Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism

Consiglia Pacelli, Giovannina Rotundo, Lucia Lecce, Marta Menga, Eris Bidollari, Rosella Scrima, Olga Cela, Claudia Piccoli, Tiziana Cocco, Angelo Luigi Vescovi, Gianluigi Mazzoccoli, Jessica Rosati, Nazzareno Capitanio

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Volume20
Issue number11
DOIs
Publication statusPublished - Jun 5 2019

Keywords

  • circadian clock
  • mitochondria
  • neurodegeneration
  • parkin
  • Parkinson´s disease
  • phenotypic reprogramming

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    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. (2019). Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism. International Journal of Molecular Sciences, 20(11). https://doi.org/10.3390/ijms20112772