Ubiquitin-Conjugating Enzymes Ubc1 and Ubc4 Mediate the Turnover of Hap4, a Master Regulator of Mitochondrial Biogenesis in .

Mitochondrial biogenesis is tightly regulated in response to extracellular and intracellular signals, thereby adapting yeast cells to changes in their environment. The Hap2/3/4/5 complex is a master transcriptional regulator of mitochondrial biogenesis in yeast. Hap4 is the regulatory subunit of the complex and exhibits increased expression when the Hap2/3/4/5 complex is activated. In cells grown under glucose derepression conditions, both the transcript level and Hap4 protein level are increased. As part of an inter-organellar signaling mechanism coordinating gene expression between the mitochondrial and nuclear genomes, the activity of the Hap2/3/4/5 complex is reduced in respiratory-deficient cells, such as cells lacking mitochondrial DNA, as a result of reduced Hap4 protein levels. However, the underlying mechanism is unclear. Here, we show that reduced expression in cells is mediated through both transcriptional and post-transcriptional mechanisms. We show that loss of mitochondrial DNA increases the turnover of Hap4, which requires the 26S proteasome and ubiquitin-conjugating enzymes Ubc1 and Ubc4. Stabilization of Hap4 in the double mutant leads to increased expression of Hap2/3/4/5-target genes. Our results indicate that mitochondrial biogenesis in yeast is regulated by the functional state of mitochondria partly through ubiquitin/proteasome-dependent turnover of Hap4.