Neuronal degeneration and mitochondrial dysfunction Eric A. Schon, Giovanni Manfredi J Clin Invest. 2003;111(3):303-312. https://doi.org/10.1172/JCI17741. Perspective 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 […] Find the latest version: https://jci.me/17741/pdf PERSPECTIVE Neurodegeneration | Serge Przedborski, Series Editor Neuronal degeneration and mitochondrial dysfunction Eric A. Schon1,2 and Giovanni Manfredi3 1Department of Neurology, and 2Department of Genetics and Development, Columbia University, New York, New York, USA 3Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA J. Clin. Invest. 111:303–312 (2003). doi:10.1172/JCI200317741. Over the last decade, the underlying genetic bases of produce energy can have catastrophic consequences, not several neurodegenerative disorders, including Hunt- only due to the primary loss of ATP, but also due to indi- ington disease (HD), Friedreich ataxia, hereditary spas- rect impairment of “downstream” functions, such as the tic paraplegia, and rare familial forms of Parkinson dis- maintenance of organellar and cellular calcium home- ease (PD), Alzheimer disease (AD), and amyotrophic ostasis. Moreover, deficient mitochondrial metabolism lateral sclerosis (ALS), have been identified. However, may generate reactive oxygen species (ROS) that can the etiologies of sporadic AD, PD, and ALS, which are wreak havoc in the cell. It is for these reasons that mito- among the most common neurodegenerative diseases, chondrial dysfunction is such an attractive candidate for are still unclear, as are the pathogenic mechanisms giv- an “executioner’s” role in neuronal degeneration. ing rise to the various, and often highly stereotypical, The mitochondrion is the only organelle in the cell, clinical features of these diseases. Despite the differen- aside from the nucleus, that contains its own genome tial clinical features of the various neurodegenerative and genetic machinery. The human mitochondrial disorders, the fact that neurons are highly dependent genome (1) is a tiny 16.6-kb circle of double-stranded on oxidative energy metabolism has suggested a uni- mitochondrial DNA (mtDNA) (Figure 1). It encodes 13 fied pathogenetic mechanism of neurodegeneration, polypeptides, all of which are components of the respi- based on an underlying dysfunction in mitochondrial ratory chain/OXPHOS system, plus 24 genes, specify- energy metabolism. ing two ribosomal RNAs (rRNAs) and 22 transfer RNAs Mitochondria are the seat of a number of important (tRNAs), that are required to synthesize the 13 polypep- cellular functions, including essential pathways of inter- tides. Obviously, an organelle as complex as a mito- mediate metabolism, amino acid biosynthesis, fatty acid chondrion requires more than 37 gene products; in fact, oxidation, steroid metabolism, and apoptosis. Of key about 850 polypeptides, all encoded by nuclear DNA importance to our discussion here is the role of mito- (nDNA), are required to build and maintain a func- chondria in oxidative energy metabolism. Oxidative tioning organelle. These proteins are synthesized in the phosphorylation (OXPHOS) generates most of the cell’s cytoplasm and are imported into the organelle, where ATP, and any impairment of the organelle’s ability to they are partitioned into the mitochondrion’s four main compartments — the outer mitochondrial mem- brane (OMM), the inner mitochondrial membrane Address correspondence to: Eric A. Schon, Department of (IMM), the intermembrane space (IMS), and the matrix, Neurology, P&S 4-431, Columbia University, 630 West 168th located in the interior (the organelle’s “cytoplasm”). Of Street, New York, New York 10032, USA. Phone: (212) 305-1665; the 850 proteins, approximately 75 are structural com- Fax: (212) 305-3986; E-mail: [email protected]. Conflict of interest: The authors have declared that no conflict of ponents of the respiratory complexes (Figure 2) and at interest exists. least another 20 are required to assemble and maintain Nonstandard abbreviations used: Huntington disease (HD); them in working order. The five complexes of the respi- Parkinson disease (PD); familial Parkinson disease (FPD); ratory chain/OXPHOS system — complexes I (NADH Alzheimer disease (AD); familial Alzheimer disease (FAD); ubiquinone oxidoreductase), II (succinate ubiquinone amyotrophic lateral sclerosis (ALS); sporadic amyotrophic lateral sclerosis (SALS); oxidative phosphorylation (OXPHOS); reactive oxidoreductase), III (ubiquinone–cytochrome c reduc- oxygen species (ROS); mitochondrial DNA (mtDNA); ribosomal tase), IV (cytochrome c oxidase), and V (ATP synthase) RNA (rRNA); transfer RNA (tRNA); nuclear DNA (nDNA); inner — are all located in the IMM. There are also two electron mitochondrial membrane (IMM); intermembrane space (IMS); carriers, ubiquinone (also called coenzyme Q), located mitochondrial encephalomyopathy with lactic acidosis and in the IMM, and cytochrome c, located in the IMS. strokelike episodes (MELAS); myoclonus epilepsy with ragged-red fibers (MERRF); ragged-red fiber (RRF); Kearns-Sayre syndrome Besides the fact that it operates under dual genetic (KSS); progressive external ophthalmoplegia (PEO); cytochrome c control, four other features unique to the behavior of oxidase (CCO); Leber hereditary optic neuropathy (LHON); this organelle are important in understanding mito- Leigh syndrome (LS); Friedreich ataxia (FRDA); mitochondrial chondrial function in neurodegeneration. First, as superoxide dismutase (Mn-SOD); Cu,Zn-superoxide dismutase (Cu,Zn-SOD); β-amyloid peptide (Aβ); progressive supranuclear opposed to the nucleus, in which there are two sets of palsy (PSP); terminal deoxynucleotidyl transferase–mediated chromosomes, there are thousands of mtDNAs in each dUTP nick end-labeling (TUNEL). cell, with approximately five mtDNAs per organelle. The Journal of Clinical Investigation | February 2003 | Volume 111 | Number 3 303 ited mutations in mtDNA are recessive, that is, a very high amount of mutated mtDNA must be present (typ- ically more than 70% of the total population of mtDNAs) in order to cause overt dysfunction. Since mtDNA encodes subunits of the respiratory complex- es, pathogenic mutations in mtDNA cause diseases arising from problems in OXPHOS. On the other hand, mutations in nucleus-encoded proteins that are targeted to mitochondria, or that affect organellar function indirectly, can affect almost any aspect of cel- lular function, not just oxidative energy metabolism. Neurodegenerative diseases associated with mutations in mitochondrial genes Diseases associated with mtDNA mutations are typi- cally heterogeneous and are often multisystemic. Since heart, skeletal muscle, and brain are among the most energy-dependent tissues of the body, it is not surpris- Figure 1 ing that many mitochondrial disorders are encephalo- Map of the human mitochondrial genome (1). Polypeptide-coding genes cardiomyopathies. For example, mutations in the (boldface) are outside the circle and specify seven subunits of NADH Leu(UUR) dehydrogenase–coenzyme Q oxidoreductase (ND), one subunit of coen- tRNA gene cause mitochondrial encephalomy- zyme Q–cytochrome c oxidoreductase (Cyt b), three subunits of opathy with lactic acidosis and strokelike episodes cytochrome c oxidase (CCO), and two subunits of ATP synthase (A) (see (MELAS), mutations in tRNALys cause myoclonus also Figure 2). Protein synthesis genes (12S and 16S rRNAs, and 22 epilepsy with ragged-red fibers (MERRF), and large- tRNAs [one-letter code]) are inside the circle. Mutations in mtDNA asso- scale spontaneous deletions cause Kearns-Sayre syn- ciated with MELAS and MERRF, and mutations with features of neuro- drome (KSS) and progressive external ophthalmoplegia degenerative disorders, such as ataxia, chorea, dystonia, motor neuron (PEO) (2). While these diseases are clinically distinct, disease (MND), and parkinsonism, are boxed. A complete list of patho- they share a number