Abstract
This mini-review summarizes our present view of the biochemical alterations associated with mitochondrial DNA (mtDNA) point mutations. Mitochondrial cytopathies caused by mutations of mtDNA are well-known genetic and clinical entities, but the biochemical pathogenic mechanisms are often obscure. Leber's hereditary optic neuropathy (LHON) is due to three main mutations in genes for complex I subunits. Even if the catalytic activity of complex I is maintained except in cells carrying the 3460/ND1 mutation, in all cases there is a change in sensitivity to complex I inhibitors and an impairment of mitochondrial respiration, eliciting the possibility of generation of reactive oxygen species (ROS) by the complex. Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP), is due to a mutation in the ATPase-6 gene. In NARP patients ATP synthesis is strongly depressed to an extent proportional to the mutation load; nevertheless, ATP hydrolysis and ATP-driven proton translocation are not affected. It is suggested that the NARP mutation affects the ability of the enzyme to couple proton transport to ATP synthesis. A point mutation in subunit III of cytochrome c oxidase is accompanied by a syndrome resembling MELAS: however, no major biochemical defect is found, if we except an enhanced production of ROS. The mechanism of such enhancement is at present unknown. In this review, we draw attention to a few examples in which the overproduction of ROS might represent a common step in the induction of clinical phenotypes and/or in the progression of several human pathologies associated with mtDNA point mutations.
| Original language | English |
|---|---|
| Pages (from-to) | 89-94 |
| Number of pages | 6 |
| Journal | Biochimica et Biophysica Acta - Bioenergetics |
| Volume | 1658 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - Jul 23 2004 |
Fingerprint
Keywords
- ATP synthase
- Complex I
- Cytochrome oxidase subunit III
- LHON
- Mitochondrial cytopathy
- NARP
ASJC Scopus subject areas
- Biophysics
Cite this
Bioenergetics of mitochondrial diseases associated with mtDNA mutations. / Lenaz, Giorgio; Baracca, Alessandra; Carelli, Valerio; D'Aurelio, Marilena; Sgarbi, Gianluca; Solaini, Giancarlo.
In: Biochimica et Biophysica Acta - Bioenergetics, Vol. 1658, No. 1-2, 23.07.2004, p. 89-94.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Bioenergetics of mitochondrial diseases associated with mtDNA mutations
AU - Lenaz, Giorgio
AU - Baracca, Alessandra
AU - Carelli, Valerio
AU - D'Aurelio, Marilena
AU - Sgarbi, Gianluca
AU - Solaini, Giancarlo
PY - 2004/7/23
Y1 - 2004/7/23
N2 - This mini-review summarizes our present view of the biochemical alterations associated with mitochondrial DNA (mtDNA) point mutations. Mitochondrial cytopathies caused by mutations of mtDNA are well-known genetic and clinical entities, but the biochemical pathogenic mechanisms are often obscure. Leber's hereditary optic neuropathy (LHON) is due to three main mutations in genes for complex I subunits. Even if the catalytic activity of complex I is maintained except in cells carrying the 3460/ND1 mutation, in all cases there is a change in sensitivity to complex I inhibitors and an impairment of mitochondrial respiration, eliciting the possibility of generation of reactive oxygen species (ROS) by the complex. Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP), is due to a mutation in the ATPase-6 gene. In NARP patients ATP synthesis is strongly depressed to an extent proportional to the mutation load; nevertheless, ATP hydrolysis and ATP-driven proton translocation are not affected. It is suggested that the NARP mutation affects the ability of the enzyme to couple proton transport to ATP synthesis. A point mutation in subunit III of cytochrome c oxidase is accompanied by a syndrome resembling MELAS: however, no major biochemical defect is found, if we except an enhanced production of ROS. The mechanism of such enhancement is at present unknown. In this review, we draw attention to a few examples in which the overproduction of ROS might represent a common step in the induction of clinical phenotypes and/or in the progression of several human pathologies associated with mtDNA point mutations.
AB - This mini-review summarizes our present view of the biochemical alterations associated with mitochondrial DNA (mtDNA) point mutations. Mitochondrial cytopathies caused by mutations of mtDNA are well-known genetic and clinical entities, but the biochemical pathogenic mechanisms are often obscure. Leber's hereditary optic neuropathy (LHON) is due to three main mutations in genes for complex I subunits. Even if the catalytic activity of complex I is maintained except in cells carrying the 3460/ND1 mutation, in all cases there is a change in sensitivity to complex I inhibitors and an impairment of mitochondrial respiration, eliciting the possibility of generation of reactive oxygen species (ROS) by the complex. Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP), is due to a mutation in the ATPase-6 gene. In NARP patients ATP synthesis is strongly depressed to an extent proportional to the mutation load; nevertheless, ATP hydrolysis and ATP-driven proton translocation are not affected. It is suggested that the NARP mutation affects the ability of the enzyme to couple proton transport to ATP synthesis. A point mutation in subunit III of cytochrome c oxidase is accompanied by a syndrome resembling MELAS: however, no major biochemical defect is found, if we except an enhanced production of ROS. The mechanism of such enhancement is at present unknown. In this review, we draw attention to a few examples in which the overproduction of ROS might represent a common step in the induction of clinical phenotypes and/or in the progression of several human pathologies associated with mtDNA point mutations.
KW - ATP synthase
KW - Complex I
KW - Cytochrome oxidase subunit III
KW - LHON
KW - Mitochondrial cytopathy
KW - NARP
UR - http://www.scopus.com/inward/record.url?scp=3543045616&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3543045616&partnerID=8YFLogxK
U2 - 10.1016/j.bbabio.2004.03.013
DO - 10.1016/j.bbabio.2004.03.013
M3 - Article
VL - 1658
SP - 89
EP - 94
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
SN - 0005-2728
IS - 1-2
ER -