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Biochim Biophys Acta. 2016 Apr;1863(4):596-606. doi: 10.1016/j.bbamcr.2015.12.018. Epub 2015 Dec 28.

Clock genes-dependent acetylation of complex I sets rhythmic activity of mitochondrial OxPhos.

Author information

1
Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
2
Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
3
Medical Genetics Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
4
Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
5
Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, Berlin, Germany.
6
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.
7
Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy. Electronic address: nazzareno.capitanio@unifg.it.

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.

KEYWORDS:

Clock-genes; Complex I; Mitochondria; NAD; Oxidative phosphorylation; Sirtuins

PMID:
26732296
DOI:
10.1016/j.bbamcr.2015.12.018
[Indexed for MEDLINE]
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