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Mitochondrial DNA mutations in disease and aging.

Park CB, Larsson NG - J. Cell Biol. (2011)

Bottom Line: The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation.There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level.In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Medical Sciences, Ajou University School of Medicine, Suwon 443-721, Korea.

ABSTRACT
The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

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Related in: MedlinePlus

Schematic representation of mammalian mtDNA. The double-stranded circular mammalian mtDNA molecule of ∼16.5 kb contains a single longer noncoding region, the displacement loop (D loop) region, harboring the promoters for transcription of both mtDNA strands (HSP and LSP) and the origin of leading strand replication (OH). The origin of lagging strand replication (OL) is embedded in a cluster of tRNA genes. The genes for the two rRNAs (12S and 16S rRNA), 13 mRNAs (ND1–6, ND4L, Cyt b, COI–III, ATP6, and ATP8), and 22 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A, and Q) are indicated by boxes. Illustration by Annika Röhl.
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fig1: Schematic representation of mammalian mtDNA. The double-stranded circular mammalian mtDNA molecule of ∼16.5 kb contains a single longer noncoding region, the displacement loop (D loop) region, harboring the promoters for transcription of both mtDNA strands (HSP and LSP) and the origin of leading strand replication (OH). The origin of lagging strand replication (OL) is embedded in a cluster of tRNA genes. The genes for the two rRNAs (12S and 16S rRNA), 13 mRNAs (ND1–6, ND4L, Cyt b, COI–III, ATP6, and ATP8), and 22 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A, and Q) are indicated by boxes. Illustration by Annika Röhl.

Mentions: Mammalian mtDNA encodes 13 proteins that all are subunits of the oxidative phosphorylation system and 22 tRNAs and 2 ribosomal RNAs (rRNAs; Fig. 1). The transcription of mtDNA is polycistronic and is initiated at one main promoter on each strand, the light strand promoter (LSP) and heavy strand promoter (HSP). The existence of a second HSP dedicated to the transcription of the rRNA genes has been reported (Montoya et al., 1983; Martin et al., 2005); however, its existence has been questioned, as transcription from this putative promoter cannot be reconstituted in vitro with known components of the basal transcription machinery (Litonin et al., 2010). The steady-state levels of rRNAs are much higher than the levels of the downstream mRNAs, but this is, in principle, compatible with polycistronic transcription from a single HSP as the rRNAs are incorporated into ribosomes and therefore may be much more stable than the downstream mRNAs.


Mitochondrial DNA mutations in disease and aging.

Park CB, Larsson NG - J. Cell Biol. (2011)

Schematic representation of mammalian mtDNA. The double-stranded circular mammalian mtDNA molecule of ∼16.5 kb contains a single longer noncoding region, the displacement loop (D loop) region, harboring the promoters for transcription of both mtDNA strands (HSP and LSP) and the origin of leading strand replication (OH). The origin of lagging strand replication (OL) is embedded in a cluster of tRNA genes. The genes for the two rRNAs (12S and 16S rRNA), 13 mRNAs (ND1–6, ND4L, Cyt b, COI–III, ATP6, and ATP8), and 22 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A, and Q) are indicated by boxes. Illustration by Annika Röhl.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105550&req=5

fig1: Schematic representation of mammalian mtDNA. The double-stranded circular mammalian mtDNA molecule of ∼16.5 kb contains a single longer noncoding region, the displacement loop (D loop) region, harboring the promoters for transcription of both mtDNA strands (HSP and LSP) and the origin of leading strand replication (OH). The origin of lagging strand replication (OL) is embedded in a cluster of tRNA genes. The genes for the two rRNAs (12S and 16S rRNA), 13 mRNAs (ND1–6, ND4L, Cyt b, COI–III, ATP6, and ATP8), and 22 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A, and Q) are indicated by boxes. Illustration by Annika Röhl.
Mentions: Mammalian mtDNA encodes 13 proteins that all are subunits of the oxidative phosphorylation system and 22 tRNAs and 2 ribosomal RNAs (rRNAs; Fig. 1). The transcription of mtDNA is polycistronic and is initiated at one main promoter on each strand, the light strand promoter (LSP) and heavy strand promoter (HSP). The existence of a second HSP dedicated to the transcription of the rRNA genes has been reported (Montoya et al., 1983; Martin et al., 2005); however, its existence has been questioned, as transcription from this putative promoter cannot be reconstituted in vitro with known components of the basal transcription machinery (Litonin et al., 2010). The steady-state levels of rRNAs are much higher than the levels of the downstream mRNAs, but this is, in principle, compatible with polycistronic transcription from a single HSP as the rRNAs are incorporated into ribosomes and therefore may be much more stable than the downstream mRNAs.

Bottom Line: The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation.There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level.In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Medical Sciences, Ajou University School of Medicine, Suwon 443-721, Korea.

ABSTRACT
The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

Show MeSH
Related in: MedlinePlus