Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly

Fridell, Yih-Woei C.; Sánchez-Blanco, Adolfo; Silvia, Brian A.; Helfand, Stephen L.

doi:10.1016/j.cmet.2005.01.005

Cited by 164 publications

(155 citation statements)

References 57 publications

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“…Furthermore, some, but not all, studies have indicated a role for IRS2 gene variants in the pathogenesis of obesity and obesity-associated insulin resistance (Sesti et al 2001;Stefan et al 2003). Indeed, we have recently found that subjects with one or two IRS2 Asp alleles displayed a greater chance of living between 96 and 104 years of age (Barbieri et al 2010) Recent experimental evidences suggest that the effect of the insulin IGF1 signaling pathway on life span may be partially mediated by regulating the expression of uncoupling protein 2 (UCP2) (Bratic and Trifunovic 2010;Andrews et al 2005) In flies, over-expressing human UCP2 (hUCP2) to adult neurons resulted in decreased oxidative damage and extended life span without compromising fertility or physical activity (Fridell et al 2005). Furthermore, a very recent study has demonstrated that the absence of UCP2 shortens life span in wild-type mice, and the level of UCP2 positively correlates with the postnatal survival of superoxide dismutase 2 mutant animals (Andrews and Horvath 2009).…”

Section: Discussionmentioning

confidence: 99%

“…A role for UCP2 in regulating lifespan is strongly suggested by the ability of UCP2 to reduce ROS and regulate mitochondrial function in a diverse range of tissues (Fridell et al 2005;Andrews et al 2009) since mitochondrial dysfunction and ROS production lies at the heart of the aging process. In humans, some, but not all (Klannemark et al 1998), studies showed that UCP2 gene variants are implicated in diabetes, obesity, and fat metabolism (Zhang et al 2001) and are strongly linked to resting energy expenditure (Astrup et al 1999;Buemann et al 2001;Walder et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…In flies, over-expressing human UCP2 (hUCP2) to adult neurons resulted in increased uncoupled respiration, decreased ROS production, decreased oxidative damage and extended life span without compromising fertility or physical activity (Fridell et al 2005). Furthermore, a very recent study has demonstrated that the absence of UCP2 shortens life span in wildtype mice, and the level of UCP2 positively correlates with the postnatal survival of superoxide dismutase 2 mutant animals (Andrews and Horvath 2009).…”

Section: Introductionmentioning

confidence: 99%

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A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Barbieri

Boccardi

Esposito

et al. 2011

AGE

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A large array of gene involved in human longevity seems to be in relationship with insulin/ IGF1 pathway. However, if such genes interact each other, or with other genes, to reduce the age-related metabolic derangement and determine the long-lived phenotype has been poorly investigated. Thus, we tested the role of interchromosomal interactions among IGF1R, IRS2, and UCP2 genes on the probability to reach extreme old age in 722 unrelated Italian subjects (401 women and 321 men; mean age, 62.83±25.30 years) enrolled between 1998 and 1999. In particular, the G/A-IGF1R, Gly/Asp-IRS2, and Ala/ Val-UCP2 allele combination was tested for association with longevity, metabolic profile and energy expenditure parameters. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years. The analysis revealed that AAV allele combination is associated with a decreased all-cause mortality risk (HR, 0.72; 95% CI, 0.63-0.91; p=0.03) and with a higher probability to reach the extreme of old age (OR, 3.185; 95% CI, 1.63-6.19; p=0.0006). The analysis also revealed lower HOMA-IR (Diff, −0.532, 95% CI, 0.886-0.17; p= 0.003), higher respiratory quotient (Diff, 0.0363, 95% CI, 0.014-0.05; p=0.001), and resting metabolic rate (Diff, 101.80693, 95% CI, p=0.038) for AAV allele combination. In conclusion, A-IGF1R/ Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Barbieri

Boccardi

Esposito

et al. 2011

AGE

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“…Effect of UCP2 on Erythroid Cell ROS-UCP2 expression in cardiomyocytes and neurons has been shown to alter the levels of ROS (12,13). We tested the levels of protein oxidation in isolated mitochondria and in whole cells from untreated bone marrow samples of UCP2 KO and WT (Fig.…”

Section: Ucp2 Function In Erythropoiesismentioning

confidence: 99%

UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Elorza

Hyde

Mikkola

et al. 2008

Journal of Biological Chemistry

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UCP2, an inner membrane mitochondrial protein, has been implicated in bioenergetics and reactive oxygen species (ROS) modulation. High levels of UCP2 mRNA were recently found in erythroid cells where UCP2 is hypothesized to function as a facilitator of heme synthesis and iron metabolism by reducing ROS production. We examined UCP2 protein expression and role in mice erythropoiesis in vivo. UCP2 was mainly expressed at early stages of erythroid maturation when cells are not fully committed in heme synthesis. Iron incorporation into heme was unaltered in reticulocytes from UCP2-deficient mice. Although heme synthesis was not influenced by UCP2 deficiency, mice lacking UCP2 had a delayed recovery from chemically induced hemolytic anemia. Analysis of progenitor cells from bone marrow and fetal liver both in vitro and in vivo revealed that UCP2 deficiency results in a significant decrease in cell proliferation at the erythropoietin-dependent phase of erythropoiesis. This was accompanied by reduction in the phosphorylated form of ERK, a ROS-dependent cytosolic regulator of cell proliferation. Analysis of ROS in UCP2 null erythroid cells revealed altered distribution of ROS, resulting in decreased cytosolic and increased mitochondrial ROS. Restoration of the cytosol oxidative state of erythroid progenitor cells by the pro-oxidant Paraquat reversed the effect of UCP2 deficiency on cell proliferation in in vitro differentiation assays. Together, these results indicate that UCP2 is a regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.

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“…The generation of ROS has been clearly established as a contributor to several neurodegenerative diseases and may underlie cellular changes seen in aging. Interestingly, targeted expression of UCP2 to the mitochondria of adult neurons can extend the life span in the fly by decreasing mitochondrial ROS production and attenuation of oxidative damage (51). We found that cells expressing hUCP4 exhibited reduced mitochondrial Ca 2ϩ uptake and ROS formation compared with control cells after store depletion with TG.…”

Section: Discussionmentioning

confidence: 59%

Mitochondrial Uncoupling Protein-4 Regulates Calcium Homeostasis and Sensitivity to Store Depletion-induced Apoptosis in Neural Cells

Chan

Liu

Kyriazis

et al. 2006

Journal of Biological Chemistry

101

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An increase in the cytoplasmic-free Ca2؉ concentration mediates cellular responses to environmental signals that influence a range of processes, including gene expression, motility, secretion of hormones and neurotransmitters, changes in energy metabolism, and apoptosis. Mitochondria play important roles in cellular Ca 2؉ homeostasis and signaling, but the roles of specific mitochondrial proteins in these processes are unknown. Uncoupling proteins (UCPs) are a family of proteins located in the inner mitochondrial membrane that can dissociate oxidative phosphorylation from respiration, thereby promoting heat production and decreasing oxyradical production. Here we show that UCP4, a neuronal UCP, influences store-operated Ca

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Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly

Cited by 164 publications

References 57 publications

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Mitochondrial Uncoupling Protein-4 Regulates Calcium Homeostasis and Sensitivity to Store Depletion-induced Apoptosis in Neural Cells

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