Biological Implications of Differential Expression of Mitochondrial-Shaping Proteins in Parkinson’s Disease

Abstract

It has long been accepted that mitochondrial function and morphology is affected in Parkinson’s disease, and that mitochondrial function can be directly related to its morphology. So far, mitochondrial morphological alterations studies, in the context of this neurodegenerative disease, have been performed through microscopic methodologies. The goal of the present work is to address if the modifications in the mitochondrial-shaping proteins occurring in this disorder have implications in other cellular pathways, which might constitute important pathways for the disease progression. To do so, we conducted a novel approach through a thorough exploration of the available proteomics-based studies in the context of Parkinson’s disease. The analysis provided insight into the altered biological pathways affected by changes in the expression of mitochondrial-shaping proteins via different bioinformatic tools. Unexpectedly, we observed that the mitochondrial-shaping proteins altered in the context of Parkinson’s disease are, in the vast majority, related to the organization of the mitochondrial cristae. Conversely, in the studies that have resorted to microscopy-based techniques, the most widely reported alteration in the context of this disorder is mitochondria fragmentation. Cristae membrane organization is pivotal for mitochondrial ATP production, and changes in their morphology have a direct impact on the organization and function of the oxidative phosphorylation (OXPHOS) complexes. To understand which biological processes are affected by the alteration of these proteins we analyzed the binding partners of the mitochondrial-shaping proteins that were found altered in Parkinson’s disease. We showed that the binding partners fall into seven different cellular components, which include mitochondria, proteasome, and endoplasmic reticulum (ER), amongst others. It is noteworthy that, by evaluating the biological process in which these modified proteins are involved, we showed that they are related to the production and metabolism of ATP, immune response, cytoskeleton alteration, and oxidative stress, amongst others. In summary, with our bioinformatics approach using the data on the modified proteins in Parkinson’s disease patients, we were able to relate the alteration of mitochondrial-shaping proteins to modifications of crucial cellular pathways affected in this disease.

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

“…It was noted the increased ATP was largely from non-mitochondrial sources [ 32 ]. Perturbations in mitochondria-shaping proteins and disruption to supercomplex formation and thereby cristae structure have been implicated in various diseases, for example Parkinson’s disease [ 58 ]. Indeed, an analysis of the mitochondria-shaping proteins altered in the context of Parkinson’s disease (the vast majority of which were related to the organization of cristae) found many of their binding partners were related to the mitochondria and the proteasome [ 58 ].…”

“…Perturbations in mitochondria-shaping proteins and disruption to supercomplex formation and thereby cristae structure have been implicated in various diseases, for example Parkinson’s disease [ 58 ]. Indeed, an analysis of the mitochondria-shaping proteins altered in the context of Parkinson’s disease (the vast majority of which were related to the organization of cristae) found many of their binding partners were related to the mitochondria and the proteasome [ 58 ]. Also sharing similarity with our ME/CFS findings, the mitochondria-shaping proteins altered in Parkinson’s disease are involved in biological pathways relating to the production and metabolism of ATP, immune response and oxidative stress [ 58 ].…”

Inhibition of histone deacetylase promotes a neuroprotective mechanism in an experimental model of Parkinson’s disease

“…Conversely, the present study results also reflect decreased isoform 3 expression in the PD-animal group and returned to near normalcy in the entinostat-treated group. Much of the gene expression profiling already performed to differentiate between the PD patients and healthy controls identifies ATP synthase subunit α (ATP5A1), voltage-dependent anion-selective channel protein 3 (VDAC-3) [45], growth differentiation factor 3 (GDF3) [46], glutamate receptors, glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) [47], chromobox homologue 5, and CBX5, confirmed by qRT-PCR to be found in the substantia nigra dopaminergic neuron degeneration [48] or acting upon mitochondria in the pathogenesis of PD. More studies are needed to elucidate the exact roles that they play in PD animals beyond the scope of PD marker identification.…”

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

“…It was noted the increased ATP was largely from non-mitochondrial sources [32]. Perturbations in mitochondria-shaping proteins and disruption to supercomplex formation and thereby cristae structure have been implicated in various diseases, for example Parkinson's disease [62]. Indeed, an analysis of the mitochondria-shaping proteins altered in the context of Parkinson's disease (the vast majority of which were related to the organization of cristae) found many of their binding partners were related to the mitochondria and the proteasome [62].…”

“…Perturbations in mitochondria-shaping proteins and disruption to supercomplex formation and thereby cristae structure have been implicated in various diseases, for example Parkinson's disease [62]. Indeed, an analysis of the mitochondria-shaping proteins altered in the context of Parkinson's disease (the vast majority of which were related to the organization of cristae) found many of their binding partners were related to the mitochondria and the proteasome [62]. Also sharing similarity with our ME/CFS ndings, the mitochondria-shaping proteins altered in Parkinson's disease are involved in biological pathways relating to the production and metabolism of ATP, immune response and oxidative stress [62].…”