Correlation of functional and ultrastructural abnormalities of mitochondria in mouse heart carrying a pathogenic mutant mtDNA with a 4696-bp deletion

We examined the correlation of functional and structural abnormalities of c ardiac mitochondria. created by pathogenic mutant mtDNAs using mito-mice wi th hearts carrying 88% mutant Delta mtDNA4696 with a 4696 deletion. COX his tochemistry, quantitative PCR analysis, and electronmicrographs showed that accumulation of 91.6% Delta mtDNA4696 in single cardiac muscle fibers indu ced progressive reduction of COX activity to form COX-negative fibers. More over, hearts carrying 88% Delta mtDNA4696 consisted of three types of cardi ac muscle fibers with different functional properties, COX-positive, -negat ive, and -intermediate fibers, which corresponded respectively to three typ es of fibers with different structural properties; type A fibers containing mitochondria with only lamellar cristae, type B containing mitochondria wi th only tubular cristae, and type C possessing mitochondria with both lamel lar and tubular cristae. These observations suggest that lamellar cristae w ith COX activity transform into tubular cristae without COX activity along with the accumulation of Delta mtDNA4696, which would be responsible for in sufficient supply of mtDNA products required to keep the normal structure a nd function of mitochondrial cristae. The correlation of these structural a nd functional abnormalities of cristae should provide important insight int o diagnosis of cardiomyopathies caused by accumulation of pathogenic mutant mtDNAs. (C) 2001 Academic Press.