Mitochondrial thioredoxin system is required for enhanced stress resistance and extended longevity in long-lived mitochondrial mutants

Harris-Gauthier, Namasthée; Traa, Annika; AlOkda, Abdelrahman; Moldakozhayev, Alibek; Anglas, Ulrich; Soo, Sonja K.; Raamsdonk, Jeremy M. Van

doi:10.1016/j.redox.2022.102335

Cited by 16 publications

(19 citation statements)

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“…While disruption of tbc-2 decreases resistance to oxidative stress, heat stress, bacterial pathogen stress, osmotic stress and anoxia in daf-2 mutants, resistance to heat stress, bacterial pathogen stress and anoxic stress is not decreased in either of the long-lived mitochondrial mutants when tbc-2 is deleted. As our previous work suggests that the effect of tbc-2 deletion on resistance to stress is primarily mediated by DAF-16 (Traa et al, 2022), it is plausible that stress resistance is more affected in daf-2 mutants than nuo-6 or isp-1 mutants because the enhanced stress resistance of daf-2 worms is entirely dependent on DAF-16 (Dues et al, 2019), while the long-lived mitochondrial mutants also rely on other pathways such as the mitochondrial unfolded protein response (Wu et al, 2018), the p38-mediated innate immune signaling pathway (Campos et al, 2021) and the mitochondrial thioredoxin system (Harris-Gauthier et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Among the most well studied mitochondrial mutants in Caenorhabditis elegans are nuo-6 and isp-1 .The nuo-6 gene encodes a subunit of Complex I of the mitochondrial electron transport chain (Yang and Hekimi, 2010), while the isp-1 gene encodes a subunit of the Rieske iron sulfur protein in Complex III of the electron transport chain (Feng et al, 2001). Although a number of studies have identified factors that are important for the long lifespan of these mitochondrial mutants (Baruah et al, 2014; Campos et al, 2021; Harris-Gauthier et al, 2022; Hwang et al, 2014; Jung et al, 2021; Lee et al, 2010; Munkacsy et al, 2016; Senchuk et al, 2018; Walter et al, 2011; Wu et al, 2018; Yee et al, 2014), the mechanism by which mild mitochondrial impairment extends longevity remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Traa¹,

Shields²,

AlOkda³

et al. 2023

Preprint

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Mutations that result in a mild impairment of mitochondrial function can extend longevity. Previous studies have shown that the increase in lifespan is dependent on stress responsive transcription factors, including DAF-16/FOXO, which exhibits increased nuclear localization in long-lived mitochondrial mutants. We recently found that the localization of DAF-16 within the cell is dependent on the endosomal trafficking protein TBC-2. Based on the important role of DAF-16 in both longevity and resistance to stress, we examined the effect of disrupting tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants nuo-6 and isp-1 in C. elegans. Loss of tbc-2 markedly reduced the long lifespans of both mitochondrial mutants. Disruption of tbc-2 also decreased resistance to specific exogenous stressors in nuo-6 and isp-1 mutants. In contrast, tbc-2 inhibition had no effect on oxidative stress resistance or lifespan in isp-1 worms when DAF-16 is absent suggesting that the effect of tbc-2 on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion of daf-16 markedly decreases both phenotypes in isp-1 worms. Surprisingly, disruption of tbc-2 did not prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants, suggesting the possibility that the effect of tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants is at least partially independent of its effects on DAF-16 localization. Overall, this work demonstrates the importance of endosomal trafficking for the extended longevity and enhanced stress resistance resulting from mild impairment of mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Traa¹,

Shields²,

AlOkda³

et al. 2023

Preprint

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“…In fact, protein oxidation was increased in this model leading the authors to speculate that overexpression of superoxide dismutase resulted in changes in longevity-promoting transcriptional activity, rather than an antioxidant effect per se [76,77]. Increased SOD gene activity has also been reported to be necessary for longevity-assurance in a long-lived mutant strain of C. elegans [78]. Interestingly, SOD mutants with reduced enzyme activity display a marked increase in oxidative damage but have a normal longevity [79] that is partially dependent on the cellular location that a specific isoform is normally expressed, for example in the mitochondria versus the cytosol [79][80][81].…”

Section: Impact Of Enzymatic and Non-enzymatic Antioxidants On Invert...mentioning

confidence: 90%

“…Other enzymatic antioxidants that extend longevity in invertebrates when overexpressed include thioredoxin in both D. melanogaster and C. elegans [78,88,89]. In budding yeast, increased peroxiredoxin activity increases replicative lifespan via scavenging peroxide and due to its chaperone activity [90].…”

Section: Impact Of Enzymatic and Non-enzymatic Antioxidants On Invert...mentioning

confidence: 99%

Do Antioxidants Extend Longevity in Invertebrate and Vertebrate Animals?

Badwan¹,

Harper²

2023

OBM Geriatr

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In the 1950’s Denham Harman proposed the Free Radical Theory of Aging whereby species lifespan and individual longevities are the consequence of free radical driven damage to biomolecules. This led to decades of research to ascertain the effect of altered antioxidant defense systems on aging and mortality in an array of species using reverse genetics and dietary manipulation. Within invertebrates, the data generally support the Free Radical Theory in that overexpression of antioxidant enzymes or dietary supplementation with antioxidant compounds increases longevity and resistance to oxidative damage. Likewise, genetic knockdown of antioxidant defenses generally shortens longevity within invertebrates. On the other hand, for endothermic vertebrates (i.e., birds and mammals) the results have been equivocal. Downregulation of antioxidant enzymes typically results in an increased oxidative burden, but without an appreciable effect on longevity, while dietary supplementation with antioxidants has little-to-no effect, at least at the concentrations used. Upregulation of antioxidant enzyme genes also fails to increase longevity in vertebrates most of the time. Interestingly, manipulating antioxidant defenses in fishes increases longevity in conjunction with reduced oxidative damage akin to what is seen in invertebrates. Since invertebrates and fishes are both exothermic this raises the possibility that the evolution of endothermy interferes with the ability of antioxidants to slow the aging process.

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“…TRX-1 and TRXR-1 make up the cytoplasmic thioredoxin system, while TRX-2 and TRXR-2 form the mitochondrial thioredoxin system ( Table S1 ). In C. elegans, disruption of the cytoplasmic thioredoxin gene trx-1 results in a clear decrease in lifespan in wild-type worms and multiple long-lived mutant strains [ 74 , 75 , 76 , 77 ] ( Table 1 ). Deletion of trx-1 also results in decreased resistance to exogenous stressors and elevated levels of reactive oxygen species [ 74 , 75 ].…”

Section: Cytoplasmic Thioredoxin Is Important For Longevity In ...mentioning

confidence: 99%

Evolutionarily Conserved Role of Thioredoxin Systems in Determining Longevity

AlOkda

Raamsdonk

2023

Antioxidants

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Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. A number of studies have examined the role of thioredoxin and thioredoxin reductase in determining longevity. Disruption of either thioredoxin or thioredoxin reductase is sufficient to shorten lifespan in model organisms including yeast, worms, flies and mice, thereby indicating conservation across species. Similarly, increasing the expression of thioredoxin or thioredoxin reductase can extend longevity in multiple model organisms. In humans, there is an association between a specific genetic variant of thioredoxin reductase and lifespan. Overall, the cytoplasmic and mitochondrial thioredoxin systems are both important for longevity.

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Mitochondrial thioredoxin system is required for enhanced stress resistance and extended longevity in long-lived mitochondrial mutants

Cited by 16 publications

References 68 publications

Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Do Antioxidants Extend Longevity in Invertebrate and Vertebrate Animals?

Evolutionarily Conserved Role of Thioredoxin Systems in Determining Longevity

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