Increasing mitochondrial substrate-level phosphorylation can rescue respiratory growth of an ATP synthase-deficient yeast.
In a previous study we have identified Fmc1p, a mitochondrial protein involved in the assembly/stability of the yeast F0F1-ATP synthase at elevated temperatures. The deltafmc1 mutant was shown to exhibit a severe phenotype of very slow growth on respiratory substrates at 37 degrees C. We have isolated ODC1 as a multicopy suppressor of the fmc1 deletion restoring a good respiratory growth. Odc1p expression level was estimated to be at least 10 times higher in mitochondria isolated from the deltafmc1/ODC1 transformant as compared with wild type mitochondria. Interestingly, ODC1 encodes an oxodicarboxylate carrier, which transports alpha-ketoglutarate and alpha-ketoadipate or any other transported tricarboxylic acid cycle intermediate in a counter-exchange through the inner mitochondrial membrane. We show that the suppression of the respiratory-growth-deficient fmc1 by the overexpressed Odc1p was not due to a restored stable ATP synthase. Instead, the rescuing mechanism involves an increase in the flux of tricarboxylic acid cycle intermediate from the cytosol into the mitochondria, leading to an increase in the alpha-ketoglutarate oxidative decarboxylation, resulting in an increase in mitochondrial substrate-level-dependent ATP synthesis. This mechanism of metabolic bypass of a defective ATP synthase unravels the physiological importance of intramitochondrial substrate-level phosphorylations. This unexpected result might be of interest for the development of therapeutic solutions in pathologies associated with defects in the oxidative phosphorylation system.
Schwimmer
Christine
C
Institut de Biochimie et Génétique Cellulaires CNRS/Université Victor Ségalen Bordeaux2, 1 rue Camille St Saëns, 33077 Bordeaux Cedex, France. christine.schwimmer@ibgc.u-bordeaux2.fr
Lefebvre-Legendre
Linnka
L
Rak
Malgorzata
M
Devin
Anne
A
Slonimski
Piotr P
PP
di Rago
Jean-Paul
JP
Rigoulet
Michel
M
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D019069:Cell Respiration / Q000502:physiology*; D002952:Citric Acid Cycle / Q000502:physiology; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013696:Temperature
D029382:Dicarboxylic Acid Transporters; C504819:Fmc1 protein, S cerevisiae; D024101:Mitochondrial Proteins; C504820:ODC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases