Neuronal degeneration and mitochondrial dysfunction

Abstract

Over the last decade, the underlying genetic bases of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, and rare familial forms of Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS), have been identified. However, the etiologies of sporadic AD, PD, and ALS, which are among the most common neurodegenerative diseases, are still unclear, as are the pathogenic mechanisms giving rise to the various, and often highly stereotypical, clinical features of these diseases. Despite the differential clinical features of the various neurodegenerative disorders, the fact that neurons are highly dependent on oxidative energy metabolism has suggested a unified pathogenetic mechanism of neurodegeneration, based on an underlying dysfunction in mitochondrial energy metabolism.Mitochondria are the seat of a number of important cellular functions, including essential pathways of intermediate metabolism, amino acid biosynthesis, fatty acid oxidation, steroid metabolism, and apoptosis. Of key importance to our discussion here is the role of mitochondria in oxidative energy metabolism. Oxidative phosphorylation (OXPHOS) generates most of the cell's ATP, and any impairment of the organelle's ability to produce energy can have catastrophic consequences, not only due to the primary loss of ATP, but also due to indirect impairment of "downstream" functions, such as the maintenance of organellar and cellular calcium homeostasis. Moreover, deficient mitochondrial metabolism may generate reactive oxygen species (ROS) that can wreak havoc in the cell. It is for these reasons that mitochondrial dysfunction is such an attractive candidate for an "executioner's" role in neuronal degeneration.The mitochondrion is the only organelle in the cell, aside from the nucleus, that contains its own genome and genetic machinery. The human mitochondrial genome (1) is a tiny 16.6-kb circle of double-stranded mitochondrial DNA (mtDNA) (Figure 1). It encodes 13 polypeptides, all of which are components of the respiratory chain/OXPHOS system, plus 24 genes, specifying two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs), that are required to synthesize the 13 polypeptides. Obviously, an organelle as complex as a mitochondrion requires more than 37 gene products; in fact, about 850 polypeptides, all encoded by nuclear DNA (nDNA), are required to build and maintain a functioning organelle. These proteins are synthesized in the cytoplasm and are imported into the organelle, where they are partitioned into the mitochondrion's four main compartments -the outer mitochondrial membrane (OMM), the inner mitochondrial membrane (IMM), the intermembrane space (IMS), and the matrix, located in the interior (the organelle's "cytoplasm"). Of the 850 proteins, approximately 75 are structural components of the respiratory complexes ( Figure 2) and at least another 20 are required to assemble and maintain them in working order. The five complexes of the respiratory chain...

Genetic Variation of <b><i>MT-ND</i></b> Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

“…This can suggest that a decrease in complex I activity may be involved in the pathogenesis of the disease. These results are in agreement with previous studies that have also demonstrated mitochondrial impairment activity in related diseases, such as AD, PD, ALS and tauopathies [32,85,86,87,88]. Moreover, our group has previously reported a complex I deficiency in a patient with FTLD [22].…”

“…Polymorphisms and specific haplogroups in mtDNA have also been associated with neurodegenerative diseases, dementia and longevity [21,26,27], and structural as well as functional mitochondrial abnormalities have been reported [25,27,28,29,30,31,32]. Mitochondrial dysfunction is related to increased reactive oxygen species production and mtDNA somatic mutations that accumulate throughout the years, leading to energy insufficiency, signaling defects, apoptosis and replicative senescence, which culminates in loss of cell function [33].…”

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

“…This process stays in a highly sensitive balance. In the specific case when ROS and RNS synthesis exceeds antioxidant synthesis it results in oxidative stress and cell components are damaged in the cell [90,91,94,95,96,97]. Mitochondrial dysfunction results in a decrease in ATP synthesis, impaired Ca 2+ content, and increased ROS and RNS at the same time [98].…”

Mitochondrial Dysfunction in the Pathogenesis of Rett Syndrome: Implications for Mitochondria-Targeted Therapies

“…Despite being caused by different mutated genes, many of these diseases share major clinical features. These include, but are not limited to, early symptomatic onset, developmental delay, motor and mental regression, dystonia, ataxia, muscle weakness (hypotonia), cardiomyopathy, seizures, gastrointestinal reflux, and impaired function of the respiratory system (Schon and Manfredi, 2003). Mitochondrial diseases are also characterized by oxidative damage, a decrease in electron transport chain (ETC) complex activities, and elevated levels of lactate and pyruvate in blood (Chinnery and Schon, 2003; Mattman et al, 2011).…”