Thioredoxin 2 haploinsufficiency in mice results in impaired mitochondrial function and increased oxidative stress

Pérez, Viviana; Lew, Christie M.; Cortez, Lisa A.; Webb, Celeste R.; Rodriguez, Marisela; Liu, Yuhong; Qi, Wenbo; Li, Yan; Chaudhuri, Asish; Remmen, Holly Van; Richardson, Arlan; Ikeno, Yuji

doi:10.1016/j.freeradbiomed.2007.11.018

Cited by 102 publications

(97 citation statements)

References 37 publications

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“…Indeed, instead of being short-lived as would have been predicted by the theory, the lifespan of these mutants for a crucial mitochondrial antioxidant is perfectly normal, in spite of increase oxidative stress [40,41]. Recently, heterozygous mice for thioredoxin 2, a small cysteine-rich protein with antioxidant properties localized to the mitochondrial matrix, have been generated and are characterized by impaired mitochondrial function and high mitochondrial oxidative stress [42]. The lifespan phenotype of these mitochondrial mutants, which a preliminary report describes as surprisingly unaffected [43], will be another new test for the theory.…”

Section: Unexpected Results That Have Shaken Up the Mfrtamentioning

confidence: 98%

When a theory of aging ages badly

Lapointe

Hekimi

2009

Cell. Mol. Life Sci.

227

151

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According to the widely acknowledged mitochondrial free radical theory of aging (MFRTA), the macromolecular damage that results from the production of toxic reactive oxygen species (ROS) during cellular respiration is THE cause of aging. However, although it is clear that oxidative damage increases during aging, the fundamental question regarding whether mitochondrial oxidative stress is in any way causal to the aging process remains unresolved. An increasing number of studies on long-lived vertebrate species, mutants and transgenic animals have seriously challenged the pervasive MFRTA. Here, we describe some of these new results, including those pertaining to the phenotype of the long-lived Mclk1 +/− mice, which appear irreconcilable with the MFRTA. Thus, we believe that it is reasonable to now consider the MFRTA as refuted and that it is time to use the insight gained by many years of testing this theory to develop new views as to the physiological causes of aging.

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Section: Unexpected Results That Have Shaken Up the Mfrtamentioning

confidence: 98%

When a theory of aging ages badly

Lapointe

Hekimi

2009

Cell. Mol. Life Sci.

227

151

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“…The thiol group in cysteine is sensitive to oxidation and exhibits various oxidation states, including reversible and irreversible states. We have developed 3 distinct fluorescence-based assays to quantify the various states of cysteine oxidation; 2 measure reversible states (disulfide and sulfenic acid) (31) and the third measures total cysteine and indirectly indicates the levels of irreversible oxidation [sulfinic/sulfonic/others (23,32)] that we have used in liver tissues of young and old MRs and mice. The disulfide content detected in young MRs tends (P Ͼ 0.07) to be higher than that found in young mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cysteine oxidation was measured by detection of disulfides (31,41). Briefly, liver tissues were homogenized in 50 mM potassium phosphate buffer (pH 8.0) containing 0.5 mM MgCl2, 1 mM EDTA, 150 mM iodoacetamide, and protease inhibitor mixture [500 M 4-(2-aminoethyl)benzenesulfonyl fluoride, 150 nM aprotinin, 0.5 mM EDTA, and 1 M leupeptin hemisulfate] and centrifuged for 30 min at 16,000 ϫ g at 4°C.…”

mentioning

confidence: 99%

Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat

Pérez¹,

Buffenstein

Masamsetti³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

373

349

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The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. Surprisingly, data from the longest-living rodent known, naked molerats [MRs; mass 35 g; maximum lifespan (MLSP) > 28.3 years], when compared with mice (MLSP 3.5 years) exhibit higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage even at a young age. We hypothesize that age-related changes in protein structural stability, oxidation, and degradation are abrogated over the lifespan of the MR. We performed a comprehensive study of oxidation states of protein cysteines [both reversible (sulfenic, disulfide) and indirectly irreversible (sulfinic/sulfonic acids)] in liver from young and old C57BL/6 mice (6 and 28 months) and MRs (2 and >24 years). Furthermore, we compared interspecific differences in urea-induced protein unfolding and ubiquitination and proteasomal activity. Compared with data from young mice, young MRs have 1.6 times as much free protein thiol groups and similar amounts of reversible oxidative damage to cysteine. In addition, they show less urea-induced protein unfolding, less protein ubiquitination, and higher proteasome activity. Mice show a significant age-related increase in cysteine oxidation and higher levels of ubiquitination. In contrast, none of these parameters were significantly altered over 2 decades in MRs. Clearly MRs have markedly attenuated age-related accrual of oxidation damage to thiol groups and age-associated up-regulation of homeostatic proteolytic activity. These pivotal mechanistic interspecies differences may contribute to the divergent aging profiles and strongly implicate maintenance of protein stability and integrity in successful aging.cysteine oxidation ͉ Heterocephalus glaber ͉ mechanisms of aging ͉ proteasome activity ͉ protein homeostasis

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“…Expression of catalase in mitochondria increased longevity in transgenic mice (154). Decreased Trx-2 in hemizygous Trx-2 ϩ/Ϫ mice had increased sensitivity to oxidants (141), and Trx-1 transgenic mice were protected against cardiotoxicity from doxorubicin (159). Gpx1 knockout mice demonstrated increased susceptibility to H 2 O 2 (36).…”

Section: Oxidative Stress As a Disruption Of Redox Signaling And Controlmentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

1,034

839

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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Thioredoxin 2 haploinsufficiency in mice results in impaired mitochondrial function and increased oxidative stress

Cited by 102 publications

References 37 publications

When a theory of aging ages badly

When a theory of aging ages badly

Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat

Radical-free biology of oxidative stress

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