title: Microtubule disorganization affects the mitochondrial permeability transition pore in cardiac myocytes.
abstract: BACKGROUND
  Microtubule (MT) disorganization is related to cardiac disorders. To elucidate the mechanism by which disorganization of the MT network deteriorates cardiac function, the relationship between MT disorganization and mitochondrial permeability transition pore (mPTP) in cardiac myocytes was investigated.
  
  
  RESULTS
  The effects of MT stabilization (by paclitaxel) and MT disruption (by nocodazole) on mitochondrial membrane potential (ΔΨm) and the opening of mPTP were measured in permeabilized Sprague-Dawley rat myocytes. Both paclitaxel and nocodazole depolarized ΔΨm and opened mPTP. When isolated mitochondria were exposed to paclitaxel or nocodazole, there were no changes in ΔΨm. The effects of paclitaxel or nocodazole on ΔΨm depolarization and mPTP were inhibited by cyclosporin A. Treatment of myocytes with 0Ca+BAPTA or inhibition of sarcoplasmic reticulum (SR) Ca(2+) uptake by thapsigargin prevented the effect of paclitaxel on mPTP, but not that of nocodazole. Inhibition of the mitochondrial Ca(2+) uniporter by Ru360 did not alter the effect of paclitaxel on mPTP. Paclitaxel reduced the expression of the mitochondrial fusion protein, mitofusin-2, and induced mitochondrial fragmentation.
  
  
  CONCLUSIONS
  Disruption of the MT network by nocodazole might destroy the MT-mitochondria connection and alter mitochondrial function. MT disorganization by paclitaxel could regulate mPTP through the outer mitochondrial membrane complex and the Ca(2+)-sensitive signaling pathway, which also interacts with the mitochondrial fusion protein, mitofusin-2.
authors.affiliation: Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine.
authors.forename: Azumi
authors.initials: A
authors.lastname: Kumazawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Katoh
authors.forename: Daishi
authors.initials: D
authors.lastname: Nonaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masao
authors.initials: M
authors.lastname: Saotome
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Urushida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017975:Ruthenium Compounds / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; C112020:Ru 360; D017975:Ruthenium Compounds; D050257:Tubulin Modulators; D019284:Thapsigargin; D016572:Cyclosporine; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; D017239:Paclitaxel; D015739:Nocodazole