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.
Highlights
Parkinson’s disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta
Considering mitochondrial function rhythmicity and the prominent role of metabolic dysfunction in PD, in the present study we focused on the interplay between circadian clock circuits and metabolism in parkin-null fibroblasts isolated from PD patients
We demonstrated an alteration in the autonomous bioenergetic rhythmicity in fibroblasts obtained from PD patients with parkin mutation
Summary
Parkinson’s disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. While most cases of PD occur sporadically as the result of many different environmental factors, several gene products have been identified as responsible for Mendelian forms of PD, both autosomal and recessive [1]. Since the discovery of mutations in the parkin encoding gene (PARK2) as a cause of autosomal recessive juvenile parkinsonism [2] almost half of all PD cases have been associated with mutations in this gene. Several studies on parkin-null animal models strongly suggest an important role of the parkin encoding gene for the preservation of mitochondrial function. Parkin has emerged as an important factor in the mitochondrial quality control mechanisms [14,15] and in Ca2+-dependent homeostasis [16,17,18]
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