Human Molecular Genetics, Vol 6, 185-191, Copyright © 1997 by Oxford University Press
NG Larsson, A Oldfors, JD Garman, GS Barsh and DA Clayton
Mitochondrial transcription factor A (mtTFA) is a key activator of
mitochondrial transcription in mammals. It also has a role in mitochondrial
DNA (mtDNA) replication, since transcription generates an RNA primer
necessary for initiation of mtDNA replication. In the mouse,
testis-specific mtTFA transcripts encode a protein isoform that is imported
to the nucleus rather than into mitochondria of spermatocytes and
elongating spermatids. We now report molecular characterization of human
mtTFA (h-mtTFA) expression in somatic tissues and male germ cells.
Similarly to the mouse, analysis of cDNAs and Northern blots identified
abundant testis-specific transcript isoforms generated by use of alternate
transcription initiation sites. However, unlike the mouse, none of the
testis-specific transcripts predicts a nuclear protein isoform, and Western
blot analysis identified only the mitochondrial form of h-mtTFA in human
testis. Immunohistochemistry and in situ were used to compare the
distribution of mtTFA protein, testis- specific mtTFA transcripts, mtDNA
and mtRNA in sections of human testis. Our results show that the mtTFA
protein and mtDNA exhibit parallel gradients with high levels in
undifferentiated male germ cells and low levels or an absence in different
male germ cells. Testis- specific transcripts exhibit the opposite pattern,
suggesting that in both humans and mice, these testis-specific mtTFA
transcripts down- regulate mtTFA protein levels in mammalian mitochondria.
Our findings demonstrate that mtTFA does not have a critical role in the
nucleus, suggest a mechanism for reducing mtDNA copy number during
spermatogenesis and have implications for the understanding of maternal
transmission of mtDNA.
ARTICLES
Down-regulation of mitochondrial transcription factor A during spermatogenesis in humans
Department of Developmental Biology, Stanford University School of Medicine, CA 94305-5427, USA.
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