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The v-ATPase is a fundamental eukaryotic enzyme that is central to cellular homeostasis. Although its impact on key metabolic regulators such as TORC1 is well documented, our knowledge of mechanisms that regulate v-ATPase activity is limited. Here, we report that the Drosophila transcription factor Mitf is a master regulator of this holoenzyme. Mitf directly controls transcription of all 15 v-ATPase components through M-box cis-sites and this coordinated regulation affects holoenzyme activity in vivo. In addition, through the v-ATPase, Mitf promotes the activity of TORC1, which in turn negatively regulates Mitf. We provide evidence that Mitf, v-ATPase and TORC1 form a negative regulatory loop that maintains each of these important metabolic regulators in relative balance. Interestingly, direct regulation of v-ATPase genes by human MITF also occurs in cells of the melanocytic lineage, showing mechanistic conservation in the regulation of the v-ATPase by MITF family proteins in fly and mammals. Collectively, this evidence points to an ancient module comprising Mitf, v-ATPase and TORC1 that serves as a dynamic modulator of metabolism for cellular homeostasis.

Original publication




Journal article


Journal of cell science

Publication Date





2938 - 2950


Department of Ophthalmology, Center for Vision Research and SUNY Eye Institute, Upstate Medical University, Syracuse, 13210 NY, USA.


Cell Line, Tumor, Cell Membrane, Melanocytes, Animals, Humans, Drosophila, Melanoma, Mitochondrial Proton-Translocating ATPases, Vacuolar Proton-Translocating ATPases, Drosophila Proteins, Transcription Factors, RNA, Small Interfering, Transcription, Genetic, RNA Interference, Enzyme Activation, Homeostasis, Microphthalmia-Associated Transcription Factor, Promoter Regions, Genetic