, Baltimore, MD 21218 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
McCaffery, J. Michael
;
DiMauro, Salvatore
论文数: 0引用数: 0
h-index: 0
机构:
Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
DiMauro, Salvatore
;
Abel, E. Dale
论文数: 0引用数: 0
h-index: 0
机构:Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Abel, E. Dale
;
Flanigan, Kevin M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Utah, Sch Med, Dept Neurol Human Genet Pathol & Pediat, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Flanigan, Kevin M.
;
Lawson, Victoria H.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Utah, Sch Med, Dept Neurol Human Genet Pathol & Pediat, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
Lawson, Victoria H.
;
Shaw, Janet M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USAUniv Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
机构:
Washington Univ, Hope Ctr Neurol Disorders, Dept Neurol, St Louis, MO 63110 USAWashington Univ, Hope Ctr Neurol Disorders, Dept Neurol, St Louis, MO 63110 USA