Abstract
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 PPARγ coactivator 1α (PGC-1α). Concurrent induction of the TFEB and PGC-1α pathways results in an increased mitochondrial turnover rate in GCN5L1(-/-) cells. Finally, we show that genetic knockdown of either TFEB or PGC-1α 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.
Highlights
The balance between mitochondrial biogenesis and autophagy controls cellular mitochondrial content
The first identification of a role for GCN5L1 in the regulation of mitochondrial function came through a search for proteins involved in mitochondrial lysine residue acetylation
It was shown that the expression of GCN5L1 led to an increase in lysine acetylation in the mitochondria, and that this worked in opposition to the mitochondrial deacetylase SIRT3 [16]
Summary
The balance between mitochondrial biogenesis and autophagy controls cellular mitochondrial content. 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␣). 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. To counter the effects of mitophagy and maintain sufficient organelles to meet their needs, the cell must stimulate the mechanisms that control mitochondrial biogenesis. We suggest that TFEB and PGC-1␣ act in opposition to each other, under the control of GCN5L1, to maintain cellular mitochondrial content
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