Impaired mitochondrial respiration in REM-sleep behavior disorder as possible biomarker of Parkinson's Disease

Background: Idiopathic REM sleep Behavior Disorder (iRBD) is recognized to be associated with prodromal Parkinson disease (PD). However, the mechanisms linking phenoconversion of iRBD to PD have not yet been clarified. Considering the association between mitochondrial dysfunction and sleep disturbances in PD, we aimed to explore mitochondrial activity in fibroblasts derived from iRBD patients to identify a biochemical profile that could mark the presence of impending neurodegeneration.

Methods: The study involved 28 participants, divided into three groups: patients with iRBD, PD patients converted from iRBD (RBD-PD) and healthy subjects. We performed a comprehensive assessment of mitochondrial function, including an examination of mitochondrial morphology, analysis of mitochondrial protein expression levels using western blot analysis, and measurement of mitochondrial respiration using the Seahorse XFe24 analyzer.

Results: Although no differences in mitochondrial respiration between iRBD and control fibroblasts were found in basal conditions, when cells are challenged with a higher energy demand, they exhibit a significant drop in maximal (p=0.006) and spare respiration (p=0.006). RBD patients already converted to PD, RBD-PD, show the same alterations and, in addition, have a reduction in oxygen consumption linked to ATP production (p=0.032).

Conclusions: These findings suggest that the observed mitochondrial alterations in individuals with iRBD may predispose to the worsening of the bioenergetic profile observed in RBD-PD subjects, highlighting these alterations as potential predictors of phenoconversion to PD.