Analysis of Human Mitochondrial DNA Mutations
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Mitochondria are the powerhouses of eukaryotic cells. These organelles generate energy in the form of adenosine triphosphate (ATP) from carbohydrates, fats, and proteins, via oxidative phosphorylation. By virtue of possessing their own genetic material—mitochondrial DNA (mtDNA)-mitochondria are unique mammalian organelles. Normal human mtDNA is a 16,569 base-pair (bp), double-stranded, circular molecule (
1
). The molecules contain tightly compacted genes for 22 transfer (
tRNAs
),
13
polypeptides, and two ribosomal
RNAs
(r
RNA
s) Fig. 1 ). All 13 polypeptides are subunits of the oxidative phosphorylation system: seven belong to Complex I (NADHCoQ oxidoreductase), one to Complex III (CoQ-cytochrome c oxidoreductase), three to Complex IV (cytochrome c oxidase or COX), and two to Complex V (ATP synthase). These subunits are synthesized within the mitochondrion, where they are assembled together with a larger number of subunits encoded by the nuclear
DNA
(nDNA), that are synthesized in the cytoplasm and are transported into the mitochondrion (
2
). Approximately 1,000 mitochondrial polypeptides are encoded in
nDNA
. Complex
II
(succinate dehydrogenase-CoQ oxidoreductase), of which succinate dehydrogenase (SDH) is a component, is encoded entirely by nuclear genes; SDH thus serves as a marker for mitochondrial number and activity, independent of the mtDNA.
Fig. 1.
Map of the human mitochondrial genome. The structural genes for the mtDNAencoded 12S and 16S ribosomal RNAs, the subunits of
NADH
-coenzyme Q oxidoreductase
(ND)
, cytochrome c oxidase
(COX)
, cytochrome b
(Cyt b)
, and ATP synthase
(A)
, and 22
tRNAs
(1-letter amino acid nomenclature), are shown. The origins of light-strand (O
L
) and heavy-strand (O
H
) DNA replication, and of the promoters for initiation of transcription from the light-strand (
LSP
) and heavy-strand (
HSP
), are shown by arrows. The “common” deletion, a mt
DNA
species often found in sporadic
KSS
/
PEO
is shown, as are common point mutations associated with maternally inherited encephalomyopathies (boxed).
