Mitophagy has been recently described as a mechanism of elimination of damaged organelles. Although the regulation of the amount of mitochondria is a core issue concerning cellular energy homeostasis, the relationship between mitochondrial degradation and energetic activity has not yet been considered. Here, we report that the stimulation of mitochondrial oxidative phosphorylation enhances mitochondrial renewal by increasing its degradation rate. Upon high oxidative phosphorylation activity, we found that the small GTPase Rheb is recruited to the mitochondrial outer membrane. This mitochondrial localization of Rheb promotes mitophagy through a physical interaction with the mitochondrial autophagic receptor Nix and the autophagosomal protein LC3-II. Thus, Rheb-dependent mitophagy contributes to the maintenance of optimal mitochondrial energy production. Our data suggest that mitochondrial degradation contributes to a bulk renewal of the organelle in order to prevent mitochondrial aging and to maintain the efficiency of oxidative phosphorylation.
SUMMARYThe overall aim of this study was to (1) evaluate the adaptive value of mitochondrial DNA by comparing mitochondrial performance in populations possessing different haplotypes and distribution, and to (2) evaluate the sensitivity of different enzymes of the electron transport system (ETS) during temperature-induced changes. We measured the impact of temperature of mitochondrial respiration and several key enzymes of mitochondrial metabolism in two mitotypes (siII and siIII) of Drosophila simulans. The temperature dependencies of oxygen consumption for mitochondria isolated from flight muscle was assessed with complex I substrates (pyruvate + malate + proline) and with sn glycerol-3-phosphate (to reduce complex III via glycerophosphate dehydrogenase) in both coupled and uncoupled states. Activities of citrate synthase, cytochrome c oxidase (COX), catalase and aconitase, and the excess capacity of COX at high convergent pathway flux were also measured as a function of temperature. Overall, our results showed that functional differences between the two mitotypes are few. Results suggest that differences between the two mitotypes could hardly explain the temperature-specific differences measured in mitochondria performances. It suggests that some other factor(s) may be driving the maintenance of mitotypes. We also show that the different enzymes of the ETS have different thermal sensitivities. The catalytic capacities of these enzymes vary with temperature changes, and the corresponding involvement of the different steps on mitochondrial regulation probably varies with temperature. For example, the excess COX capacity is low, even non-existent, at high and intermediate temperatures (18°C, 24°C and 28°C) whereas it is quite high at a lower temperature (12°C), suggesting release of respiration control by COX at low temperature. Supplementary material available online at
Given the presence of Src and PTP1B within rat brain mitochondria, we have investigated whether PTP1B regulates Src activity in mitochondria as in the cytosol. Results showed that Src was stimulated by in vitro addition of ATP to mitochondria, and this stimulation was reversed by a membrane-permeable allosteric inhibitor of PTP1B and by a potent selective Src inhibitor. They also indicated a direct action of PTP1B on phosphorylated tyrosine 527 residue of Src, thus implicating a role for PTP1B in the modulation of Src activity in mitochondria. Putative Src and PTP1B substrates were identified by liquid chromatography tandem mass spectrometry and two-dimensional blue native/SDS-PAGE. Both inhibitors inhibited ADP-stimulated respirations concurrently with Src activation and complex IV activation by ATP, while having no effect or increasing the activity of the other complexes. Our analysis emphasizes the regulatory function of Src and its modulation by PTP1B on oxidative phosphorylation in mitochondria.
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