Mitf is a master regulator of the v-ATPase forming an Mitf/v-ATPase/TORC1 control module for cellular homeostasis

The v-ATPase is a fundamental eukaryotic enzyme 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 impacts 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-TFE proteins in fly and mammals. Collectively, this evidence points to an ancient Mitf/v-ATPase/TORC1 module that serves as a dynamic modulator of metabolism for cellular homeostasis.