Mitochondria in Neurodegeneration

Abstract

Many neurodegenerative diseases demonstrate abnormal mitochondrial morphology and biochemical dysfunction. Alterations are often systemic rather than brain-limited. Mitochondrial dysfunction may arise as a consequence of abnormal mitochondrial DNA, mutated nuclear proteins that interact directly or indirectly with mitochondria, or through unknown causes. In most cases it is unclear where mitochondria sit in relation to the overall disease cascades that ultimately causes neuronal dysfunction and death, and there is still controversy regarding the question of whether mitochondrial dysfunction is a necessary step in neurodegeneration. In this chapter we highlight and catalogue mitochondrial perturbations in some of the major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We consider data that suggest mitochondria may be critically involved in neurodegenerative disease neurodegeneration cascades. Keywordscybrid; mitochondria; mitochondrial DNA; neurodegenerative disease The quintessential neurodegenerative diseasesNeurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems. The clinical syndromes associated with particular neuroanatomical patterns of cell dysfunction and loss are typically categorized by whether they initially affect cognition, movement, strength, coordination, sensation, vision, or autonomic control. Prototypical examples include AD, PD, ALS, and HD. HD is strictly an autosomal dominant disorder. With AD, PD, and ALS most cases are age-related and show sporadic epidemiology, although rare Mendelian variants do occur. As life expectancy continues to advance in developed countries the incidence of these disorders increases and will continue to do so.Mitochondrial dysfunction is a common theme in these diseases. Mitochondria are known to play a central role in many cell functions including ATP generation, intracellular Ca 2+ homeostasis, reactive oxygen species (ROS) formation, and apoptosis. Neurons are particularly dependent on mitochondria because of their high energy demands. It seems reasonable to hypothesize neurons are relatively intolerant of mitochondrial dysfunction. This assumption is supported by the fact that maternally inherited diseases with known homoplasmic or near-homoplasmic mitochondrial DNA (mtDNA) mutations tend to affect the central nervous system and muscle, the body's two most aerobic tissues.