Altered Calcium Homeostasis in Cells Transformed by Mitochondria from Individuals with Parkinson's Disease (original) (raw)

Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson's disease

BioFactors, 2011

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNPC) and the presence of intracytoplasmatic inclusions known as Lewy bodies, largely composed of alpha-synuclein (a-syn). PD is a multifactorial disease and its etiology remains largely elusive. Although more than 90% of the cases are sporadic, mutations in several nuclear encoded genes have been linked to the development of autosomal recessive and dominant familial parkinsonian syndromes (Bogaerts et al. (2008) Genes Brain Behav 7, 129-151), enhancing our understanding of biochemical and cellular mechanisms contributing to the disease. Many cellular mechanisms are thought to be involved in the dopaminergic neuronal death in PD, including oxidative stress, intracellular Ca 2þ homeostasis impairment, and mitochondrial dysfunctions. Furthermore, endoplasmic reticulum (ER) stress together with abnormal protein degradation by the ubiquitin proteasome system is considered to contribute to the PD pathogenesis. This review covers all the aspects related to the molecular mechanisms underlying the interplay between mitochondria, ER, and proteasome system in PD-associated neurodegeneration.

Mitochondria, calcium and cell death: A deadly triad in neurodegeneration

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2009

Mitochondrial Ca 2+ accumulation is a tightly controlled process, in turn regulating functions as diverse as aerobic metabolism and induction of cell death. The link between Ca 2+ (dys)regulation, mitochondria and cellular derangement is particularly evident in neurodegenerative disorders, in which genetic models and environmental factors allowed to identify common traits in the pathogenic routes. We will here summarize: i) the current view of mechanisms and functions of mitochondrial Ca 2+ homeostasis, ii) the basic principles of organelle Ca 2+ transport, iii) the role of Ca 2+ in neuronal cell death, and iv) the new information on the pathogenesis of Alzheimer's, Huntington's and Parkinson's diseases, highlighting the role of Ca 2+ and mitochondria.

Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease

Nature Neuroscience, 2012

Mitochondrial oxidant stress is widely viewed as critical to pathogenesis in Parkinson's disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, neurons in the dorsal motor nucleus of the vagus (DMV), a population cholinergic neurons that shows signs of pathology in the early stages of Parkinson's disease, were characterized in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a novel transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, it was found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 -a gene associated with early-onset Parkinson's disease -exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinson's disease and a therapeutic strategy to ameliorate it.

Mitochondrial homeostasis in cellular models of Parkinson's disease

2021

17 Mitochondrial function is known to be an important factor in maintaining cellular 18 homeostasis and its dysregulation has become a hallmark for multiple disease 19 conditions. This review aims to sythesise the extent of this knowledge by analysing 20 changes of mitochondrial physiology parameters in Parkinson’s disease (PD) and 21 to evaluate the contribution of cellular models of PD in the field. The analysis 22 provided here constitutes a platform for further elucidation of mitochondrial 23 function parameters relative to factors that may potentiate disease progression. 24 Keywords‒Parkinson’s Disease, cellular models, mitochondrial homeostasis 25 1. Mitochondria and Parkinson’s Disease (PD) 26 Mitochondria comprise a dynamic organellar network which take a central position 27 in maintaining eukaryotic homeostasis. Besides their role in the cellular bioenergetics, 28 namely ATP synthesis, these organelles are supporting essential metabolic processes, 29 calcium and reactive ox...

Role of mitochondria in the etiology and pathogenesis of Parkinson's disease

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1995

We discuss the etiology and pathogenesis of Parkinson's disease (PD). Our group and others have found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with PD; in addition, we reported loss of the a-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra. Dual loss of complex I and the KGDHC will deleteriously affect the electron transport and ATP synthesis; we believe that energy crisis is the most important mechanism of nigral cell death in PD. Oxidative stress has also been implicated as an important contributor to nigral cell death in PD, but we believe that oxidative stress is a secondary phenomenon to respiratory failure, because respiratory failure will increase oxygen free-radical formation and consume glutathione. The primary cause of mitochondrial respiratory failure has not been elucidated yet, but additive effect of environmental neurotoxins in genetically predisposed persons appears to be the most likely possibility.

Mitochondrial Biology and Parkinson's Disease

Cold Spring Harbor Perspectives in Medicine, 2011

Mitochondria are highly dynamic organelles with complex structural features which play several important cellular functions, such as the production of energy by oxidative phosphorylation, the regulation of calcium homeostasis, or the control of programmed cell death (PCD). Given its essential role in neuronal viability, alterations in mitochondrial biology can lead to neuron dysfunction and cell death. Defects in mitochondrial respiration have long been implicated in the etiology and pathogenesis of Parkinson's disease (PD). However, the role of mitochondria in PD extends well beyond defective respiration and also involves perturbations in mitochondrial dynamics, leading to alterations in mitochondrial morphology, intracellular trafficking, or quality control. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of dopaminergic neurodegeneration in PD.

The Centrality of Mitochondria in the Pathogenesis and Treatment of Parkinson's Disease

CNS Neuroscience & Therapeutics, 2014

Parkinson's disease (PD) is an incurable neurodegenerative disorder leading to progressive motor impairment and for which there is no cure. From the first postmortem account describing a lack of mitochondrial complex I in the substantia nigra of PD sufferers, the direct association between mitochondrial dysfunction and death of dopaminergic neurons has ever since been consistently corroborated. In this review, we outline common pathways shared by both sporadic and familial PD that remarkably and consistently converge at the level of mitochondrial integrity. Furthermore, such knowledge has incontrovertibly established mitochondria as a valid therapeutic target in neurodegeneration. We discuss several mitochondria-directed therapies that promote the preservation, rescue, or restoration of dopaminergic neurons and which have been identified in the laboratory and in preclinical studies. Some of these have progressed to clinical trials, albeit the identification of an unequivocal disease-modifying neurotherapeutic is still elusive. The challenge is therefore to improve further, not least by more research on the molecular mechanisms and pathophysiological consequences of mitochondrial dysfunction in PD.