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PLoS Genet. 2015 Apr 1;11(4):e1005116. doi: 10.1371/journal.pgen.1005116. eCollection 2015 Apr.

CAPER is vital for energy and redox homeostasis by integrating glucose-induced mitochondrial functions via ERR-α-Gabpa and stress-induced adaptive responses via NF-κB-cMYC.

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
2
Verna and Marrs McLean Department of Biochemistry and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas, United States of America; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America.
3
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, United States of America.
4
Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical School, Durham, North Carolina, United States of America.
5
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America; Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
6
Department of Statistics, University of Michigan, Ann Arbor, Michigan, United States of America.
7
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
8
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America.

Abstract

Ever since we developed mitochondria to generate ATP, eukaryotes required intimate mito-nuclear communication. In addition, since reactive oxygen species are a cost of mitochondrial oxidative phosphorylation, this demands safeguards as protection from these harmful byproducts. Here we identified a critical transcriptional integrator which eukaryotes share to orchestrate both nutrient-induced mitochondrial energy metabolism and stress-induced nuclear responses, thereby maintaining carbon-nitrogen balance, and preserving life span and reproductive capacity. Inhibition of nutrient-induced expression of CAPER arrests nutrient-dependent cell proliferation and ATP generation and induces autophagy-mediated vacuolization. Nutrient signaling to CAPER induces mitochondrial transcription and glucose-dependent mitochondrial respiration via coactivation of nuclear receptor ERR-α-mediated Gabpa transcription. CAPER is also a coactivator for NF-κB that directly regulates c-Myc to coordinate nuclear transcriptome responses to mitochondrial stress. Finally, CAPER is responsible for anaplerotic carbon flux into TCA cycles from glycolysis, amino acids and fatty acids in order to maintain cellular energy metabolism to counter mitochondrial stress. Collectively, our studies reveal CAPER as an evolutionarily conserved 'master' regulatory mechanism by which eukaryotic cells control vital homeostasis for both ATP and antioxidants via CAPER-dependent coordinated control of nuclear and mitochondrial transcriptomic programs and their metabolisms. These CAPER dependent bioenergetic programs are highly conserved, as we demonstrated that they are essential to preserving life span and reproductive capacity in human cells-and even in C. elegans.

PMID:
25830341
PMCID:
PMC4382186
DOI:
10.1371/journal.pgen.1005116
[Indexed for MEDLINE]
Free PMC Article

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