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Heterozygous mutation of Opa1 in Drosophila shortens lifespan mediated through increased reactive oxygen species production.

Tang S, Le PK, Tse S, Wallace DC, Huang T - PLoS ONE (2009)

Bottom Line: We found that heterozygous dOpa1 mutation caused shortened lifespan, increased susceptibility to oxidative stress and elevated production of ROS in the whole Drosophila.Antioxidant treatment partially restored lifespan in the male dOpa1 mutants, but had no effects in the females.Heterozygous dOpa1 mutation is also associated with irregular and dysmorphic mitochondria in the muscle.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
Optic atrophy 1 (OPA1) is a dynamin-like GTPase located in the inner mitochondrial membrane and mutations in OPA1 are associated with autosomal dominant optic atrophy (DOA). OPA1 plays important roles in mitochondrial fusion, cristae remodeling and apoptosis. Our previous study showed that dOpa1 mutation caused elevated reactive oxygen species (ROS) production and resulted in damage and death of the cone and pigment cells in Drosophila eyes. Since ROS-induced oxidative damage to the cells is one of the primary causes of aging, in this study, we examined the effects of heterozygous dOpa1 mutation on the lifespan. We found that heterozygous dOpa1 mutation caused shortened lifespan, increased susceptibility to oxidative stress and elevated production of ROS in the whole Drosophila. Antioxidant treatment partially restored lifespan in the male dOpa1 mutants, but had no effects in the females. Heterozygous dOpa1 mutation caused an impairment of respiratory chain complex activities, especially complexes II and III, and reversible decreased aconitase activity. Heterozygous dOpa1 mutation is also associated with irregular and dysmorphic mitochondria in the muscle. Our results, for the first time, demonstrate the important role of OPA1 in aging and lifespan, which is most likely mediated through augmented ROS production.

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Heterozygous dOpa1 mutation impairs mitochondrial bioenergetics.(A) dOpa1+/− Drosophila displayed compromised oxygen consumption driven by complex II substrate succinate. Mitochondrial respiratory chain complexes II and III activities were also significantly attenuated in both 7 d.o. (B) and 35 d.o. (C) dOpa1+/− Drosophila. In the 35-day old dOpa1+/− flies, mitochondrial aconitase activities were reduced by 22% relative to age-matched controls (D).
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pone-0004492-g003: Heterozygous dOpa1 mutation impairs mitochondrial bioenergetics.(A) dOpa1+/− Drosophila displayed compromised oxygen consumption driven by complex II substrate succinate. Mitochondrial respiratory chain complexes II and III activities were also significantly attenuated in both 7 d.o. (B) and 35 d.o. (C) dOpa1+/− Drosophila. In the 35-day old dOpa1+/− flies, mitochondrial aconitase activities were reduced by 22% relative to age-matched controls (D).

Mentions: In order to further investigate the mechanism by which dOpa1 mutation elevates ROS, we performed a detailed comparison of respiration of the mitochondria of dOpa1+/− and dOpa1+/+ adult Drosophila (7 d.o.), as inhibition of the mitochondrial ETC can increase ROS. In oxygen consumption assays, metabolism of NADH-linked complex I substrates pyruvate and malate was unaffected by dOpa1+/− mutation while succinate-driven respiration via complex II was significantly decreased (P<0.05) in dOpa1+/− Drosophila (Figure 3A). Consistent with these findings, while no significant differences were observed in the specific activities of complexes I and IV in 7-day old dOpa1+/− and dOpa1+/+ flies, complexes II (38% reduction, p = 0.001) and III (37% reduction, p = 0.026) activities were significantly attenuated in dOpa1+/− Drosophila (Figure 3B). In 35 d.o. dOpa1+/− flies, a similar impairment of enzymatic activities in complexes II (37% decrease, p = 1.97e-07) and III (28% decrease, p = 0.008) was observed. In addition, moderate (10%), but significant (p = 0.02) decline of complex IV activity was observed in 35 d.o. dOpa1+/− flies (Figure 3C). Our result also showed that there was a gender difference in the complex II activity. Heterozygous mutation of dOpa1 in males caused more significant inhibition of the complex II activity at 5 week of age (Supplemental Figure S1).


Heterozygous mutation of Opa1 in Drosophila shortens lifespan mediated through increased reactive oxygen species production.

Tang S, Le PK, Tse S, Wallace DC, Huang T - PLoS ONE (2009)

Heterozygous dOpa1 mutation impairs mitochondrial bioenergetics.(A) dOpa1+/− Drosophila displayed compromised oxygen consumption driven by complex II substrate succinate. Mitochondrial respiratory chain complexes II and III activities were also significantly attenuated in both 7 d.o. (B) and 35 d.o. (C) dOpa1+/− Drosophila. In the 35-day old dOpa1+/− flies, mitochondrial aconitase activities were reduced by 22% relative to age-matched controls (D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2637430&req=5

pone-0004492-g003: Heterozygous dOpa1 mutation impairs mitochondrial bioenergetics.(A) dOpa1+/− Drosophila displayed compromised oxygen consumption driven by complex II substrate succinate. Mitochondrial respiratory chain complexes II and III activities were also significantly attenuated in both 7 d.o. (B) and 35 d.o. (C) dOpa1+/− Drosophila. In the 35-day old dOpa1+/− flies, mitochondrial aconitase activities were reduced by 22% relative to age-matched controls (D).
Mentions: In order to further investigate the mechanism by which dOpa1 mutation elevates ROS, we performed a detailed comparison of respiration of the mitochondria of dOpa1+/− and dOpa1+/+ adult Drosophila (7 d.o.), as inhibition of the mitochondrial ETC can increase ROS. In oxygen consumption assays, metabolism of NADH-linked complex I substrates pyruvate and malate was unaffected by dOpa1+/− mutation while succinate-driven respiration via complex II was significantly decreased (P<0.05) in dOpa1+/− Drosophila (Figure 3A). Consistent with these findings, while no significant differences were observed in the specific activities of complexes I and IV in 7-day old dOpa1+/− and dOpa1+/+ flies, complexes II (38% reduction, p = 0.001) and III (37% reduction, p = 0.026) activities were significantly attenuated in dOpa1+/− Drosophila (Figure 3B). In 35 d.o. dOpa1+/− flies, a similar impairment of enzymatic activities in complexes II (37% decrease, p = 1.97e-07) and III (28% decrease, p = 0.008) was observed. In addition, moderate (10%), but significant (p = 0.02) decline of complex IV activity was observed in 35 d.o. dOpa1+/− flies (Figure 3C). Our result also showed that there was a gender difference in the complex II activity. Heterozygous mutation of dOpa1 in males caused more significant inhibition of the complex II activity at 5 week of age (Supplemental Figure S1).

Bottom Line: We found that heterozygous dOpa1 mutation caused shortened lifespan, increased susceptibility to oxidative stress and elevated production of ROS in the whole Drosophila.Antioxidant treatment partially restored lifespan in the male dOpa1 mutants, but had no effects in the females.Heterozygous dOpa1 mutation is also associated with irregular and dysmorphic mitochondria in the muscle.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
Optic atrophy 1 (OPA1) is a dynamin-like GTPase located in the inner mitochondrial membrane and mutations in OPA1 are associated with autosomal dominant optic atrophy (DOA). OPA1 plays important roles in mitochondrial fusion, cristae remodeling and apoptosis. Our previous study showed that dOpa1 mutation caused elevated reactive oxygen species (ROS) production and resulted in damage and death of the cone and pigment cells in Drosophila eyes. Since ROS-induced oxidative damage to the cells is one of the primary causes of aging, in this study, we examined the effects of heterozygous dOpa1 mutation on the lifespan. We found that heterozygous dOpa1 mutation caused shortened lifespan, increased susceptibility to oxidative stress and elevated production of ROS in the whole Drosophila. Antioxidant treatment partially restored lifespan in the male dOpa1 mutants, but had no effects in the females. Heterozygous dOpa1 mutation caused an impairment of respiratory chain complex activities, especially complexes II and III, and reversible decreased aconitase activity. Heterozygous dOpa1 mutation is also associated with irregular and dysmorphic mitochondria in the muscle. Our results, for the first time, demonstrate the important role of OPA1 in aging and lifespan, which is most likely mediated through augmented ROS production.

Show MeSH
Related in: MedlinePlus