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Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism

1
Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
2
Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy
3
Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), Italy
4
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari “Aldo Moro”, 70124 Bari, Italy
5
Department of Biotechnology and Biosciences, Bicocca University of Milan, 20126 Milan, Italy
6
Division of Internal Medicine and Chronobiology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(11), 2772; https://doi.org/10.3390/ijms20112772
Received: 30 April 2019 / Revised: 23 May 2019 / Accepted: 3 June 2019 / Published: 5 June 2019
(This article belongs to the Special Issue Circadian Rhythms: Molecular and Physiological Mechanisms)
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Abstract

Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases. View Full-Text
Keywords: parkin; mitochondria; circadian clock; Parkinson´s disease; neurodegeneration; phenotypic reprogramming parkin; mitochondria; circadian clock; Parkinson´s disease; neurodegeneration; phenotypic reprogramming
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Pacelli, C.; Rotundo, G.; Lecce, L.; Menga, M.; Bidollari, E.; Scrima, R.; Cela, O.; Piccoli, C.; Cocco, T.; Vescovi, A.L.; Mazzoccoli, G.; Rosati, J.; Capitanio, N. Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism. Int. J. Mol. Sci. 2019, 20, 2772.

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