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The Cell Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity
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The life span of C. elegans can be increased via reduced function of the mitochondria; however, the extent to which mitochondrial alteration in a single, distinct tissue may influence aging in the whole organism remains unknown. We addressed this question by asking whether manipulations to ETC function can modulate aging in a cell-non-autonomous fashion. We report that the alteration of mitochondrial function in key tissues is essential for establishing and maintaining a prolongevity cue. We find that regulators of mitochondrial stress responses are essential and specific genetic requirements for the electron transport chain (ETC) longevity pathway. Strikingly, we find that mitochondrial perturbation in one tissue is perceived and acted upon by the mitochondrial stress response pathway in a distal tissue. These results suggest that mitochondria may establish and perpetuate the rate of aging for the whole organism independent of cell-autonomous functions.
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“Such hormetic reactions may consist in the induction of a mitochondrial stress response either in the same tissue in which mitochondria are defective, or even in distant tissues, as shown in C. elegans”
From The Hallmarks of Aging (2013) · cites this paper as Durieux et al., 2011
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“Conversely, lifespan-extending manipulations targeting one single tissue can retard the aging process in other tissues (Durieux et al., 2011; Lavasani et al., 2012; Tomas-Loba et al., 2008).”
From The Hallmarks of Aging (2013) · cites this paper as Durieux et al., 2011
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“Interestingly, mild mitochondrial stress might elicit beneficial effects on health and lifespan through the activation of mitochondrial hormesis [28,36].”
From Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles (2019) · cites this paper as [36]
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“elegans nervous system that are activated in response to 638 metabolic, environmental, and intrinsic cues; thereby initiating distinct cell non639 autonomous signals to regulate components of the PN in peripheral tissues (Douglas et 640 al., 2015; Durieux et al., 2011; Frakes et al., 2020; Imanikia et al., 2019; Prahl…”
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“In C. elegans , mitochondrial stress in neurons not only activates mitoUPR within the neurons, but also in distal intestinal cells (136 – 139) by the secretion of serotonin and metabolic signaling molecules from stressed neuronal mitochondria (137, 140, 141).”
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“Comparable patterns are observed for other genes like NDUFB6 (complex I) and the ATP synthase component ATP50 [15].”
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“In this regard, the enhanced responsiveness to stressful states presumably elicits global protective mechanisms that have beneficial effects on animal survival (Durieux et al , 2011).”
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“However, it is possible that low or local levels of ROS may act as signaling molecules and potentially serve as the mitokine or intermediary signal to elicit a nuclear response (12).”
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“Activation of UPR mt can be advantageous as it allows for fine-tuning cellular metabolism and providing protection against pathogens [23–26].”
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“The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that promotes cell survival and restores mitochondrial function when mitochondrial health is compromised (Haynes et al. 2013; Jovaisaite et al. 2014; Shpilka and Haynes 2018).”
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BackgroundExploiting inter-tissue stress signaling mechanisms to preserve organismal proteostasis during aging
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“As with the UPR and the HSR, the UPR can also function at a cell nonautonomous level in metazoans (Durieux et al., 2011).”
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“Studies on worms have shown that after cco-1 loss of function, activation of UPR mt promotes increased worm lifespan [108, 109].”
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“In addition, adaptive responses to other forms of mitochondrial dysfunction that regulate longevity [52], particularly the mitochondrial unfolded protein response [53], which can even act cell-nonautonomously [54], are firmly established.”
BackgroundGenomic approaches for the understanding of aging in model organisms
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Maintenance of protein homeostasis in glia extends lifespan in C. elegans
Wang, L., & Bianchi, L. K. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113648 · Cited by 8
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Mass Spectrometry-Based Multi-omics Integration with a Single Set of C. elegans Samples
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Identifying longevity associated genes by integrating gene expression and curated annotations
Townes, F. W., Carr, K., & Miller, J. W. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008429 · Cited by 11
Decreased Mitochondrial Membrane Potential Activates the Mitochondrial Unfolded Protein Response
Berry, B. J., Nieves, T., & Wojtovich, A. P. (2021) · Europe PMC (PubMed Central) · doi:10.17912/micropub.biology.000445 · Cited by 9
“Further, the UPRmt has been implicated in many disease models that are not fully characterized (Jovaisaite et al. 2014).”
BackgroundA tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response
Held, J. P., Feng, G., Saunders, B. R., Pereira, C. V., Burkewitz, K., & Patel, M. R. (2022) · eLife · doi:10.7554/elife.71634 · Cited by 8
“Importantly, UPR can be activated non-cell 386 autonomously in the intestine by mitochondrial stress in neurons (Durieux et al., 2011; Berendzen et al., 387 2016; Zhang et al., 2018).”
BackgroundInfluentialLi, C., Li, N., Zhang, Z., Song, Y., Li, J., Wang, Z., Hai, B., & Zhang, Y. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1127524 · Cited by 10
Detection of Mitochondrial Toxicity of Environmental Pollutants UsingCaenorhabditis elegans
Maurer, L. L., Luz, A. L., & Meyer, J. N. (2018) · Wiley eBooks · doi:10.1002/9781119329725.ch43 · Cited by 9
Decoding Organelle Interactions: Unveiling Molecular Mechanisms and Disease Therapies
Liu, R., Hong, W., Hou, D., Huang, H., & Duan, C. (2024) · Advanced Biology · doi:10.1002/adbi.202300288 · Cited by 8
The Effects of Caloric Restriction on Inflammatory Targets in the Prostates of Aged Rats
Rago, V., Conforti, F., Russa, D. L., Antonucci, G., Urlandini, L., Lofaro, D., Bossio, S., Mandalà, M., Pellegrino, D., Aversa, A., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105236 · Cited by 9
“Furthermore, aging is accompanied by progressive mitochondrial dysfunction which, in addition to promoting intracellular damage and an increase in ROS, causes the systemic spreading of mediators, termed mitokines, which strongly affects homeostasis [5].”
BackgroundThe mitochondrial unfolded protein response: acting near and far
Charmpilas, N., Li, Q., & Hoppe, T. (2025) · Biological Chemistry · doi:10.1515/hsz-2025-0107 · Cited by 8
“…publication showed that knockdown of ETC components speci fi cally in C. elegans neurons could induce the expression of nuclear-encoded chaperones in the intestine (i.e. gut), representing a bona fi de paradigm of cell-nonautonomous signaling and inter-tissue communication (Durieux et al. 2011).”
Single-Atom Modulated Biocatalytic Selectivity on WSe2 Clusters
Zhao, R., Li, L., Yan, Y., Xue, X., Huo, Y., Liu, T., Wang, H., Liu, C., Zhang, S., Sun, S., et al. (2025) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.5c07454 · Cited by 8
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“UPRmt is a momentous mitochondrial-tonuclear stress-signaling pathway that could rewire the metabolic state and improve immune strength [11-16].”
BackgroundInfluentialNon-cell Autonomous Maintenance of Proteostasis by Molecular Chaperones and Its Molecular Mechanism
Takeuchi, T. (2018) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b18-00141 · Cited by 8
Wnt signalling and endocytosis: Mechanisms, controversies and implications for stress responses
Wu, Y., Chiang, Y., Chou, S., & Pan, C. (2020) · Biology of the Cell · doi:10.1111/boc.202000099 · Cited by 9
The Many Roles Mitochondria Play in Mammalian Aging
Batalha, C. M. P. F., Vercesi, A. E., & de Souza-Pinto, N. C. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0074 · Cited by 8
“When mitochondrial import is defective, or when mitochondrial chaperones and proteases are inhibited, ATFS-1 cannot be imported into mitochondria and, instead, accumulates in the nucleus, where it induces expression of stress response genes (3, 44).”
Franceschi, C., Capri, M., Garagnani, P., Ostan, R., Santoro, A., Monti, D., & Salvioli, S. (2017) · Springer eBooks · doi:10.1007/978-3-319-64597-1_45-1 · Cited by 9
Toward Elucidating Epigenetic and Metabolic Regulation of Stem Cell Lineage Plasticity in Skin Aging
Lyu, Y., & Ge, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.903904 · Cited by 9
“In an interesting twist, it has been shown that mild mitochondrial stress prolongs lifespan in worms (Durieux et al., 2011) and yeast (Pan et al.”
BackgroundULP-2 SUMO protease regulates UPRmt and mitochondrial homeostasis in Caenorhabditis elegans
Michaeli, L., Spector, E., Haeussler, S., Carvalho, C. A., Grobe, H., Abu‐Shach, U. B., Zinger, H., Conradt, B., & Broday, L. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.01.050 · Cited by 9
“We measured hsp-6p:: gfp (bcSi9) fluorescence in WT and in the ulp-2(tv380) mutants following control or cco-1(RNAi) induced stress conditions. cco-1 encodes a predicted subunit of the mitochondrial electron transport chain (ETC), and its knockdown using RNAi induces UPRmt [34].”
Longevity control by the nervous system: Sensory perception, stress response and beyond
Lin, C.-T., He, C.-W., Huang, T., & Pan, C. (2017) · Translational Medicine of Aging · doi:10.1016/j.tma.2017.07.001 · Cited by 9
Phenotypic Aspects of Longevity
Accardi, G., Ligotti, M. E., & Candore, G. (2019) · Springer eBooks · doi:10.1007/978-3-030-20762-5_2 · Cited by 8
Mitochondria: Master Regulator of Metabolism, Homeostasis, Stress, Aging and Epigenetics
Meiliana, A., Dewi, N. M., & Wijaya, A. (2021) · The Indonesian Biomedical Journal · doi:10.18585/inabj.v13i3.1616 · Cited by 7
Braeckman, B. P., Back, P., & Matthijssens, F. (2016) · Healthy ageing and longevity · doi:10.1007/978-3-319-44703-2_10 · Cited by 8
frpr-18, a neuropeptide receptor, regulates organismal lifespan and stress tolerance in C. elegans
Ouaakki, H., Joshi, H., Rathor, L., & Han, S. M. (2023) · PubMed Central · doi:10.17912/micropub.biology.000840 · Cited by 7
“FRPR-18 is an orexin/hypocretin receptor ortholog and has been identified as an FLP-2 receptor to regulate arousal behavior (Chen et al., 2016a; Frooninckx et al., 2012; Mertens et al., 2005).”
BackgroundHu, I. M., Molenaars, M., Jaspers, Y. R. J., Schomakers, B. V., van Weeghel, M., Bakker, A., Modder, M., Dewulf, J. P., Bommer, G. T., Gao, A. W., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61433-6 · Cited by 9
“This results in bene fi cial effects for the whole organism, including increased lifespan 8 .”
InfluentialAutophagy in proteostasis and aging in Caenorhabditis elegans
Lange, C. M., Higuchi‐Sanabria, R., & Kumsta, C. (2025) · Cell Stress and Chaperones · doi:10.1016/j.cstres.2025.100115 · Cited by 11
“133 In addition, UPR mt activation solely in glia was sufficient to drive reduction of protein aggregates in neuronal cells.”
Multilayered regulation of longevity in Caenorhabditis elegans
Bong, D., Kwon, H. C., & Lee, S. (2025) · Molecules and Cells · doi:10.1016/j.mocell.2025.100308 · Cited by 9
Kirmes, I., Hung, G. C. C., Hahn, A., Dai, C.-Y., Campbell, D., Ahier, A., Lee, R. S. Y., Palmer, A., & Zuryn, S. (2025) · Nature Communications · doi:10.1038/s41467-025-67198-2 · Cited by 7
“In C. elegans , non-autonomous UPR mt signaling is mediated by multiple neuro-transmitters, neuropeptides, and insulin-like peptides 24 – 28 .”
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“However, most models of mitohormesis including the nematode model, C. elegans , involve genetic perturbations of mitochondrial function [12, 13].”
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“Specific hgs have also been associated with longevity [98] and likelihood of being engaged in endurance athletic activities [99].”
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“Thus, the constitutive ectopic expression of XBP1 in the nervous system—in neurons or supporting glial cells—or the activation of the mitochondrial UPR in neurons induces a systemic UPRER or UPRMT respectively, in other tissues (Durieux et al., 2011; Frakes et al., 2020; Taylor et al., 2014).”
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“elegans, metabolic dysfunction in neurons has been documented to activate stress responses in other cells, namely the intestine [94,95].”
Background
Metadata
- Authors
- Durieux, J., Wolff, S., & Dillin, A.
- Affiliations
- Salk Institute for Biological Studies (US)
- Scripps Research Institute (US)
- Corresponding author
- Dillin, Andrew
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 144
- Issue
- 1
- Pages
- 79-91
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3062502
- OpenAlex
- W2023402149
- Cited by
- 1,059
- References
- 60
- Citations by year
- 2026: 54 · 2025: 52 · 2024: 80 · 2023: 58 · 2022: 82 · 2021: 78 · 2020: 70 · 2019: 62 · 2018: 74 · 2017: 59 · 2016: 82 · 2015: 73 · 2014: 88 · 2013: 62 · 2012: 60
- FWCI
- 26.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG024365)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- electron transport chain, longevity, aging, mitochondrial stress response, non-cell-autonomous signaling, Caenorhabditis elegans, mitochondrial function
- MeSH terms
- Aging, Animals, Electron Transport, Longevity, Mitochondria, Cellular Senescence, Caenorhabditis elegans, Oxidative Stress, Unfolded Protein Response
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