Structural and functional mitochondrial abnormalities associated with high levels of partially deleted mitochondrial...

Kearns-Sayre syndrome (KSS) is a progressive and ultimately fatal human encephalomyopathy that is associated with large-scale deletions of mitochondrial DNA (mtDNA). To gain new insights into the developmental pathobiology of this disease, we studied the maintenance and expression of deleted mtDNAs (delta-mtDNAs) in somatic cell hybrids generated by fusion of HeLacot cells with a KSS fibroblast clone containing both wild-type and delta-mtDNAs. We observed that delta-mtDNAs were preferentially maintained over the KSS wild-type mtDNAs (wt-mtDNAs) in almost all isolated hybrid clones. Mitochondrial metabolism was not compromised in hybrids containing as much as 70-79% delta-mtDNAs. Two clones containing more than 99% delta-mtDNA were severely deficient in oxidative phosphorylation and exhibited abnormal, enlarged mitochondria. These clones had undetectable levels of mtDNA-encoded polypeptides, but contained normal amounts of a nuclear DNA-encoded mitochondrial protein. The data suggest a nonrandom pattern of mtDNA segregation in the triplasmic hybrids and a correlation among delta-mtDNA, structural mitochondrial abnormalities, and mitochondrial dysfunction.