What do mitochondrial diseases teach us about normal mitochondrial functions...that we already knew: threshold expression of mitochondrial defects.
This paper shows how metabolic control analysis (MCA) can help to explain two important features of mitochondrial diseases: (i) the existence of a threshold in the expression of the complex deficiencies on the respiratory flux or on ATP synthesis, i.e. the fact that it is necessary to have a large complex deficiency in order to observe a substantial decrease in these fluxes; (ii) the tissue specificity, i.e. the fact that all tissues are not affected, even if the complex deficiency is present in all of them. We also show the limits of MCA, particularly when considering the in vivo situation. However, MCA offers a new way to consider mitochondrial diseases. The fact that fluxes only slightly change, when a complex is affected, is done at the expense of great changes in intermediate metabolite concentrations; intermediate metabolites situated upstream from the deficient complex are more reduced, leading to a greater generation of free radicals. This could bring an explanation for the diseases observed in conditions where the mitochondrial rate of ATP synthesis is only slightly affected.
INSERM EMI 9929, Université Bordeaux 2, 146 rue Léo-Saignat, F-33076 Bordeaux Cédex, France. jpm@u-bordeaux2.fr
J P
JP
Mazat
R
R
Rossignol
M
M
Malgat
C
C
Rocher
B
B
Faustin
T
T
Letellier
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D010085:Oxidative Phosphorylation; D011190:Potassium Cyanide / Q000494:pharmacology
D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D011190:Potassium Cyanide