title: Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels.
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 approximately 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.
authors.affiliation: Department of Evolutionary and Experimental Biology, University of Bologna, 40126 Bologna, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
authors.forename: Alessia
authors.initials: A
authors.lastname: Angelin
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Elisa
authors.initials: E
authors.lastname: Mariani
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Petronilli
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D001692:Biological Transport; D002460:Cell Line; D017077:Culture Media, Conditioned; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D005690:Galactose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes; D009154:Mutation / Q000235:genetics; D009840:Oligomycins / Q000494:pharmacology; D010101:Oxygen Consumption; D010539:Permeability; D016062:Porosity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D004272:DNA, Mitochondrial; D009840:Oligomycins; D019253:Proto-Oncogene Proteins c-bcl-2; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D005947:Glucose; D005690:Galactose