Altered threshold of the mitochondrial permeability transition pore in Ullrich congenital muscular dystrophy

We have studied the effects of rotenone in myoblasts from healthy donors and from patients with Ullrich congenital muscular dystrophy (UCMD), a severe muscle disease due to mutations in the genes encoding the extracellular matrix protein collagen VI. Addition of rotenone to normal myoblasts caused a very limited mitochondrial depolarization because the membrane potential was maintained by the FlFO synthase, as indicated by full depolarization following the subsequent addition of oligomycin. In LJCMD myoblasts rotenome instead caused complete mitochondrial depolarization, which was followed by faster ATP depletion than in healthy myoblasts. Mitochondrial depolarization could be prevented by treatment with cyclosporin A and intracellular Ca2+ chelators, while it was worsened by depleting Ca2+ stores with thapsigargin. Thus, in UCMD myoblasts rotenone-induced depolarization is due to opening of the permeability transition pore rather than to inhibition of electron flux as such. These findings indicate that in UCMD myoblasts the threshold for pore opening is very close to the resting membrane potential, so that even a small depolarization causes permeability transition pore opening and precipitates ATP depletion. (c) 2008 Elsevier B.V. All rights reserved.