Commentary Mitochondria and dystonia: The movement disorder connection?

Over the past 10 years, defects in mitochondrial oxidative phosphorylation (OXPHOS) have been implicated in a wide variety of neurodegenerative and neuromuscular diseases. Mutations in the mitochondrial tRNA and mRNA genes have been associated with various forms of epilepsy, spasticity (1, 2), stroke-like episodes (3, 4), and sensory neural deafness (5, 6), to mention a few. One neurological symptom that has definitely been associated with OXPHOS is the movement disorder dystonia. A specific missense mutation in the mtDNA complex I (NADH dehydrogenase) gene, MTND6, has been linked to maternally inherited dystonia along with the companion phenotype, Leber’s hereditary optic neuropathy (LHON) (7). In the current issue of these Proceedings, the association between the mitochondria and dystonia is extended by demonstrating that a mutation in a nuclear DNA (nDNA) gene encoding a protein involved in the import of mitochondrial inner membrane carrier proteins can also cause dystonia (8). These observations raise the intriguing possibility that, like dystonia, other movement disorders might have a mitochondrial etiology. The mitochondrial OXPHOS components are assembled from genes distributed between the mtDNA and the nDNA. These genes include those encoding the structural proteins that form the mitochondrial inner membrane OXPHOS enzyme complexes (I, II, III, IV, and V), and the associated substrate and product carriers such as the adenine nucleotide translocator (ANT), as well as the proteins necessary for mitochondrial biogenesis, the apparatus to import cytoplasmically synthesized mitochondrial proteins, and the proteins necessary for mitochondrial assembly and turnover (9). LHON was the first neurodegenerative disease to be associated with a mtDNA missense mutation, an A-to-G transition at nucleotide position (np) 11778 in the MTND4 gene of complex I. LHON is characterized by midlife, sudden-onset blindness due to atrophy of the optic nerve. The 11778 mutation converts the highly conserved arginine at codon 340 to a histidine (1). Subsequently, the LHON phenotype was observed to segregate in a large maternal pedigree along with early-onset generalized dystonia. The dystonic patients exhibited rigidity, ataxia, dysarthria, short stature, reduced intelligence, and a neuropathology characterized by bilateral basal ganglia degeneration, originally designated bilateral striatal necrosis (10). Molecular analysis of this pedigree revealed that both the LHON and the dystonia were the result of a mutation in the mtDNA complex I gene MTND6, resulting in the conversion of the highly conserved alanine codon at position 72 to a valine (7). This same mutation in different families can be associated with either LHON or dystonia or both (11). Cells containing this mutation have a 55% reduction in respiratory complex I activity, which can be transferred from one cell to another along with the mtDNA via the cytoplasmic (cybrid) transfer technique (12). Defects in complex I have also been associated with other cases of dystonia. A survey of the mitochondrial OXPHOS complexes in the blood platelet mitochondria revealed that patients with generalized or segmental dystonia had an average of a 62% reduction in complex I activity, whereas patients with focal dystonia had an average of a 37% reduction in complex I activity (13). The current Proceedings paper (8) reports the function of the gene responsible for the chromosome X-linked Mohr– Tranebjaerg syndrome, which presents in early childhood with sensory neural hearing loss that can progress to dystonia, spasticity, mental deterioration, paranoia, and cortical blindness. Those patients who develop the movement disorder characteristically exhibit progressive degeneration of the basal ganglia, corticospinal tract, and brain stem. The gene responsible for Mohr–Tranebjaerg syndrome was identified through a patient with a deletion of the locus. The identity of the gene was confirmed in two additional families, one harboring a 10-bp deletion in exon 2 and the second resulting from a 1-bp deletion in exon 1. This gene, designated DFN-1, generates a 1,167-bp cDNA encoding a 97-amino acid, 11-kDa polypeptide, designated DDP1. The predicted polypeptide has a high similarity to a Schizosaccharomyces pombe gene of unknown function (14). The function of the Mohr–Tranebjaerg syndrome DFN-1 gene was discovered through a totally different line of investigation. While studying the mitochondrial protein import pathway for multispanning carrier proteins such as ANT (AAC in yeast) into the mitochondrial inner membrane of Saccharomyces cerevisiae, Koehler, Schatz, and co-workers discovered two essential proteins of the mitochondrial intermembrane space, Tim10p and Tim12p. Tim10p is required for transport of carrier proteins through the mitochondrial outer membrane transport complex (TOM) and into the intermembrane space. Tim12p is involved in inserting the carrier proteins into the inner membrane (15). Tim10p is associated with another polypeptide, Tim9p, in a 300-kDa complex bound to the outer face of the inner membrane. This complex also includes Tim54p, Tim22p, and Tim12p. Tim9p and Tim10p are also associated in a soluble 70-kDa complex in the intermembrane space that can be cross-linked to the partially translocated carrier proteins (16). This 70-kDa complex is proposed to transfer the carrier from the outer membrane to the inner membrane. Tim9p appears to be associated with a second soluble intermembrane 70-kDa complex that assists in carrier protein manipulation. This complex includes two additional polypeptides, Tim8p and Tim13p (Fig. 1) (8). Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p are all similar to each other, and they contain a distinctive duplicated C(N)3C motif. Surprisingly, the DDP1 protein of the Mohr–Tranebjaerg syndrome was found to be similar to Tim8p, Tim9p, Tim10p, and Tim12p, with the highest similarity to Tim8p. Moreover, synthetic DDP1 is incorporated into the mitochondrial intermembrane space in yeast, and hapten-tagged DDP1 is specifically localized to yeast and mammalian mitochondria. Hence, it appears that the deafness and dystonia associated with Mohr–Tranebjaerg syndrome is due to a defect in the import of carrier proteins into the mitochondria and insertion into the mitochondrial inner membrane (8). The demonstration that the DDP1 protein is probably involved in the import of the mitochondrial proteins implies that the underlying defect of the Mohr–Tranebjaerg syndrome is a defect in mitochondrial OXPHOS, specifically due to deficiencies in