Respiratory Complex I Dysfunction Due to Mitochondrial DNA Mutations Shifts the Voltage Threshold for Opening of the Permeability Transition Pore toward Resting Levels Export

@article{citeulike:3920633, abstract = {We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an [\~{}]50\% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca2+ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases. 10.1074/jbc.M807321200}, author = {Porcelli, Anna M. and Angelin, Alessia and Ghelli, Anna and Mariani, Elisa and Martinuzzi, Andrea and Carelli, Valerio and Petronilli, Valeria and Bernardi, Paolo and Rugolo, Michela}, citeulike-article-id = {3920633}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M807321200}, citeulike-linkout-1 = {http://www.jbc.org/cgi/content/abstract/284/4/2045?rss=1}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19047048}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19047048}, day = {23}, doi = {10.1074/jbc.M807321200}, journal = {J. Biol. Chem.}, keywords = {1, bcl-2, complex, dysfunction, open, porcel09pdf, ptp}, month = {January}, number = {4}, pages = {2045--2052}, posted-at = {2009-01-21 17:39:42}, priority = {2}, title = {Respiratory Complex I Dysfunction Due to Mitochondrial DNA Mutations Shifts the Voltage Threshold for Opening of the Permeability Transition Pore toward Resting Levels}, url = {http://dx.doi.org/10.1074/jbc.M807321200}, volume = {284}, year = {2009} }

TY - JOUR ID - citeulike:3920633 L3 - citeulike-article-id:3920633 N2 - We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an [~]50% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca2+ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases. 10.1074/jbc.M807321200 IS - 4 JF - J. Biol. Chem. EP - 2052 TI - Respiratory Complex I Dysfunction Due to Mitochondrial DNA Mutations Shifts the Voltage Threshold for Opening of the Permeability Transition Pore toward Resting Levels VL - 284 SP - 2045 KW - 1 KW - bcl-2 KW - complex KW - dysfunction KW - open KW - porcel09pdf KW - ptp AU - Porcelli, Anna AU - Angelin, Alessia AU - Ghelli, Anna AU - Mariani, Elisa AU - Martinuzzi, Andrea AU - Carelli, Valerio AU - Petronilli, Valeria AU - Bernardi, Paolo AU - Rugolo, Michela PY - 2009/01/23/ UR - http://dx.doi.org/10.1074/jbc.M807321200 ER -