Targeting mitochondrial dysfunction in neurodegenerative disease: Part II.
ABSTRACT With improvements in life expectancy over the past decades, the incidence of neurodegenerative disease has dramatically increased and new therapeutic strategies are urgently needed. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.
This review examines the role of mitochondrial dysfunction in neurodegeneration, drawing examples from common diseases such as Alzheimer's disease and rarer familial disorders such as Charcot-Marie-Tooth. The review is provided in two parts. In part I we discussed the mitochondrial defects which have been most extensively researched (oxidative stress, bioenergetic dysfunction, calcium mishandling). We focus now on those defects which have more recently been implicated in neurodegeneration; in mitochondrial fusion/fission, protein import, protein quality control, kinase signalling and opening of the permeability transition pore.
An examination of mitochondrial defects observed in neurodegeneration, and existing and possible future therapies to target these defects.
The mitochondrially-targeted therapeutics that have reached clinical trials so far have produced encouraging but largely inconclusive results. Increasing understanding of mitochondrial dysfunction has, however, led to preclinical work focusing on novel approaches, which has generated exciting preliminary data.
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ABSTRACT: Cancer and neurodegeneration are often thought of as disease mechanisms at opposite ends of a spectrum; one due to enhanced resistance to cell death and the other due to premature cell death. There is now accumulating evidence to link these two disparate processes. An increasing number of genetic studies add weight to epidemiological evidence suggesting that sufferers of a neurodegenerative disorder have a reduced incidence for most cancers, but an increased risk for other cancers. Many of the genes associated with either cancer and/or neurodegeneration play a central role in cell cycle control, DNA repair, and kinase signalling. However, the links between these two families of diseases remain to be proven. In this review, we discuss recent and sometimes as yet incomplete genetic discoveries that highlight the overlap of molecular pathways implicated in cancer and neurodegeneration.PLoS Genetics 01/2010; 6(12):e1001257. · 8.69 Impact Factor
Article: High throughput microplate respiratory measurements using minimal quantities of isolated mitochondria.[show abstract] [hide abstract]
ABSTRACT: Recently developed technologies have enabled multi-well measurement of O(2) consumption, facilitating the rate of mitochondrial research, particularly regarding the mechanism of action of drugs and proteins that modulate metabolism. Among these technologies, the Seahorse XF24 Analyzer was designed for use with intact cells attached in a monolayer to a multi-well tissue culture plate. In order to have a high throughput assay system in which both energy demand and substrate availability can be tightly controlled, we have developed a protocol to expand the application of the XF24 Analyzer to include isolated mitochondria. Acquisition of optimal rates requires assay conditions that are unexpectedly distinct from those of conventional polarography. The optimized conditions, derived from experiments with isolated mouse liver mitochondria, allow multi-well assessment of rates of respiration and proton production by mitochondria attached to the bottom of the XF assay plate, and require extremely small quantities of material (1-10 µg of mitochondrial protein per well). Sequential measurement of basal, State 3, State 4, and uncoupler-stimulated respiration can be made in each well through additions of reagents from the injection ports. We describe optimization and validation of this technique using isolated mouse liver and rat heart mitochondria, and apply the approach to discover that inclusion of phosphatase inhibitors in the preparation of the heart mitochondria results in a specific decrease in rates of Complex I-dependent respiration. We believe this new technique will be particularly useful for drug screening and for generating previously unobtainable respiratory data on small mitochondrial samples.PLoS ONE 01/2011; 6(7):e21746. · 4.09 Impact Factor
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ABSTRACT: Understanding the mechanisms of neuronal dysfunction and death represents a major frontier in contemporary medicine, involving the acute cell death in stroke, and the attrition of the major neurodegenerative diseases, including Parkinson's, Alzheimer's, Huntington's and Motoneuron diseases. A growing body of evidence implicates mitochondrial dysfunction as a key step in the pathogenesis of all these diseases, with the promise that mitochondrial processes represent valuable potential therapeutic targets. Each disease is characterised by the loss of a specific vulnerable population of cells--dopaminergic neurons in Parkinson's disease, spinal motoneurons in Motoneuron disease, for example. We discuss the possible roles of cell type-specific calcium signalling mechanisms in defining the pathological phenotype of each of these major diseases and review central mechanisms of calcium-dependent mitochondrial-mediated cell death.Pflügers Archiv - European Journal of Physiology 05/2012; 464(1):111-21. · 4.46 Impact Factor