Biology subjects

Van Raamsdonk, J.

Publications and source records attributed to Van Raamsdonk, J..

13 recordsLinked to original sources

bioRxiv2026

Mild Mitochondrial Impairment Activates Overlapping Longevity Pathways Converging on the Flavin-Containing Monooxygenase FMO-2

A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of fmo-2 in the long lifespan of genetic mitochondrial mutants in C. elegans. We found that fmo-2, but not other fmo genes, are specifically upregulated in the long-lived mitochondrial mutants clk-1, isp-1 and nuo-6. Disruption of fmo-2 through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that fmo-2 is required for lifespan extension in these worms. Moreover, signaling molecules that have been shown to be involved in upregulation of fmo-2 are also required for the long life of clk-1, isp-1 and nuo-6 mutants including HLH-30, NHR-49 and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in clk-1 mutants on the expression of fmo-2. We found that in all cases, genes required for clk-1 longevity are also required for the upregulation of fmo-2 in clk-1 worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.

genetics↗

bioRxiv2025

Cyrene: A Novel Geroprotective Compound that Extends Lifespan and Healthspan in C. elegans and Drosophila

As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and healthspan in C. elegans, improving locomotor function and resistance to oxidative, thermal, osmotic, genotoxic, and proteotoxic stress. It also confers protection in neurodegenerative models of Alzheimers, Parkinsons, and Huntingtons disease. Cyrene is effective when delivered during development or early adulthood and requires administration before day 8 to extend longevity. Its benefits are independent of bacterial metabolism and partially independent of the FOXO transcription factor DAF-16. Importantly, Cyrene also extends lifespan and enhances oxidative stress resistance in Drosophila melanogaster, demonstrating cross-species efficacy. These findings identify Cyrene as a novel geroprotective compound that promotes longevity, resilience, and neuroprotection. Conservation across species supports future work to dissect molecular mechanisms and test its potential in mammals.

developmental biology↗

bioRxiv2025

Elevated mitochondrial superoxide promotes longevity through a mitochondria-to-nucleus kinase signaling pathway

The reactive oxygen species superoxide is generated by mitochondria during the process of producing energy. While superoxide can cause oxidative damage to the cell, we and others have shown that a mild increase in mitochondrial superoxide extends longevity in multiple model organisms. To elucidate the molecular mechanisms involved, we identified transcriptional changes in mitochondrial superoxide dismutase deletion mutants (sod-2 worms) using RNA sequencing. sod-2 mutants exhibit a number of changes in nuclear gene expression resulting from elevated mitochondrial superoxide suggesting that mitochondria-to-nucleus signaling is contributing to their longevity. Gene ontology enrichment analysis demonstrated that genes involved in innate immunity and cuticle formation are significantly upregulated in sod-2 worms. To identify kinases involved in this lifespan-extending pathway, we completed a targeted RNA interference screen to examine the contribution of 61 selected kinases to sod-2 longevity. From this screen, we found 25 kinases which are required for the long lifespan of sod-2 mutants including mak-2, which has an established role in a kinase signaling pathway involved in axon regeneration. Disruption of mak-2 specifically reduces sod-2 lifespan but not wild-type longevity and also decreases resistance to multiple exogenous stressors. In examining other genes that act with mak-2 in pathways controlling axon regeneration, we identified a SEK-3/PMK-3/MAK-2/CEBP-1 signaling pathway that is specifically required for sod-2 longevity but not wild-type lifespan. Combined these results suggest a novel role for kinases with established roles in axon regeneration in promoting longevity through a mitochondria-to-nucleus signaling pathway.

genetics↗

bioRxiv2024

Developmental disruption of the mitochondrial fissiongene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant

The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cells ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans. While disruption of the mitochondrial fission gene drp-1 only mildly increases wild-type lifespan, it drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with a number of different RNAi clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses and slows physiologic rates in daf-2 worms. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels or mitochondrial membrane potential. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.

genetics↗

bioRxiv2023

Overexpression of mitochondrial fusion genes enhances resilience and extends longevity

The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which appears to be at least partially due to the upregulation of multiple stress response pathways in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.

developmental biology↗

bioRxiv2023

Endosomal trafficking protein TBC-2 isrequired for the longevity of long-livedmitochondrial mutants

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.

genetics↗

bioRxiv2022

Huntingtin expression influences spontaneous seizure disorder susceptibility in FVN/B mice

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in FVB/N mice. These abnormal FVB/N mice demonstrate various cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, decreasing wild-type Htt levels increased the frequency of this disorder, while over-expression of HTT completely prevented it. Examination of the mechanism underlying huntingtins ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by altering huntingtin levels has ramifications related to Huntingtin-lowering therapies in development to treat HD.

neuroscience↗

bioRxiv2022

The glyoxylate shunt protein ICL-1 protects from mitochondrial superoxide stress through activation of the mitochondrial unfolded protein response.

Eliminating mitochondrial superoxide dismutase (SOD) causes neonatal lethality in mice and death of flies within 24 hours after eclosion. Deletion of mitochondrial sod genes in C. elegans impairs fertility as well, but surprisingly is not detrimental to survival of progeny generated. The comparison of metabolic pathways among mouse, flies and nematodes reveals that mice and flies lack the glyoxylate shunt. Here we show that ICL-1, the only protein of the glyoxylate shunt, is critical for protection against embryonic lethality resulting from elevated levels of mitochondrial superoxide. In exploring the mechanism by which ICL-1 protects against ROS-mediated embryonic lethality, we find that ICL-1 is required for the efficient activation of mitochondrial unfolded protein response (UPRmt) and that the UPRmt is essential to suppress embryonic/neonatal lethality in animals lacking mitochondrial SOD. In sum, we identified a biochemical pathway that highlights a molecular strategy for combating superoxide consequences in cells.

biochemistry↗

bioRxiv2022

Huntingtin Over-Expression Does Not Alter Overall Survival in Murine Cancer Models

A reduced incidence of various forms of cancer has been reported in Huntingtons disease (HD) patients and may be due to pro-apoptotic effects of mutant huntingtin. We tested this hypothesis by assessing the effects of huntingtin protein over-expression on survival in two murine cancer models. We generated yeast artificial chromosome (YAC) HD mice containing human huntingtin transgenes with various CAG tract lengths (YAC18, YAC72, YAC128) on either an Msh2 or p53 null background, which have increased cancer incidence. In both mouse models of cancer, the over-expression of either mutant or wild-type huntingtin had no significant effect on overall survival. These results do not support the hypothesis that mutant huntingtin expression is protective against cancer.

cancer biology↗

bioRxiv2021

Identification of novel therapeutic targets for polyglutamine toxicity disorders that target mitochondrial fragmentation

Huntingtons disease (HD) is one of at least nine polyglutamine toxicity disorders caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine toxicity disorders. While multiple studies have found beneficial effects from decreasing mitochondrial fragmentation in HD models by disrupting the mitochondrial fission protein DRP1, disrupting DRP1 can also have detrimental consequences in wild-type animals and HD models. In this work, we examine the effect of decreasing mitochondrial fragmentation in a neuronal C. elegans model of polyglutamine toxicity called Neur-67Q. We find that Neur-67Q worms have deficits in mitochondrial morphology in GABAergic neurons and decreased mitochondrial function. Disruption of drp-1 eliminates differences in mitochondrial morphology and rescues deficits in both movement and longevity in Neur-67Q worms. In testing twenty-four RNA interference (RNAi) clones that decrease mitochondrial fragmentation, we identified eleven clones that increase movement and extend lifespan in Neur-67Q worms. Overall, we show that decreasing mitochondrial fragmentation may be an effective approach to treat polyglutamine toxicity disorders and identify multiple novel genetic targets that circumvent the potential negative side effects of disrupting the primary mitochondrial fission gene drp-1. Significance StatementPolyglutamine toxicity disorders are caused by a trinucleotide CAG repeat expansion that leads to neurodegeneration. Both mitochondrial dynamics and function are disrupted in these disorders. In this work we use a simple genetic model organism, the worm C. elegans, to define the role of mitochondrial morphology in polyglutamine toxicity disorders. We show that CAG repeat expansion is sufficient to disrupt mitochondrial morphology and that genetic strategies that decrease mitochondrial fragmentation are beneficial in a neuronal model of polyglutamine toxicity. This work identifies multiple novel genes that are protective in worm models of polyglutamine toxicity, which may serve as potential therapeutic targets for Huntingtons disease and other polyglutamine toxicity disorders.

neuroscience↗

bioRxiv2021

Genetic basis of enhanced stress resistance in long-lived mutants highlights key role of innate immunity in determining longevity

Mutations that extend lifespan are associated with enhanced resistance to stress. To better understand the molecular mechanisms underlying this relationship, we studied nine long-lived C. elegans mutants representative of different pathways of lifespan extension. We directly compared the magnitude of their lifespan extension and their ability to resist various external stressors (heat, oxidative stress, bacterial pathogens, osmotic stress, and anoxia). Furthermore, we analysed gene expression in each of these mutants to identify genes and pathways responsible for the enhanced resistance to stress. All of the examined long-lived mutants have increased resistance to one or more type of stress. Resistance to each of the examined types of stress had a significant, positive correlation with lifespan, with bacterial pathogen resistance showing the strongest relationship. All of the examined long-lived mutants have significant upregulation of multiple stress response pathways but differ in which stress response pathway has the greatest enrichment of genes. We used RNA sequencing data to identify which genes are most highly correlated with each type of stress resistance. There was a highly significant overlap between genes highly correlated with stress resistance, and genes highly correlated with longevity, suggesting that the same genetic pathways drive both phenotypes. This was especially true for genes correlated with bacterial pathogen resistance, which showed an 84% overlap with genes correlated with lifespan. Overall, our results demonstrate a strong correlation between stress resistance and longevity that results from the high degree of overlap in genes contributing to each phenotype. SIGNIFICANCE STATEMENTWhile increased resistance to stress has been correlated with longevity, the genetic basis for this relationship is incompletely understood. To advance our understanding of the relationship between stress resistance and lifespan, we measured lifespan, stress resistance and gene expression in a panel of nine long-lived mutants in C. elegans. All of the long-lived mutants exhibit enhanced resistance to at least one external stressor resulting from significant upregulation of multiple stress response pathways. Importantly, our data indicates that the same genetic pathways control stress resistance and lifespan, thereby accounting for the strong correlation between these two phenotypes. This work demonstrates the importance of innate immune signaling and other stress response pathways in determining longevity.

genetics↗

bioRxiv2021

Mitochondrial unfolded protein response transcription factor ATFS-1 increases resistance to exogenous stressors through upregulation of multiple stress response pathways

The mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to various insults to the mitochondria through transcriptional changes that restore mitochondrial homeostasis in order to facilitate cell survival. Gene expression changes resulting from the activation of the mitoUPR are mediated by the transcription factor ATFS-1/ATF-5. To further define the mechanisms through which the mitoUPR protects the cell during mitochondrial dysfunction, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause upregulation of genes involved in multiple stress response pathways, including the DAF-16-mediated stress response pathway, the SKN-1-mediated oxidative stress response pathway, the HIF-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Moreover, ATFS-1 is required for the upregulation of stress response genes after exposure to exogenous stressors, especially oxidative stress and bacterial pathogens. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, while disruption of atfs-1 decreases stress resistance. Although ATFS-1-dependent genes are upregulated in multiple long-lived mutants, constitutive activation of ATFS-1 in wild-type animals results in decreased lifespan. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stresses through its ability to activate multiple stress response pathways, but that chronic ATFS-1 activation is detrimental for longevity.

genetics↗

bioRxiv2021

Mild impairment of mitochondrial function increases longevity and pathogen resistance through ATFS-1-driven activation of p38-regulated innate immunity

While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain resulted in upregulation of genes involved in innate immunity, which we found to be dependent on not only the canonical p38-mediated innate immune signaling pathway but also on the mitochondrial unfolded protein response. Both of these pathways are absolutely required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitochondrial unfolded protein response can act on the same innate immunity genes to promote resistance to bacterial pathogens, and that input from the mitochondria can extend longevity by signaling through these two pathways. Combined, this indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan. Significance StatementIn this work, we explore the relationship between mitochondrial function, aging and innate immunity. We find that mild impairment of mitochondrial function results in upregulation of genes involved in innate immunity, increased resistance to bacterial pathogens and lifespan extension, all of which are dependent on two evolutionarily conserved signaling pathways. This work demonstrates how changes in functional status of the mitochondria can trigger activation of innate immunity, and that the underlying mechanisms are important for the longevity of the organism. This work advances our understanding of connections between metabolism and immunity. As the pathways studied here are conserved up to mammals, these insights may help us to understand the role of mitochondrial health, innate immunity and lifespan in humans.

cell biology↗