Parkin mutant iPSC-derived dopaminergic neurons display altered circadian clock-dependent mitochondrial energy metabolism and dynamics

Mutations in genes related to mitochondrial quality control, like PARK2, have been associated with almost half of the autosomal recessive forms of early onset Parkinson’s disease (PD). The PARK2 gene encodes for Parkin, an E3 ubiquitin ligase involved in mitophagy-mediated removal of damaged mitochondria. Recent studies have highlighted a link between mitochondrial function and the cell’s molecular circadian clock. The aim of this study was to investigate the interplay between mitochondrial bioenergetics, mitochondrial dynamics, and the cellautonomous circadian clock in iPSC-derived dopaminergic neurons from PD patients carrying PARK2 mutation. We demonstrated that in vitrosynchronized control neurons exhibited robust autonomous oscillations of mitochondrial oxidative phosphorylation (OxPhos) and of mitochondrial network dynamics. By contrast, neurons carrying the Parkin mutation displayed a pronounced dampening of these oscillations. Morphological analysis showed that control neurons cyclically shifted between interconnected and fragmented mitochondrial network states, whereas Parkin-mutant neurons remained persistently fragmented. Transcriptional profiling indicated dysregulation of fusion–fission and mitophagy regulators, with DRP1 and PINK1 upregulated in PD neurons. Notably, analysis of the core clock genes revealed deregulated expression patterns in PD derived dopaminergic neurons. These findings support a reciprocal interplay between the circadian clock gene machinery and mitochondrial function, suggest a Parkin-mediated regulatory mechanism, and unveil a previously underappreciated layer of complexity in Parkinson’s disease pathophysiology that may contribute to dopaminergic neurons vulnerability.