title: 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.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Yun Kyoung
authors.initials: YK
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.affiliation: 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.
authors.forename: Suman
authors.initials: S
authors.lastname: Maity
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical School, Durham, North Carolina, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.affiliation: 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.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Lonard
authors.affiliation: Department of Statistics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Michailidis
authors.affiliation: 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.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical School, Durham, North Carolina, United States of America.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: 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.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.affiliation: 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.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004734:Energy Metabolism; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D051268:GA-Binding Protein Transcription Factor; D005947:Glucose; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D015534:Trans-Activators; D000097983:ERRalpha Estrogen-Related Receptor; C495656:Gabpa protein, mouse; C446024:Rnpc2 protein, mouse
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