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In a recently published study, findings revealed that mitochondrial dysfunction in patients with idiopathic REM sleep behavior disorder may serve as a predictor for the progression of Parkinson disease.
Gerardo Ongari, PhD
Newly published in Movement Disorders, findings from a recent analysis showed that patients with idiopathic REM sleep behavior disorder (iRBD), demonstrated mitochondrial dysfunction in fibroblasts and were associated with early stage of Parkinson disease (PD). These results suggest that mitochondrial dysfunction in patients with iRBD might predispose to worsening of the bioenergetic profile in patients with PD who convert (RBD-PD), underscoring these alterations as potential predictors of the phenoconversion to PD.1
Following the clinical evaluation of 28 individuals, patients with iRBD (n = 10) showed deterioration in nonmotor scores compared with healthy controls (n = 10). This included a reduction in the Scale for Outcomes in Parkinson's Disease-Autonomic and University of Pennsylvania Smell Identification Test scores. As expected, patients with RBD-PD (n = 8) had significantly higher MDS-Unified Parkinson's Disease Rating Scale motor subscale scores compared with patients with iRBD (P = .006), which did not differ from controls.
“From a clinical perspective, enrolled patients with iRBD exhibited constipation (50%), depression (30%), and a general reduction in UPSIT scale scores, although only 1 patient had overt hyposmia. No baseline variations in mitochondrial respiration were observed between iRBD and control fibroblasts,” lead author Gerardo Ongari, PhD, postdoctoral researcher, in the section of cellular and molecular neurobiology at IRCCS Mondino Foundation, in Pavia, Italy, and colleagues wrote.1 “However, when challenged with an increased energy demand, cells showed a significant decline in maximal and spare respiration. Furthermore, patients with RBD-PD exhibited reduced oxygen consumption associated with adenosine triphosphate (ATP) production.”
In this study, investigators explored mitochondrial activity in fibroblasts derived from patients with iRBD to identify a biochemical profile that could mark the presence of impending neurodegeneration. The researchers divided the participants into 3 groups: patients diagnosed with iRBD, patients with RBD-PD, and healthy controls. Ongari and colleagues performed a comprehensive assessment of mitochondrial function, which included an evaluation of mitochondrial morphology, an analysis of mitochondrial protein expression levels by western blot, and a measurement of mitochondrial respiration using the Seahorse XFe24 analyzer.
READ MORE: Specific Cerebellar Structural Alterations in Parkinson Disease Associated With Disease Staging
Under basal conditions, findings showed a mild, nonsignificant decrease of basal respiration and ATP production in fibroblast of patients with iRBD compared with the controls. Both values were reduced further in fibroblasts among patients with RBD-PD, particularly those associated with the ATP production that was significantly lower in respect with the controls (CTR) (CTR vs. RBD-PD, P = .032). At maximal work capacity, both iRBD and RBD-PD cells were unable to respond efficiently to the stimulus which were confirmed by the oxygen consumption rate associated with maximal respiration, (CTR vs. iRBD, P = .006; CTR vs. RBD-PD, P = .006). Additionally, spare respiration, which corresponds to the difference between the basal and maximal respiration, was significantly reduced in both groups (CTR vs. iRBD, P = .016; CTR vs. RBD-PD, P = .007).
“The more pronounced deficit in mitochondrial respiration observed in patients with RBD-PD in comparison with the iRBD ones might be linked to altered expression levels of proteins involved in the mitochondrial electron transport chain (ETC), particularly complexes III and V,” Ongari et al noted.1 “In the presence of mitochondrial fragmentation, cells may fail to reach maximal respiration levels, reducing respiratory reserve, as seen in RBD-PD. Although patients with iRBD lacked significant ETC protein or network alterations, they displayed robust reductions in maximal and spare respiration. This might result from multiple, milder alterations, including slight decreases in complexes I and V expression and network branch reduction. Although these changes may not affect baseline mitochondrial respiration, they can impact cellular response under stress conditions.”
Findings showed a slight, nonsignificant decrease of complex I levels in both patients with iRBD and patients with RBD-PD. The authors noted a significant reduction in complex III, the ubiquinol cytochrome c reductase (CTR vs. RBD-PD, P = .0152), and V, the ATP synthase (CTR vs. RBD-PD, P = .0028), in fibroblasts of patients with RBD-PD. All told, that the iRBD cells did not have a similar reduction in complex III levels although they showed an intermediate level of expression of complex V in respect with the controls and RBD-PD.
Further in the analysis, confocal images of mitochondrial network displayed the presence of a widespread fragmentation in RBD-PD fibroblasts. The patients with RBD-PD showed a reduction in the number of mitochondrial branches (CTR vs. RBD-PD, P = .005) as well as their complexity (CTR vs. RBD-PD, P = .021). Although researchers observed reduction in network complexity, a significant alteration in mitochondrial footprint was not observed between the groups.
“We believe the reported alterations may serve as predictive biomarkers for neurodegeneration and potentially progression to PD. However, because of the limited number of patients in our study, we acknowledge the need for larger population studies with extended patient follow-up to validate these hypotheses,” Ongari et al noted.1 “A comprehensive analysis of mitochondrial dysfunction in iRBD patients may offer new tools for identifying individuals at a higher risk of impending neurodegeneration, making them potential candidates for neuroprotective strategies before irreversible damage occurs. To this end, we are currently assessing additional changes, including reactive oxygen species overproduction, alterations in the enzymatic activity of ETC complexes, and the role of other mitochondrial proteins in these changes.”
