title: Charcot-Marie-Tooth-related gene GDAP1 complements cell cycle delay at G2/M phase in Saccharomyces cerevisiae fis1 gene-defective cells.
abstract: Mutations in the GDAP1 gene are responsible of the Charcot-Marie-Tooth CMT4A, ARCMT2K, and CMT2K variants. GDAP1 is a mitochondrial outer membrane protein that has been related to the fission pathway of the mitochondrial network dynamics. As mitochondrial dynamics is a conserved process, we reasoned that expressing GDAP1 in Saccharomyces cerevisiae strains defective for genes involved in mitochondrial fission or fusion could increase our knowledge of GDAP1 function. We discovered a consistent relation between Fis1p and the cell cycle because fis1Δ cells showed G(2)/M delay during cell cycle progression. The fis1Δ phenotype, which includes cell cycle delay, was fully rescued by GDAP1. By contrast, clinical missense mutations rescued the fis1Δ phenotype except for the cell cycle delay. In addition, both Fis1p and human GDAP1 interacted with β-tubulins Tub2p and TUBB, respectively. A defect in the fis1 gene may induce abnormal location of mitochondria during budding mitosis, causing the cell cycle delay at G(2)/M due to its anomalous interaction with microtubules from the mitotic spindle. In the case of neurons harboring defects in GDAP1, the interaction between mitochondria and the microtubule cytoskeleton would be altered, which might affect mitochondrial axonal transport and movement within the cell and may explain the pathophysiology of the GDAP1-related Charcot-Marie-Tooth disease.
authors: Genetics and Molecular Medicine Unit, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors: Anna
authors: A
authors: Estela
authors: David
authors: D
authors: Pla-Martín
authors: Maribel
authors: M
authors: Sánchez-Piris
authors: Hiromi
authors: H
authors: Sesaki
authors: Francesc
authors: F
authors: Palau
mesh_terms: D002455:Cell Division; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase; D005816:Genetic Complementation Test; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: C464859:FIS1 protein, S cerevisiae; C118663:GDAP protein; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D029701:Saccharomyces cerevisiae Proteins; D014404:Tubulin