The Homeobox Protein CEH-23 Mediates Prolonged Longevity in Response to Impaired Mitochondrial Electron Transport Chain in C. elegans

Walter, Ludivine; Baruah, Aiswarya; Chang, Hung‐Hao; Pace, Heather Mae; Lee, Siu Sylvia

doi:10.1371/journal.pbio.1001084

Cited by 75 publications

(72 citation statements)

References 65 publications

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“…7 B and C; note that hif-1 and aak-2 mutations tended to increase the survival of animals in wild-type background; see figure legends for discussion). We also found that knockdown of dve-1 (a homeodomain-containing transcription factor), ubl-5 (a ubiquitin-like protein), or ceh-23 (a homeobox transcription factor), which are genetic factors required for the longevity of isp-1 mutants (11,13), had indistinguishable effects on the survival of wild-type and isp-1 mutant animals (Fig. 7 D, E, and F).…”

Section: Mitochondrial Ros Increase Immunity Against Bacterial Pathogmentioning

confidence: 63%

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Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Hwang

Ryu

Artan

et al. 2014

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

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158

139

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Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS-induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.aging | mitochondria | immunity | reactive oxygen species | C. elegans M itochondria are essential for various physiological processes, including energy production, apoptosis, metabolism, and signaling (1). Thus, it is not surprising that defects in mitochondrial function are linked to many diseases. Interestingly, however, mild inhibition of mitochondrial respiration increases the lifespans of many organisms (2, 3). In particular, genetic inhibition of components of the mitochondrial electron transport chain (ETC) increases longevity of the roundworm Caenorhabditis elegans. For example, mutations in clk-1 (a ubiquinone hydroxylase) and isp-1 (iron-sulfur protein 1 in the mitochondrial complex III) extend the lifespans of worms (4, 5). Longevity resulting from mitochondrial ETC inhibition also has been observed in Drosophila (6, 7) and mice (8, 9). Thus, the mechanisms responsible for longevity may be evolutionarily conserved.Key genetic factors that mediate longevity caused by reduced mitochondrial respiration in C. elegans have been identified recently (10-17). However, the mechanisms are not completely understood. Hypoxia-inducible factor 1 (HIF-1), the master transcriptional regulator of cellular responses to hypoxia, is one of the mediators of longevity caused by inhibition of mitochondrial respiration in C. elegans (12). The physiological importance of HIF-1α in humans is underscored by the fact that mutations in VHL, the von HippelLindau tumor suppressor gene, which encodes an E3-ubiquitin ligase component required for the degradation of HIF-1, lead to an inherited form of cancer (18,19). HIF-1 regulates adaptation to low oxygen and various other biological processes, including axon guidance, immunity, iron homeostasis, and aging (20-29). Increased levels of HIF-1 by vhl-1 mutations or by overexpression of HIF-1 lengthen the lifespan of C. elegans (27, 28). In addition, we previously showed that inhibition of mitochondrial respiration promotes longevity by elevating reactive oxygen species (ROS) levels and incr...

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Section: Mitochondrial Ros Increase Immunity Against Bacterial Pathogmentioning

confidence: 63%

“…Key genetic factors that mediate longevity caused by reduced mitochondrial respiration in C. elegans have been identified recently (10)(11)(12)(13)(14)(15)(16)(17). However, the mechanisms are not completely understood.…”

mentioning

confidence: 99%

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Hwang

Ryu

Artan

et al. 2014

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

Self Cite

158

139

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“…Thus, factors other than HIF‐1 appear to contribute to the regulation of nhr‐57 expression and longevity. These factors may include transcription factors, DVE‐1, CEH‐23, and CEP‐1, which regulate longevity in response to inhibition of mitochondrial components (Durieux et al ., 2011; Walter et al ., 2011; Baruah et al ., 2014), because nhr‐57 is induced by impaired mitochondrial functions (Lee et al ., 2010). In addition, transcription factors, such as ELT‐3, EOR‐1, BLMP‐1, ALR‐1, PHA‐4, PQM‐1, SKN‐1, MDL‐1, and PES‐1, bind to the promoter region of nhr‐57 , based on modENCODE data analysis (Gerstein et al ., 2010; Van Nostrand & Kim, 2013).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

et al. 2015

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SummaryThe transcription factor hypoxia‐inducible factor 1 (HIF‐1) is crucial for responses to low oxygen and promotes longevity in Caenorhabditis elegans. We previously performed a genomewide RNA interference screen and identified many genes that act as potential negative regulators of HIF‐1. Here, we functionally characterized these genes and found several novel genes that affected lifespan. The worm ortholog of elongin C, elc‐1, encodes a subunit of E3 ligase and transcription elongation factor. We found that knockdown of elc‐1 prolonged lifespan and delayed paralysis caused by impaired protein homeostasis. We further showed that elc‐1 RNA interference increased lifespan and protein homeostasis by upregulating HIF‐1. The roles of elongin C and HIF‐1 are well conserved in eukaryotes. Thus, our study may provide insights into the aging regulatory pathway consisting of elongin C and HIF‐1 in complex metazoans.

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“…Consequently, mitochondrial stress presumably activates parallel cytoprotective pathways. For instance, mitochondrial stress results in the activation of multiple signaling modules in addition to the UPR mt , including the hypoxia-response transcription factor HIF-1, the AMP-activated kinase pathway, and the transcription factors TAF-4 and CEH-23 (55)(56)(57). As well, increased mitochondrial ROS can activate an oxidative stress response regulated by the transcription factor SKN-1 (58).…”

Section: The Future Of the Upr Mtmentioning

confidence: 99%

The mitochondrial unfolded protein response: Signaling from the powerhouse

Qureshi

Haynes

Pellegrino

2017

Journal of Biological Chemistry

122

115

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Edited by Ruma BanerjeeMitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPR mt ). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPR mt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.Mitochondria are double membrane organelles commonly associated with the production of cellular energy via oxidative phosphorylation (OXPHOS).2 Mitochondria are also required for the metabolism of nucleotides, amino acids, and lipids and have an essential function in regulating apoptosis. Maintaining mitochondrial integrity is therefore a key aspect in ensuring cellular and organismal viability. Consequently, a decline in mitochondrial function is frequently associated with the development of numerous diseases (1).Mitochondria are dependent on a diverse compilation of proteins to carry out their vital functions. However, the mitochondrial proteome is faced with various challenges, most notably the partitioning of protein encoding genes between the mitochondrial and nuclear genomes. Remarkably, the human mitochondrial genome only encodes ϳ1% of the total mitochondrial proteome with the remaining proteins being encoded by nuclear genes (2). Sophisticated mechanisms have evolved to efficiently transfer nuclear-encoded mitochondrial proteins to their proper organelle destination following translation on cytosolic ribosomes. To accomplish this complex task, proteins are sorted to mitochondria via targeting sequences that form characteristic amphipathic helices composed of positively charged residues. Such mitochondrial targeting sequences (MTS) are recognized and translocated via the mitochondrial Tom-Tim complex to their respective sub-organelle compartment (3). Exquisite coordination of expression between the mitochondrial and nuclear genomes exists during mitochondrial biogenesis, as failure in genome coordination can disrupt the precise stoichiometry of these OXPHOS complexes resulting in orphan subunit accumulation and proteotoxicity (4). Further contributing to mitochondrial proteotoxicity is the possible damage to the mitochondrial genome from reactive oxygen species (ROS) produced by OXPHOS machinery as well as the ill effects of various environmental toxins. Mechanisms must therefore exist to ensure the protection of the mitochondrial proteome.Quality control of the mitochondrial proteome includes the functions of mitochondrial chaperones that assist in proper protein folding and proteases that promote clearance of misfolded proteins (5). Each sub-compartment of mitochondria houses its own quality control machinery to ensure protein homeostasis and organelle function. ...

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The Homeobox Protein CEH-23 Mediates Prolonged Longevity in Response to Impaired Mitochondrial Electron Transport Chain in C. elegans

Cited by 75 publications

References 65 publications

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

The mitochondrial unfolded protein response: Signaling from the powerhouse

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