Mitochondrial Dysfunction in Neurodegenerative Diseases
Description of the project
Two genomes code for the subunits of the mitochondrial respiratory chain. Most of the subunits are encoded by nuclear genes, translated in the cytoplasm and transported into the mitochondria. The mitochondrial genome (mtDNA) is a 16.6 kb circular double helix that encodes 13 of the subunits of the respiratory chain complexes. The most common mutation in mtDNA is probably 3243A>G in the MTTL1 gene causing the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes). Among families with 3243A>G in northern Finland we have found clustering of maternal ancestors in the population of the province of Kainuu suggesting that a founder effect may partly determine the frequency of the mutation in the population.
The existence of slightly deleterious mutations has been proposed on the basis of pairwise differences between and within populations and our analysis on 840 human mtDNA sequences confirmed that phylogenetically recent nonsynonymous variants are less conserved than the older ones thus corroborating the presence of slightly deleterious mutations in humans. Such nonconserved nonsynonymous variants may slightly impair the capacity of oxidative phosphorylation and make cells subject to degeneration precipitated by other genetic factors, by environmental factors or by aging. An excess of maternal inheritance compared to paternal inheritance has been observed in many complex diseases suggesting that mtDNA may be etiologically involved. These diseases include diabetes mellitus, Parkinson´s disease (PD) and Alzheimer´s disease.
The mitochondrial oxidative phosphorylation (OXPHOS) system consists of five multisubunit complexes that are embedded in the inner mitochondrial membrane. Complex I is the largest of these complexes being composed of 45 subunits, seven of which are encoded by mtDNA and the remaining are encoded by nuclear DNA (nDNA). Complex I deficiency may be the most common energy generation disorder, but the underlying genetic defect can be ascribed to mutations in mtDNA in approximately 5 % of the patients. These mutations cause infantile or childhood encephalomyopathies or multisystem disorders in homozygotes.
Parkinson´s disease (PD) is multifactorial in origin, but studies on genetic epidemiology have shown a definite degree of heritability. Mutations in e.g. dardarin (LRRK2) and parkin genes have been found in patients with familial PD. Complex I activity has been found to be decreased in substantia nigra and in skeletal muscle of patients with PD suggesting that mitochondrial aberration may be involved in the pathogenesis, although no causative mtDNA mutations have been detected so far. Interestingly, the parkinsonism inducing toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is oxidized by monoamine oxidase to 1-methyl-4-phenyl pyridinium (MPP+) that is a Complex I inhibitor accumulating into mitochondria. MPP+ binds at the same site as rotenone, a well-known Complex I inhibitor. In the rat, chronic exposure to rotenone can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
Aims of the studies on mitochondrial diseases: (1) Mitochondrial DNA mutations and polymorphisms in neurodegenerative diseases like Parkinson´s disease, age-related sensorineural hearing impairment and Alzheimer´s disease. (2) Mutations in genes encoding subunits of the OXPHOS Complex I as a cause of childhood encephalomyopathies. (3) Genetic epidemiology of the MTTL1 mutation 3243A>G in the Finnish population.
Aims of the studies on neurodegenerative diseases associated with mitochondrial dysfunction: (1) Genetic epidemiology of early-onset Parkinson´s disease in a nationwide ascertainment of cases. (2) The role of mutations in nine highly conserved genes encoding subunits of the OXPHOS Complex I. (3) Mutations in genes encoding proteins involved in mitochondrial iron metabolism.