title: GCN5-like protein 1 (GCN5L1) controls mitochondrial content through coordinated regulation of mitochondrial biogenesis and mitophagy.
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.
authors.affiliation: From the Laboratory of Mitochondrial Biology and Metabolism, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Iain
authors.initials: I
authors.lastname: Scott
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Webster
authors.forename: Carmen K
authors.initials: CK
authors.lastname: Chan
authors.forename: Joshua U
authors.initials: JU
authors.lastname: Okonkwo
authors.forename: Kim
authors.initials: K
authors.lastname: Han
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001343:Autophagy / Q000502:physiology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D008247:Lysosomes / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D063306:Mitophagy / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C000619640:BLOC1S1 protein, mouse; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C484068:Tcfeb protein, mouse; D014157:Transcription Factors; D000105:Acetyl Coenzyme A
keywords: Acetyl Coenzyme A; Acetylation; Autophagy; GCN5L1; Lysosomes; Mitochondria; Mitophagy; PGC1α; Subcellular Organelles