title: Sequential actions of SIRT1-RELB-SIRT3 coordinate nuclear-mitochondrial communication during immunometabolic adaptation to acute inflammation and sepsis.
abstract: We reported that NAD(+)-dependent SIRT1, RELB, and SIRT6 nuclear proteins in monocytes regulate a switch from the glycolysis-dependent acute inflammatory response to fatty acid oxidation-dependent sepsis adaptation. We also found that disrupting SIRT1 activity during adaptation restores immunometabolic homeostasis and rescues septic mice from death. Here, we show that nuclear SIRT1 guides RELB to differentially induce SIRT3 expression and also increases mitochondrial biogenesis, which alters bioenergetics during sepsis adaptation. We constructed this concept using TLR4-stimulated THP1 human promonocytes, a model that mimics the initiation and adaptation stages of sepsis. Following increased expression, mitochondrial SIRT3 deacetylase activates the rate-limiting tricarboxylic acid cycle (TCA) isocitrate dehydrogenase 2 and superoxide dismutase 2, concomitant with increases in citrate synthase activity. Mitochondrial oxygen consumption rate increases early and decreases during adaptation, parallel with modifications to membrane depolarization, ATP generation, and production of mitochondrial superoxide and whole cell hydrogen peroxide. Evidence of SIRT1-RELB induction of mitochondrial biogenesis included increases in mitochondrial mass, mitochondrial-to-nuclear DNA ratios, and both nuclear and mitochondrial encoded proteins. We confirmed the SIRT-RELB-SIRT3 adaptation link to mitochondrial bioenergetics in both TLR4-stimulated normal and sepsis-adapted human blood monocytes and mouse splenocytes. We also found that SIRT1 inhibition ex vivo reversed the sepsis-induced changes in bioenergetics.
authors.affiliation: From the Section of Molecular Medicine, tliu@wakehealth.edu.
authors.forename: Tie Fu
authors.initials: TF
authors.lastname: Liu
authors.affiliation: From the Section of Molecular Medicine, the Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Vidula
authors.initials: V
authors.lastname: Vachharajani
authors.affiliation: From the Section of Molecular Medicine.
authors.forename: Patrick
authors.initials: P
authors.lastname: Millet
authors.affiliation: Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, and.
authors.forename: Manish S
authors.initials: MS
authors.lastname: Bharadwaj
authors.affiliation: Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, and.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Molina
authors.affiliation: From the Section of Molecular Medicine, chmccall@wakehealth.edu.
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D061251:Primary Cell Culture; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C497594:Relb protein, mouse; C525046:Sirt3 protein, mouse; D051841:Transcription Factor RelB; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D056566:Sirtuin 3
keywords: Acute Inflammation; Mitochondrial Bioenergetics; Mitochondrial Respiratory Chain Complex; Monocyte; Nuclear-mitochondrial Communication; RELB; Reactive Oxygen Species (ROS); SIRT3; Sepsis; Sirtuin 1 (SIRT1)