Enteric neurons from Parkinson’s disease patients display ex vivo aberrations in mitochondrial structure

Abstract

Based on autopsy material mitochondrial dysfunction has been proposed being part of the pathophysiological cascade of Parkinson’s disease (PD). However, in living patients, evidence for such dysfunction is scarce. As the disease presumably starts at the enteric level, we studied ganglionic and mitochondrial morphometrics of enteric neurons. We compared 65 ganglia from 11 PD patients without intestinal symptoms and 41 ganglia from 4 age-matched control subjects. We found that colon ganglia from PD patients had smaller volume, contained significantly more mitochondria per ganglion volume, and displayed a higher total mitochondrial mass relative to controls. This suggests involvement of mitochondrial dysfunction in PD at the enteric level. Moreover, in PD patients the mean mitochondrial volume declined in parallel with motor performance. Ganglionic shrinking was evident in the right but not in the left colon. In contrast, mitochondrial changes prevailed in the left colon suggesting that a compensatory increase in mitochondrial mass might counterbalance mitochondrial dysfunction in the left colon but not in the right colon. Reduction in ganglia volume and combined mitochondrial morphometrics had both predictive power to discriminate between PD patients and control subjects, suggesting that both parameters could be used for early discrimination between PD patients and healthy individuals.

Mitochondria-mitochondria interaction networks show altered topological patterns in Parkinson’s disease

“…To obtain more precise information on mitochondria-mitochondria interactions, we used highresolution 3D mitochondrial immunofluorescence images in colon ascendens (left) and descendens (right) ganglia collected from idiopathic PD patients and healthy controls 13 . We extracted network adjacency matrixes of mitochondria-mitochondria interactions from all ganglia neurons in such a way that mitochondria were represented as nodes, with an undirected link being present if an interaction is observed between a pair of nodes at the imaging moment.…”

“…In the mitochondria interacting 'social' networks of PD, 'dysfunctional' mitochondria relative to 'normal' mitochondria might need to fully interact with each other in order to more efficiently maintain the necessary cellular energy supply. Higher frequency of this type of motifs may also partially compensate for the substantial right-side ganglionic shrinking in PD patients 13 . It is noteworthy that the fully-connected triangle 3-node motifs, as that analyzed in the index of transivity, are the most recurring motifs in many different types of biological and social networks 28,29 , reflecting the relevance and importance of such types of motifs in establishing network efficiency and maintaining network function.…”

“…Adjacency matrices of the mitochondrial interaction networks (MINs) were extracted from confocal three dimensional (3D, with Z-stack) mitochondrial immunofluorescence images of colonic ganglia 13 , according to a reported method which has been optimized for image-based network analysis 45 . In classical adjacency matrices (A) of undirected graphs, the element A i,j =1…”

“…Accordingly, in the following network analysis, we considered the existence of a link between the nodes i and j if A i,j is larger than zero. The other criteria, masks and filters used for mitochondrial segmentation and pixel calculation were described in our previous work 13 .…”

“…similar principles and whether and how the network topological properties are affected in relevant pathological conditions that are related to mitochondrial deficiency. To this end, we here comprehensively analyzed a variety of network topological indexes of MINs, contrary to a conventional analysis focusing on individual-mitochondria-based phenotypes such as mitochondrial number, volume, size, shape and even recent simplified network-like analysis only on connection degree13,36 . Beyond the initially only intended proof-of-principle analysis, we found remarkable pattern differences in the MINs of enteric ganglia of sporadic PD patients vs. healthy controls.…”