Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels.
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.
Porcelli
Anna Maria
AM
Department of Evolutionary and Experimental Biology, University of Bologna, 40126 Bologna, Italy.
Angelin
Alessia
A
Ghelli
Anna
A
Mariani
Elisa
E
Martinuzzi
Andrea
A
Carelli
Valerio
V
Petronilli
Valeria
V
Bernardi
Paolo
P
Rugolo
Michela
M
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
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