Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson’s disease

Abstract

BackgroundParkinson disease is an intractable disorder with heterogeneous clinical presentation that may reflect different underlying pathogenic mechanisms. Surrogate indicators of pathogenic processes correlating with clinical measures may assist in better patients stratification. Mitochondrial function - which is impaired in and central to PD pathogenesis - may represent one of such surrogate indicators.\n\nMethodsMitochondrial function was assessed by respirometry experiment in fibroblasts derived from idiopathic patients (n=47) in normal conditions and in experimental settings that do not permit glycolysis and therefore force energy production through mitochondrial function. Respiratory parameters and clinical measures were correlated with bivariate analysis. Machine learning based classification and regression trees were used to classify patients on the basis of biochemical and clinical measures. Effects of mitochondrial respiration on alpha-synuclein stress was assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions.\n\nResultsBioenergetics properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients and correlation is stronger with predominantly non-dopaminergic signs. Bioenergetics analysis under metabolic stress, in which energy is produced solely by mitochondria, shows that patients fibroblasts can augment respiration, therefore indicating that mitochondrial defects are reversible. Forcing energy production through mitochondria, however, favors alpha-synuclein stress in different cellular experimental systems. Machine learning-based classification identified different groups of patients in which increasing disease severity parallels higher mitochondrial respiration.\n\nConclusionSuppression of mitochondrial activity in Parkinson disease may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures are potential biomarkers to follow disease progression.