'Secondary' 4216/ND1 and 13708/ND5 Leber's hereditary optic neuropathy mitochondrial DNA mutations do not further impair in vivo mitochondrial oxidative metabolism when associated with the 11778/ND4 mitochondrial DNA mutation.
The pathogenic role of 'secondary' mitochondrial DNA (mtDNA) point mutations, when occurring in patients with Leber's hereditary optic neuropathy (LHON) in association with 'primary' mutations, is still controversial. We used phosphorus magnetic resonance spectroscopy to establish whether two of these 'secondary' LHON mtDNA mutations, 4216/ND1 and 13708/ND5 (haplogroup J), further affect in vivo mitochondrial oxidative metabolism in subjects with the 'primary' 11778/ND4 mtDNA mutation. Brain and skeletal muscle energy metabolism was assessed in 10 subjects homoplasmic for the 11778/ND4 mtDNA mutation and 10 subjects homoplasmic for the same mutation occurring on the haplogroup J mtDNA background. Brain phosphocreatine concentration and phosphorylation potential were significantly reduced and brain inorganic phosphate concentration was significantly increased compared with controls in both groups of 11778/ND4-positive subjects. The degree of reduction in the phosphocreatine concentration and phosphorylation potential and of increase in the inorganic phosphate concentration was, however, similar in the two groups with the 11778/ND4 mtDNA mutation with or without the haplogroup J. Similarly, the rate of muscle phosphocreatine resynthesis after exercise, a sensitive index of the rate of mitochondrial ATP production, was reduced by the same extent in both groups of LHON subjects. This in vivo study does not support synergism of the 4216/ND1 and 13708/ND5 'secondary' mutations with the 11778/ND4 'primary' mutation in determining the deficit of energy metabolism in LHON.
Lodi
R
R
Dipartimento di Medicina Clinica e Biotecnologia Applicata D. Campanacci, Università di Bologna, Bologna, Italy. lodi@med.unibo.it
Montagna
P
P
Cortelli
P
P
Iotti
S
S
Cevoli
S
S
Carelli
V
V
Barbiroli
B
B
D000328:Adult; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D010084:Oxidation-Reduction
D004272:DNA, Mitochondrial