Abstract
The Drosophila mutant tko25t exhibits a deficiency of mitochondrial protein synthesis, leading to a global insufficiency of respiration and oxidative phosphorylation. This entrains an organismal phenotype of developmental delay and sensitivity to seizures induced by mechanical stress. We found that the mutant phenotype is exacerbated in a dose-dependent fashion by high dietary sugar levels. tko25t larvae were found to exhibit severe metabolic abnormalities that were further accentuated by high-sugar diet. These include elevated pyruvate and lactate, decreased ATP and NADPH. Dietary pyruvate or lactate supplementation phenocopied the effects of high sugar. Based on tissue-specific rescue, the crucial tissue in which this metabolic crisis initiates is the gut. It is accompanied by down-regulation of the apparatus of cytosolic protein synthesis and secretion at both the RNA and post-translational levels, including a novel regulation of S6 kinase at the protein level.
Highlights
Mitochondrial DNA encodes just 13 polypeptides in most metazoans, representing a small but vital subset of the subunits of the apparatus of oxidative phosphorylation (OXPHOS). In addition it encodes the RNA components, i.e. 2 rRNAs and 22 tRNAs, that contribute to the separate machinery of protein synthesis inside mitochondria, that generates these polypeptides
Our analyses have focused on a Drosophila model of mitochondrial disease [3] in which a nuclear mis-sense mutation in the gene for mitoribosomal protein S12 [4] gives rise to a quantitative defect in mitochondrial protein synthesis [5] impacting all four OXPHOS enzyme complexes dependent on mitochondrial translation products [6]
Comparisons of larvae grown on different diets revealed a set of metabolic disturbances in tko25t larvae that were generally accentuated by high-sugar diet
Summary
Mitochondrial DNA encodes just 13 polypeptides in most metazoans, representing a small but vital subset of the subunits of the apparatus of oxidative phosphorylation (OXPHOS). Polyamines did show alterations in tko25t (Panel D in S3 Fig), but the effect was the same, regardless of diet, whereas wild-type larvae showed clear increases in polyamine levels when grown on high sugar.
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