title: Clock genes-dependent acetylation of complex I sets rhythmic activity of mitochondrial OxPhos.
abstract: Physiology of living beings show circadian rhythms entrained by a central timekeeper present in the hypothalamic suprachiasmatic nuclei. Nevertheless, virtually all peripheral tissues hold autonomous molecular oscillators constituted essentially by circuits of gene expression that are organized in negative and positive feed-back loops. Accumulating evidence reveals that cell metabolism is rhythmically controlled by cell-intrinsic molecular clocks and the specific pathways involved are being elucidated. Here, we show that in vitro-synchronized cultured cells exhibit BMAL1-dependent oscillation in mitochondrial respiratory activity, which occurs irrespective of the cell type tested, the protocol of synchronization used and the carbon source in the medium. We demonstrate that the rhythmic respiratory activity is associated to oscillation in cellular NAD content and clock-genes-dependent expression of NAMPT and Sirtuins 1/3 and is traceable back to the reversible acetylation of a single subunit of the mitochondrial respiratory chain Complex I. Our findings provide evidence for a new interlocked transcriptional-enzymatic feedback loop controlling the molecular interplay between cellular bioenergetics and the molecular clockwork.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Cela
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Scrima
authors.affiliation: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
authors.affiliation: Medical Genetics Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.affiliation: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Benegiamo
authors.affiliation: Medical Genetics Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Augello
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: Fugetto
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Menga
authors.affiliation: Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rubino
authors.affiliation: Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Fuhr
authors.affiliation: Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Relógio
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Piccoli
authors.affiliation: Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy. Electronic address: g.mazzoccoli@operapadrepio.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy. Electronic address: nazzareno.capitanio@unifg.it.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Capitanio
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D056926:CLOCK Proteins / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010507:Periodicity; D011499:Protein Processing, Post-Translational; D013997:Time Factors
chemical_list: D000123:Acetyltransferases; D056926:CLOCK Proteins; D042967:Electron Transport Complex I
keywords: Clock-genes; Complex I; Mitochondria; NAD; Oxidative phosphorylation; Sirtuins