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

Abstract

Background Parkinson's 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 patient stratification. Mitochondrial function, which is impaired in and central to PD pathogenesis, may represent one such surrogate indicator. Methods Mitochondrial 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. The effects of mitochondrial respiration on α‐synuclein stress were assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions. Results Bioenergetic properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients, and the correlation is stronger with predominantly nondopaminergic signs. Bioenergetic 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 α‐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. Conclusion The suppression of mitochondrial activity in PD may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures in fibroblasts are potential peripheral biomarkers to follow disease progression. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Deficits in Mitochondrial Spare Respiratory Capacity Contribute to the Neuropsychological Changes of Alzheimer’s Disease

“…This metabolic phenotype could potentially represent a biomarker that can stratify and define a specific subset of sAD patients that might then respond to a personalised therapeutic approach. Previous research has shown that the metabolic profile identified in fibroblasts from sporadic Parkinson's disease patients differs from that identified here in fibroblasts from sAD [46,47].…”

“…This is not the first study, however, to show that the metabolism of peripheral cells outside the nervous system is affected in sAD. White blood cells [55], platelets [56] and fibroblasts have been shown to have metabolic abnormalities in multiple studies [46,47,57,58]. Identifying that fibroblast mitochondrial abnormalities correlate with neuropsychological markers of AD opens up avenues to use fibroblast metabolic parameters as biomarkers of sAD, and also as a high throughput drug screening model, as well as potential outcome measures of therapeutic efficacy.…”

Peripheral Glycolysis in Neurodegenerative Diseases

“…Patient-derived fibroblasts have become a popular model for Parkinson’s research; they have been utilised in mechanistic and drug screening studies. However, it is proposed that fibroblasts must be cultured in glucose-free media to study mitochondrial dysfunction [ 59 , 60 , 61 , 62 ] in PD. Fibroblasts cultured in glucose media have a net ATP production via glycolysis and oxidative phosphorylation.…”

“…Fibroblasts cultured in glucose media have a net ATP production via glycolysis and oxidative phosphorylation. Whereas fibroblasts cultured in media containing galactose alone do not have a net production of ATP from glycolysis, unmasking aberrations in mitochondrial function [ 59 ]. This suggests that glycolysis may play a protective role in PD pathology, and like in AD, compensates for abnormal mitochondrial function.…”

“…This suggests that glycolysis may play a protective role in PD pathology, and like in AD, compensates for abnormal mitochondrial function. Research in PINK1 KO mouse embryonic fibroblasts (MEF) has shown that glycolysis and glucose uptake were reported to be 2-fold higher and the PPS activity is reduced [ 59 ]. Elevated glycolysis seen in these PINK KO MEFs, is associated with an increase in HK2, glyceraldehyde-3-phosphatase and PDK1, and the glucose receptors GLUT1, GLUT3, protein and mRNA levels.…”