Partially-deleted mitochondrial DNA (DeltamtDNA) accumulates during aging of postmitotic tissues. This accumulation has been linked to decreased metabolic activity, increased reactive oxygen species formation and the aging process. Taking advantage of cell lines with heteroplasmic mtDNA mutations, we showed that, after severe mtDNA depletion, organelles are quickly and predominantly repopulated with DeltamtDNA, whereas repopulation with the wild-type counterpart is slower. This behavior was not observed for full-length genomes with pathogenic point mutations. The faster repopulation of smaller molecules was supported by metabolic labeling of mtDNA with [3H]thymidine during relaxed copy number control conditions. We also showed that hybrid cells containing two defective mtDNA haplotypes tend to retain the smaller one as they adjust their normal mtDNA copy number. Taken together, our results indicate that, under relaxed copy number control, DeltamtDNAs repopulate mitochondria more efficiently than full-length genomes.

We have isolated transmitochondrial cybrids containing a mitochondrial DNA cytochrome b 4-base pair deletion previously identified in a patient with parkinsonism. This presentation is in contrast to that of most patients with cytochrome b mutations, who present with exercise intolerance. Clones containing different levels of the cytochrome b 4-base pair deletion showed that high levels of the mutation were associated with a respiratory deficiency and a specific complex III defect. Newly synthesized full-length cytochrome b was undetectable by metabolic labeling of mutant cells, and these cells were unable to grow in media that restricts proliferation of cells with defective oxidative phosphorylation. Steady state levels of some subunits previously found to be in close association with cytochrome b by crystallography and biochemical analysis (ie, Rieske [2Fe-2S] protein and subunit VI) were drastically reduced in clones containing high levels of the mutation, whereas the reduction in the core-1 subunit was milder. The absence of cytochrome b and complex III activity was also associated with increased hydrogen peroxide production. These findings, together with the variable tissue distribution of pathogenic mitochondrial DNA molecules, provide clues to the heterogeneous phenotypes associated with mitochondrial DNA mutations and establish a link between different forms of parkinsonism and oxidative phosphorylation defects.

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Cardiomyopathy was reported in a few Duchenne muscular dystrophy (DMD) carriers with clinical evidence of myopathy. We report two carriers with dilated cardiomyopathy, increased serum CK, and no symptoms of muscle weakness. In heart biopsies of both patients, dystrophin-the protein product of DMD locus--was absent in many fibers. Dilated cardiomyopathy may be the only manifestation of dystrophin gene mutation in carriers.

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