GCN5-like Protein 1 (GCN5L1) Controls Mitochondrial Content through Coordinated Regulation of Mitochondrial Biogenesis and Mitophagy

Background: The balance between mitochondrial biogenesis and autophagy controls cellular mitochondrial content. Results: Mitochondrial deacetylation-induced mitophagy evokes concurrent and interdependent up-regulation of TFEB and PGC-1 to sustain cellular mitochondrial content. Conclusion: Mitochondrial content is coordinately regulated by the mitochondrial and lysosome biogenesis programs under GCN5L1 control. Significance: Counter-regulatory interdependent programs function to sustain mitochondrial content/homeostasis in a nutrient-sensing, acetylation-dependent manner. Cellular mitochondrial content is governed by the competing processes of organelle biogenesis and degradation. It is proposed that these programs are tightly regulated to ensure that the cell maintains sufficient organelles to meet its biosynthetic, energetic, and other homeostatic requirements. We recently reported that GCN5L1, a putative nutrient-sensing regulator, controls mitochondrial removal by autophagy. Here we show that genetic deletion of GCN5L1 has a direct positive effect on the expression and activity of Transcriptional Factor EB (TFEB), which acts as a master regulator of autophagy. Surprisingly, the induction of TFEB-mediated autophagy pathways does not diminish cellular mitochondrial content, as its activity is countered by induction of the mitochondrial biogenesis transcriptional co-activator PPAR coactivator 1 (PGC-1). Concurrent induction of the TFEB and PGC-1 pathways results in an increased mitochondrial turnover rate in GCN5L1(-/-) cells. Finally, we show that genetic knockdown of either TFEB or PGC-1 leads to a corresponding decrease in the expression of the other gene, indicating that these proteins act coordinately, and in opposition, to maintain cellular mitochondrial content in response to the modulation of nutrient-sensing signatures.