High mitochondrial DNA copy number is a protective factor from vision loss in heteroplasmic leber’s hereditary optic neuropathy (LHON)

PURPOSE. Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. It is characterized by as yet undisclosed genetic and environmental factors affecting the incomplete penetrance. METHODS. We identified 27 LHON subjects who possess heteroplasmic primary LHON mutations. Mitochondrial DNA (mtDNA) copy number was evaluated. RESULTS. The presence of centrocecal scotoma, an edematous, hyperemic optic nerve head, and vascular tortuosity, as well as telangiectasia was recognized in affected subjects. We found higher cellular mtDNA content in peripheral blood cells of unaffected heteroplasmic mutation carriers with respect to the affected. CONCLUSIONS. The increase of cellular mtDNA content prevents complete loss of vision despite the presence of a heteroplasmic state of LHON primary mutation, suggesting that it is a key factor responsible for penetrance of LHON

Allosteric interactions and proton conducting pathways in proton pumping aa(3) oxidases: Heme a as a key coupling element.

AbstractIn this paper allosteric interactions in protonmotive heme aa3 terminal oxidases of the respiratory chain are dealt with. The different lines of evidence supporting the key role of H+/e− coupling (redox Bohr effect) at the low spin heme a in the proton pump of the bovine oxidase are summarized. Results are presented showing that the I-R54M mutation in P. denitrificans aa3 oxidase, which decreases by more than 200mV the Em of heme a, inhibits proton pumping. Mutational aminoacid replacement in proton channels, at the negative (N) side of membrane-inserted prokaryotic aa3 oxidases, as well as Zn2+ binding at this site in the bovine oxidase, uncouples proton pumping. This effect appears to result from alteration of the structural/functional device, closer to the positive, opposite (P) surface, which separates pumped protons from those consumed in the reduction of O2 to 2 H2O. This article is part of a Special Issue entitled: Respiratory Oxidases

Allosteric interactions and proton conducting pathways in proton pumping aa3 oxidases: Heme a as a key coupling element

In this paper allosteric interactions in protonmotive heme aa3 terminal oxidases of respiratory chain are dealt with. The different lines of evidence supporting the key role of H+/e- coupling (redox Bohr effect) at the low spin heme a in the proton pump of the bovine oxidase are summarized. Results are presented showing that the I-R54M mutation in P. denitrificans aa3 oxidase, which decreases by more than 200 mV the Em of heme a, inhibits proton pumping. Mutational aminoacid replacement in proton channels, at the negative (N) side of membrane-inserted prokaryotic aa3 oxidases, as well as Zn2 + binding at this site in the bovine oxidase, uncouple proton pumping. This effect appears to result from alteration of the structural/functional device, closer to the positive, opposite (P) surface, which separate pumped protons from those consumed in the reduction of O2 to 2 H2O. This article is part of a Special Issue entitled: Respiratory Oxidase