Neuronal degeneration and mitochondrial dysfunction.

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 ​(Figure1). 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 ​(Figure2)2) and at least another 20 are required to assemble and maintain them in working order. The five complexes of the respiratory chain/OXPHOS system — complexes I (NADH ubiquinone oxidoreductase), II (succinate ubiquinone oxidoreductase), III (ubiquinone–cytochrome c reductase), IV (cytochrome c oxidase), and V (ATP synthase) — are all located in the IMM. There are also two electron carriers, ubiquinone (also called coenzyme Q), located in the IMM, and cytochrome c, located in the IMS. Figure 1 Map of the human mitochondrial genome (1). Polypeptide-coding genes (boldface) are outside the circle and specify seven subunits of NADH dehydrogenase–coenzyme Q oxidoreductase (ND), one subunit of coenzyme Q–cytochrome c oxidoreductase . Figure 2 Schematic representation of the mitochondrion with its electron transport chain (ETC). The ETC is the principal source of ROS in the cell. In addition to mutations in mtDNA- and nDNA-encoded components of the ETC, a number of mutant mitochondrial proteins . Besides the fact that it operates under dual genetic control, four other features unique to the behavior of this organelle are important in understanding mitochondrial function in neurodegeneration. First, as opposed to the nucleus, in which there are two sets of chromosomes, there are thousands of mtDNAs in each cell, with approximately five mtDNAs per organelle. Second, organellar division and mtDNA replication operate independently of the cell cycle, both in dividing cells (such as glia) and in postmitotic nondividing cells (such as neurons). Third, upon cell division, the mitochondria (and their mtDNAs) are partitioned randomly between the daughter cells (mitotic segregation). Finally, the number of organelles varies among cells, depending in large part on the metabolic requirements of that cell. Thus, skin fibroblasts contain a few hundred mitochondria, whereas neurons may contain thousands and cardiomyocytes tens of thousands of organelles. Taken together, these features highlight the fact that mitochondria obey the laws of population genetics, not mendelian genetics.