Estela A, Pla-Martin D, Sanchez-Piris M, Sesaki H, Palau F

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 ...

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strains defective for genes involved in mitochondrial fission or fusion could show some knowledge on GDAP1 function. We have discovered a consistent relation between Fis1p and the cell cycle as fis1Δ cells showed G2/M delay during the cell cycle progression. fis1Δ phenotype, which includes cell cycle delay, is fully rescued by GDAP1. By contrast, clinical missense mutations rescued fis1Δ phenotype except for the cell cycle delay. In addition, both Fis1p and the human GDAP1 interact with β-tubulins Tub2p and TUBB, respectively. Defect in the fis1 gene may induce abnormal location of mitochondria during budding mitosis causing the cell cycle delay at G2/M due to its anomalous interaction with microtubules from the mitotic spindle. In the case of neurons harboring defects in GDAP1, mitochondria and microtubule cytoskeleton interaction would be altered, which might affect mitochondrial axonal transport and movement within the cell, and may explain the pathophysiology of the Charcot-Marie-Tooth disease.

Date: Sep. 02, 2011

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