PMID- 10220377
OWN - NLM
STAT- MEDLINE
DCOM- 19990610
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 9
DP  - 1999 Apr 27
TI  - Mitochondrial disease in mouse results in increased oxidative stress.
PG  - 4820-5
AB  - It has been hypothesized that a major factor in the progression of mitochondrial 
      disease resulting from defects in oxidative phosphorylation (OXPHOS) is the
      stimulation of the mitochondrial production of reactive oxygen species (ROS) and 
      the resulting damage to the mtDNA. To test this hypothesis, we examined the
      mitochondria from mice lacking the heart/muscle isoform of the adenine nucleotide
      translocator (Ant1), designated Ant1(tm2Mgr) (-/-) mice. The absence of Ant1
      blocks the exchange of ADP and ATP across the mitochondrial inner membrane, thus 
      inhibiting OXPHOS. Consistent with Ant1 expression, mitochondria isolated from
      skeletal muscle, heart, and brain of the Ant1-deficient mice produced markedly
      increased amounts of the ROS hydrogen peroxide, whereas liver mitochondria, which
      express a different Ant isoform, produced normally low levels of hydrogen
      peroxide. The increased production of ROS by the skeletal muscle and heart was
      associated with a dramatic increase in the ROS detoxification enzyme manganese
      superoxide dismutase (Sod2, also known as MnSod) in muscle tissue and muscle
      mitochondria, a modest increase in Sod2 in heart tissue, and no increase in heart
      mitochondria. The level of glutathione peroxidase-1 (Gpx1), a second ROS
      detoxifying enzyme, was increased moderately in the mitochondria of both tissues.
      Consistent with the lower antioxidant defenses in heart, the heart mtDNAs of the 
      Ant1-deficient mice showed a striking increase in the accumulation of mtDNA
      rearrangements, whereas skeletal muscle, with higher antioxidant defenses, had
      fewer mtDNA rearrangements. Hence, inhibition of OXPHOS does increase
      mitochondrial ROS production, eliciting antioxidant defenses. If the antioxidant 
      defenses are insufficient to detoxify the ROS, then an increased mtDNA mutation
      rate can result.
FAU - Esposito, L A
AU  - Esposito LA
AD  - Center for Molecular Medicine, Emory University School of Medicine, Atlanta, GA
      30322, USA.
FAU - Melov, S
AU  - Melov S
FAU - Panov, A
AU  - Panov A
FAU - Cottrell, B A
AU  - Cottrell BA
FAU - Wallace, D C
AU  - Wallace DC
LA  - eng
GR  - HL45572/HL/NHLBI NIH HHS/United States
GR  - NS21328/NS/NINDS NIH HHS/United States
GR  - R01 NS021328/NS/NINDS NIH HHS/United States
GR  - R01 AG013154/AG/NIA NIH HHS/United States
GR  - AG13154/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Protein Isoforms)
RN  - 0 (Reactive Oxygen Species)
RN  - 9068-80-8 (Mitochondrial ADP, ATP Translocases)
SB  - IM
MH  - Animals
MH  - Brain/metabolism
MH  - *DNA Damage
MH  - DNA, Mitochondrial/genetics
MH  - Mice
MH  - Mitochondria/genetics/metabolism
MH  - Mitochondria, Heart/genetics/metabolism
MH  - Mitochondrial ADP, ATP Translocases/*deficiency/genetics
MH  - Mitochondrial Encephalomyopathies/genetics/*metabolism
MH  - Muscle, Skeletal/metabolism
MH  - Myocardium/metabolism
MH  - *Oxidative Stress
MH  - Protein Isoforms/genetics/metabolism
MH  - Reactive Oxygen Species/*metabolism
PMC - PMC21775
EDAT- 1999/04/29 00:00
MHDA- 1999/04/29 00:01
CRDT- 1999/04/29 00:00
PHST- 1999/04/29 00:00 [pubmed]
PHST- 1999/04/29 00:01 [medline]
PHST- 1999/04/29 00:00 [entrez]
AID - 10.1073/pnas.96.9.4820 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4820-5. doi: 10.1073/pnas.96.9.4820.