Mitochondrial alterations in Parkinson’s disease: new clues (original) (raw)

Mitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis

2009

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder with unknown etiology. It is marked by widespread neurodegeneration in the brain with profound loss of A9 midbrain dopaminergic neurons in substantia nigra pars compacta. Several theories of biochemical abnormalities have been linked to pathogenesis of PD of which mitochondrial dysfunction due to an impairment of mitochondrial complex I and subsequent oxidative stress seems to take the center stage in experimental models of PD and in postmortem tissues of sporadic forms of illness. Recent identification of specific gene mutations and their influence on mitochondrial functions has further reinforced the relevance of mitochondrial abnormalities in disease pathogenesis. In both sporadic and familial forms of PD abnormal mitochondrial paradigms associated with disease include impaired functioning of the mitochondrial electron transport chain, aging associated damage to mitochondrial DNA, impaired calcium buffering, and anomalies in mitochondrial morphology and dynamics. Here we provide an overview of specific mitochondrial functions affected in sporadic and familial PD that play a role in disease pathogenesis. We propose to utilize these gained insights to further streamline and focus the research to better understand mitochondria's role in disease development and exploit potential mitochondrial targets for therapeutic interventions in PD pathogenesis.

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.

Mitochondrial matters in Parkinson disease: introduction

Journal of Bioenergetics and Biomembranes, 2009

Individuals with Parkinson disease (PD) are encountered frequently and have progressively severe neurologic changes. The central nervous system changes involve dopaminergic neurons in the basal ganglia and substantia nigra. Although usually sporadic, rare forms of PD are familial and the responsible genes have been identified. These genes affect mitochondrial function and can be studied in animals. Brains of affected animals reveal consequences of reactive oxygen species (ROS)-quinones, dopamine oxidation products, tyrosine nitration, lipid peroxidation and amino-aldehyde adducts. The three genes are important for maintaining physical and functional mitochondrial integrity. The cumulative effects of mitochondrial dysfunction, particularly those mediated by ROS, ultimately lead to at least some of the clinical and pathologic changes of PD.

Mitochondrial dysfunction in parkinson's disease

Annals of Neurology, 1998

The review highlights mitochondrial structural and functional abnormalities in Parkinson's dis ease and experimental animal models of this pathology. Special attention is paid to the inactivation of mito chondrial enzymes, mutations in mitochondrial and nuclear DNA, and genomic and proteomic studies of mitochondrial proteins in Parkinson's disease and experimental parkinsonism in animals.

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 dynamics in Parkinson's disease

Experimental Neurology, 2009

The unique energy demands of neurons require well-orchestrated distribution and maintenance of mitochondria. Thus, dynamic properties of mitochondria, including fission, fusion, trafficking, biogenesis, and degradation, are critical to all cells, but may be particularly important in neurons. Dysfunction in mitochondrial dynamics has been linked to neuropathies and is increasingly being linked to several neurodegenerative diseases, but the evidence is particularly strong, and continuously accumulating, in Parkinson's disease (PD). The unique characteristics of neurons that degenerate in PD may predispose those neuronal populations to susceptibility to alterations in mitochondrial dynamics. In addition, evidence from PD-related toxins supports that mitochondrial fission, fusion, and transport may be involved in pathogenesis. Furthermore, rapidly increasing evidence suggests that two proteins linked to familial forms of the disease, parkin and PINK1, interact in a common pathway to regulate mitochondrial fission/fusion. Parkin may also play a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Taken together, the current data suggests that mitochondrial dynamics may play a role in PD pathogenesis, and a better understanding of mitochondrial dynamics within the neuron may lead to future therapeutic treatments for PD, potentially aimed at some of the earliest pathogenic events.