Role of Mitochondrial Dysfunction in Degenerative Brain Diseases, an Overview
AuthorDagda, Ruben K.
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A mouse model that expresses a dysfunctional mitochondrial transcription factor (TFAM) (Mito-Park) faithfully recapitulates several aspects of PD pathology, including a significant loss of midbrain dopamine neurons, deficits in neurotransmitter levels, and loss of motor movement . In neurodegenerative diseases, it is important to bear in mind that damaged mitochondria are not only characterized as unable to produce a sufficient level of ATP via oxidative phosphorylation, but are also impaired for movement (trafficking), incapable to undergo efficient fission or fusion, mitochondrial turnover (mitophagy) or be replaced via mitochondrial biogenesis. Each of these features of mitochondrial dysfunction is further elaborated below. Therefore, elevating mitochondrial function is a viable therapeutic strategy for reversing neurodegeneration in neurodegenerative diseases associated with mitochondrial dysfunction.
Mitochondria are multifaceted organelles that serve to power critical neuronal functions. Additionally, mitochondria buffer calcium, produce intracellular reactive oxygen species (ROS), act as heat generators, regulate lipid metabolism, and modulate cell survival.Unlike proliferating cells, neurons predominantly rely on oxidative phosphorylation to thrive and establish neuronal networks. Although the brain comprises less than 2% of human body weight, it consumes of up to 20% of the total energy levels produced by the body. Indeed, the high reliance of neurons on oxidative phosphorylation is evident as mitochondrial dysfunction underlies the etiology of a many neurodegenerative disorders including Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease (HD), optic neuropathy (ON), Marie-Charcot-Tooth (MCT) disease, and Parkinson’s disease (PD) [1,2,3,4]. In addition, several studies using cell culture and in vivo models have provided convincing proof-of-concept that high quality/functional mitochondria are critical for neuronal survival.