Mouse models for mitochondrial disease

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neurom uscular diseases. MtDNA base substitution and rearrangement mutations gener ally inactivate one or more tRNA or rRNA genes and can cause myopathy, card iomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations ca n cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypopla sia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nu cleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, c aused by adenine nucleotide translocator-l (ANT1) mutations. Mouse models h ave been prepared that recapitulate a number of these diseases. The mtDNA 1 6S rRNA chloramphenicol (CAP) resistance mutation was introduced into the m ouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals . A mtDNA deletion was introduced into the mouse germline and caused myopat hy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA m itochondrial transcription factor (Tfam) gene in the heart resulted in neon atal lethal cardiomyopathy, while its inactivation in the pancreatic beta - cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial di abetes through transgenic modification of the beta -cell ATP-sensitive K+ c hannel (K-ATP) Mutational inactivation of the mouse Anti gene resulted in m yopathy, cardiomyopathy, and multiple mtDNA deletions in association with e levated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta psi regulated ROS pro duction. The role of mitochondrial ROS toxicity in disease and aging was co nfirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismuta se (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and a ccelerated apoptosis in aging, respectively. The importance of mitochondria l ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs. (C) 2001 Wiley-Liss, Inc.