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Vol. 10, Issue 10, 3345-3356, October 1999
Departments of *Neurology and Although the regulation of mitochondrial DNA (mtDNA) copy number is
performed by nuclear-coded factors, very little is known about the
mechanisms controlling this process. We attempted to introduce nonhuman
ape mtDNA into human cells harboring either no mtDNA or mutated mtDNAs
(partial deletion and tRNA gene point mutation). Unexpectedly, only
cells containing no mtDNA could be repopulated with nonhuman ape mtDNA.
Cells containing a defective human mtDNA did not incorporate or
maintain ape mtDNA and therefore died under selection for oxidative
phosphorylation function. On the other hand, foreign human mtDNA was
readily incorporated and maintained in these cells. The suicidal
preference for self-mtDNA showed that functional parameters associated
with oxidative phosphorylation are less relevant to mtDNA maintenance
and copy number control than recognition of mtDNA self-determinants.
Non-self-mtDNA could not be maintained into cells with mtDNA even if
no selection for oxidative phosphorylation was applied. The
repopulation kinetics of several mtDNA forms after severe depletion by
ethidium bromide treatment showed that replication and maintenance of
mtDNA in human cells are highly dependent on molecular features,
because partially deleted mtDNA molecules repopulated cells
significantly faster than full-length mtDNA. Taken together, our
results suggest that mtDNA copy number may be controlled by competition
for limiting levels of trans-acting factors that
recognize primarily mtDNA molecular features. In agreement with this
hypothesis, marked variations in mtDNA levels did not affect the
transcription of nuclear-coded factors involved in mtDNA replication.
Cell Biology and
Anatomy, University of Miami, School of Medicine, Miami, Florida 33136
Corresponding author. E-mail
address: cmoraes{at}med.miami.edu.
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