title: Clock-genes and mitochondrial respiratory activity: Evidence of a reciprocal interplay.
abstract: In the past few years mounting evidences have highlighted the tight correlation between circadian rhythms and metabolism. Although at the organismal level the central timekeeper is constituted by the hypothalamic suprachiasmatic nuclei practically all the peripheral tissues are equipped with autonomous oscillators made up by common molecular clockworks represented by circuits of gene expression that are organized in interconnected positive and negative feed-back loops. In this study we exploited a well-established in vitro synchronization model to investigate specifically the linkage between clock gene expression and the mitochondrial oxidative phosphorylation (OxPhos). Here we show that synchronized cells exhibit an autonomous ultradian mitochondrial respiratory activity which is abrogated by silencing the master clock gene ARNTL/BMAL1. Surprisingly, pharmacological inhibition of the mitochondrial OxPhos system resulted in dramatic deregulation of the rhythmic clock-gene expression and a similar result was attained with mtDNA depleted cells (Rho0). Our findings provide a novel level of complexity in the interlocked feedback loop controlling the interplay between cellular bioenergetics and the molecular clockwork. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Scrima
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Cela
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: Medical Genetics Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Augello
authors.affiliation: Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, Germany; Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rubino
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarato
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: Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, Germany; Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Fuhr
authors.affiliation: Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, Germany; Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin and Humboldt-Universität zu 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: D056930:ARNTL Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000968:Antimycin A / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D057906:Circadian Clocks / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D004272:DNA, Mitochondrial; D009840:Oligomycins; D034741:RNA, Small Interfering; D012402:Rotenone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000968:Antimycin A; D008156:Luciferases
keywords: Clock-genes; Mitochondria; Oxidative phosphorylation