The Cell Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity

“…because reactive oxygen species (ROS) are generated as a byproduct of the metabolic activity of the mitochondrial ETC during the production of ATP (Harman, 1956), a decrease in ROS production is the major contributing factor to the long-lived phenotypes of ETC mutants (Feng et al., 2001; Rea and…”

“) is also induced under conditions of protein misfolding, although confined to the ER (Ron and Walter , 2007).”

“We testedwhethermitochondrial reduction resulted in a general upregulation of all protein misfolding pathways by treating hsp-4p::GFP reporter worm strains (Calfon et al., 2002) with cco-1 RNAi.”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“These changes occur coordinately across multiple tissues and organs, in concordance with theories that posit a strong role for the participation of the endocrine system in the regulation of age-related phenotypes (Russell and Kahn, 2007; Tatar et al., 2003).”

“…Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the…”

“RNAi of cco-1 slows development, growth, movement and reduces fecundity (Dillin et al., 2002b).”

“The Mitochondrial Unfolded Protein Response Is Required for ETC-Mediated Longevity In response to a mitochondrial perturbation there exists a stress response mechanism that is communicated to the nucleus to increase the expression of mitochondrial associated protein chaperones, such as HSP-6 andHSP-60, referred to as…”

“These include alteration of signals from the somatic germline which control the aging of nonmitotic tissues (Arantes-Oliveira et al., 2002; Hsin and Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al.”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…et al., 2002; Hsin and Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter…”

“Life-Span Analysis of cco-1 Hairpin Transgenic Animals (A) Wild-type worms allow import of dsRNA from surrounding tissues, but sid-1(qt9) mutant worm can not import dsRNA and RNAi knockdown is no longer systemic but is maintained locally within the tissue in which the dsRNA is produced (Winston et al., 2002).”

“…(Arantes-Oliveira et al., 2002; Hsin and Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific…”

“…or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the entire animal to…”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the entire animal to respond to dietary…”

“A modification to this theory has suggested alternatively that, because reactive oxygen species (ROS) are generated as a byproduct of the metabolic activity of the mitochondrial ETC during the production of ATP (Harman, 1956), a decrease in ROS production is the major contributing factor to the long-lived phenotypes o…”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“…in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the entire animal to respond to dietary restriction (Bishop and Guarente, 2007).”

“Furthermore, markers of the UPR mt , namely hsp-6p::GFP, have their greatest activation late in larval development at the L4 stage when challenged with mitochondrial stress (Yoneda et al., 2004 ).”

“…promoter driving wild-type sid-1 was injected into rab-3p::cco-1HP transgenic worms to enable knockdown of cco-1 in the neurons by the hairpin transgene and in the intestine by feeding RNAi. ubl-5 knockdown strains were generated with constructs as described (Esposito et al., 2007; Hobert, 2002).”

“ClpP is the homolog of the E.coli ClpP protease located in the mitochondria that plays a role in generating the mitochondrial derived signal to activate DVE-1/UBL-5 stress responsive genes (Haynes et al., 2007).”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“…cco-1 did not affect the response of animals to oxidative stress induced by paraquat in a manner correlated with their longevity phenotype (Table S2), consistent with recent results in worms and flies (Copeland et al., 2009; Doonan et al., 2008; Van Raamsdonk and Hekimi, 2009) (Lee et al., 2002).”

“…cco-1 did not affect the response of animals to oxidative stress induced by paraquat in a manner correlated with their longevity phenotype (Table S2), consistent with recent results in worms and flies (Copeland et al., 2009; Doonan et al., 2008; Van Raamsdonk and Hekimi, 2009) (Lee et al., 2002).”

“RNAi of cco-1 slows development, growth, movement and reduces fecundity (Dillin et al., 2002b).”

“…function in nuclear genes encoding electron transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et…”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“cco-1 was chosen because knockdown of this gene results in intermediate phenotypes compared to knockdown of the other ETC genes by RNAi, allowing both positive and negative modulation of longevity to be identified (Dillin et al., 2002b; Lee et al., 2002; Rea et al., 2007).”

“Together, UBL-5 and DVE-1 respond to mitochondrial perturbation to increase expression of mitochondrial chaperones, including hsp-6 and hsp-60 (Benedetti et al., 2006).”

“These changes occur coordinately across multiple tissues and organs, in concordance with theories that posit a strong role for the participation of the endocrine system in the regulation of age-related phenotypes (Russell and Kahn, 2007; Tatar et al., 2003).”

“…an inverted repeat of the cco-1 cDNA under the control of well-characterized promoters expressed in neurons (unc-119 and rab-3) (Maduro and Pilgrim, 1995; Nonet et al., 1997), intestine (ges-1) (Aamodt et al., 1991), and body-wall muscle cells (myo-3) (Miller et al., 1986; Okkema et al., 1993).”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“elegans, Drosophila, andmice delay the aging process (Copeland et al., 2009; Dell’Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“Life-span analyses were performed with rde-1(ne219) mutant animals in which rde-1 was restored by tissue-specific expression of wild-type rde-1 cDNA (Qadota et al., 2007). rde-1 was rescued in transgenic lines under the control of the lin-26 hypodermal promoter, the hlh-1 body wall muscle promoter,…”

“elegans, mitochondria undergo a period of dramatic proliferation during the L3/L4 stage (Tsang and Lemire, 2002).”

“…RNAi does not result in the detrimental phenotypes observed when bacterial feeding RNAi against other components of the ETC is administered undiluted, such as severe developmental delay and lethality (Copeland et al., 2009; Gems and Doonan, 2008; Van Raamsdonk and Hekimi, 2009; Yang et al., 2007).”

“…promoter driving wild-type sid-1 was injected into rab-3p::cco-1HP transgenic worms to enable knockdown of cco-1 in the neurons by the hairpin transgene and in the intestine by feeding RNAi. ubl-5 knockdown strains were generated with constructs as described (Esposito et al., 2007; Hobert, 2002).”

“…an inverted repeat of the cco-1 cDNA under the control of well-characterized promoters expressed in neurons (unc-119 and rab-3) (Maduro and Pilgrim, 1995; Nonet et al., 1997), intestine (ges-1) (Aamodt et al., 1991), and body-wall muscle cells (myo-3) (Miller et al., 1986; Okkema et al., 1993).”

“For example, exposure of the intestine to bacterially expressed dsRNA results in the dsRNA entering through the intestinal lumen but eliciting knockdown in other cells, such as the muscle and hypodermis (Jose et al., 2009).”

“A modification to this theory has suggested alternatively that, because reactive oxygen species (ROS) are generated as a byproduct of the metabolic activity of the mitochondrial ETC during the production of ATP (Harman, 1956), a decrease in ROS production is the major contributing factor to the long-lived phenotypes o…”

“…an inverted repeat of the cco-1 cDNA under the control of well-characterized promoters expressed in neurons (unc-119 and rab-3) (Maduro and Pilgrim, 1995; Nonet et al., 1997), intestine (ges-1) (Aamodt et al., 1991), and body-wall muscle cells (myo-3) (Miller et al., 1986; Okkema et al., 1993).”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…is not surprising given the roles of dve-1 in growth and development and the embryonic lethality observed for homozygous dve-1 mutant animals (Burglin and Cassata, 2002; Haynes et al., 2007 suppressed longevity in the same manner as dve-1, suggesting that these RNAi treatments were…”

“…RNAi does not result in the detrimental phenotypes observed when bacterial feeding RNAi against other components of the ETC is administered undiluted, such as severe developmental delay and lethality (Copeland et al., 2009; Gems and Doonan, 2008; Van Raamsdonk and Hekimi, 2009; Yang et al., 2007).”

“Hormetic reactions may trigger a mitochondrial defensive response both in the same tissue in which mitochondria are defective and even in distant tissues, as shown in C. elegans (Durieux et al., 2011).”

“A non-cell-autonomous mitochondrial regulatory pathway was also reported in C. elegans: a tissuespecific RNA interference-mediated knockdown of cytochrome c oxidase subunit in neurons causes a local cellular stress response in neurons that is also communicated to the gut (Durieux et al., 2011).”

“In fact, in C. elegans, conditions of increased ROS generation such as ETC dysfunction, loss of sod-2, PQ treatment, and reduced glucose metabolism were shown to promote longevity (Schulz et al., 2007; Durieux et al., 2011; Wang and Hekimi, 2015).”

“Mitonuclear protein imbalance can be defined as a stoichiometric difference between nuclear and mitochondrial-encoded respiratory subunit proteins (Houtkooper et al., 2013), an effect known to promote longevity in worms (Durieux et al., 2011; Houtkooper et al., 2013).”

“…phosphorylation of PGC-1 α allows it to be deacetylated and activated by SIRT1 (Cantó et al., 2009; Gerhart-Hines et al., 2007; Rodgers et al., 2005), whereas under basal conditions, acetylation status is primarily regulated by the acetyltransferase GCN5 (Fernandez-Marcos and Auwerx, 2011).”

“The link between the UPRmt and lifespan was made initially in the setting of attempting to explain why mutant worms, such as Molecular Cell 61, March 3, 2016 ª2016 Elsevier Inc. 657 those with knockdown of cco-1, live longer (Durieux et al., 2011).”

“elegans downstream of ETC disruption and mtROS (Durieux et al., 2011; Schieber and Chandel, 2014) will be important to consider.”

“…PARP1 and PARP2 representing the main PARP activities in mammals—were classically described as DNA repair proteins (Gibson and Kraus, 2012; Schreiber et al., 2006), but recent studies have linked these proteins to metabolism (Asher et al., 2010; Bai et al., 2011a, 2011b; Erener et al., 2012).”

“…apparent contradiction, such as the requirement of additional regulatory components, like epigenetic modifications or non–cell-autonomous factors (Durieux et al., 2011; Merkwirth et al., 2016; Tian et al., 2016), as well as particular specificities of given cells, tissues, or stressors to…”

“Recent studies 416 Cell Metabolism 18, 416–430, September 3, 2013 ª2013 Elsevie in worms and flies have also suggested that systemic interplay between multiple tissues regulates aging and longevity (Demontis and Perrimon, 2010; Durieux et al., 2011).”

“…elegans, a stress-induced tissue-specific signal originating from mitochondria has been shown to communicate with distant organs and extend lifespan; the exact identity of this signal, termed ‘‘mitokine,’’ is unknown and currently being investigated (Durieux et al., 2011; Woo and Shadel, 2011).”

“Life span of the skn-1; daf-16 mutant was unaffected by raga-1 RNAi but increased by inhibition of mitochondrial genes (cco-1, cyc-1; Tables S3 and S4), which involves a distinct longevity pathway (Durieux et al., 2011; Kenyon, 2010).”

“17,267 Besides mito-nuclear signaling, ROS production by individual mitochondria also locally contributes to communication with the ER.”

“We studied the electron transport chain (ETC) complex I inhibitor rotenone, because inhibition of ETC complexes is a wellknown cause of mitochondrial stress (Durieux et al., 2011).”

“In addition to tunicamycin and thapsigargin, heat stress and exposure to pathogenic bacteria also induce the UPRER (Galbadage and Hartman, 2008; Richardson et al., 2010).”

“elegans[61,62].”

“This phenotype seems at least partly mediated by the mitochondrial unfolded protein response and acts in a cell-non-autonomous fashion involving a yet unidentified “mitokine”

“elegans where an induction of the mitochondrial unfolded protein response (UPR) in neurons led to changes in mitochondria within physically distinct, noninnervated tissues (Durieux et al., 2011), but has more recently been supported by evidence linking FGF21 to the ISR (Salminen et al.”

“This in turn activates adaptive mitochondrial stress signaling that is reported to improve “fitness” and promote longevity (147), so-called “mitohormesis” (123, 148, 149).”

“In fact, proper UPRmt activation is essential for the lifespan extension observed in long-lived mitochondrial worm mutants (Durieux et al., 2011; Houtkooper et al., 2013).”

“This cellnonautonomous response helps control the rate of aging for these other tissues, and indeed for the whole organism, through diffusible signals that come from limited numbers of cell types (Durieux et al. 2011).”

“elegans, where RNAi-mediated knockdown of cytochrome c oxidase-1 subunit Vb in neurons activates the UPR autonomously in neurons and nonautonomously in the gut (Durieux et al., 2011).”

“lin-65/met-2 and atfs-1 Are Required for Mitochondrial Stress-Induced Longevity Mitochondrial stress induced by cco-1 RNAi during development increases lifespan and induces the UPR (Dillin et al., 2002; Durieux et al., 2011).”

“These results demonstrate that NR induced mitochondrial biogenesis and oxidative ATP production capacity robustly and significantly delayed the progression of MM, irrespective of the disease stage.”

“…flies, and mice, mitochondrial dysfunction can delay the aging process (Copeland et al., 2009; Dell’agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Kirchman et al., 1999; Lee et al., 2003; Liu et al., 2005), but, when occurring later in life, has deleterious effects and is…”

“Interconnectedness of mitochondria in different tissues [358_TD$DIFF]and mitokines Interestingly, a recent study showed that mitochondrial perturbations in one tissue may trigger mitochondrial stress response in distal tissues (Durieux et al., 2011).”

“In particular, mitochondrial dysfunction in neurons caused a UPR mt response in the intestines, implicating a soluble factor that the authors deemed a mitokine (102).”

“Recently, it has been shown that ETC mutations that extend lifespan also activate the UPRmt [83].”

“In multiple model organisms, genetic and pharmacological induction of the UPRmt exerts beneficial effects on lifespan, consistent with overall improvements in systemic metabolic homeostasis (Feng et al., 2001; Dillin et al., 2002; Durieux et al., 2011; Houtkooper et al., 2013; Owusu-Ansah et al., 2013).”

“Sod3 was taken as a non mtUPR related stress protein.”

“(G) Intestinal-specific overexpression of drp-1 is sufficient to increase the lifespan (H) The level of mitochondrial chaperone HSP-6::GFP was used to measure UPR RNAi induces the HSP-6::GFP level, which is further elevated by CA supplemen (I) In the loss-of-functionmutant of atfs-1(gk3094), the lifespan extension con…”

“Likewise, downregulation of nuclear-encoded cco-1 (complex IV), isp-1 (complex III) and clk-1 (ubiquinone synthesis) also induces UPRmt (Baker et al., 2012; Durieux et al., 2011).”

“maintaining mitochondrial protein homeostasis [50].”

“elegans lifespan can be extended by respiratory chain impairment, which also induces mitochondrial protein quality-control systems (Durieux et al., 2011).”

“…in stem cell function in the forebrain, epidermis, intestinal epithelium, and hematopoietic system through cell-autonomous (Lee et al., 1998; Allsopp et al., 2003; Choudhury et al., 2007; Ferrón et al., 2009; Jaskelioff et al., 2011) and non-cell-autonomous effects on stem cells (Ju et al., 2007).”

“…that stress responses are under neuronal control, communicated between tissues and integrated to the metabolic processes of the animal (Baumeister et al., 2006; Durieux et al., 2011; Garcia et al., 2007; van Oosten-Hawle et al., 2013; Prahlad et al., 2008; reviewed in Gidalevitz et al., 2011).”

“Recently, Andrew Dillin and his team [96] identified so-called mitokines which could induce systemic effects on the mitochondrial pool in C.”

“Our findings are consistent with recent reports [31, 32] that suggested that unknown factors termed ‘mitokines’ are produced from the mitochondria of Caenorhabditis elegans and secreted to communicate with other cells.”

“Furthermore, stem cell self-renewal and/or multi- or pluripotency are promoted by hypoxia in murine HSCs, MSCs and NSCs and human ESCs (D’Ippolito et al., 2006; Ezashi et al., 2005; Jeong et al., 2007; Morrison et al., 2000).”

“in the worm intestine, and leads to an extension of life span, most likely mediated by an unidentified circulating signal(s) that allows the mitochondria of neuronal and intestinal cells to communicate stress conditions [30, 31].”

“In the worm, neuronal inactivation of mitochondrial cytochrome-c-oxidase elicited UPRmt locally, but also in the gut, pointing to a secreted factor mediating stress signals from the affected neurons to periphery (Durieux et al., 2011).”

“These mito-toxic antibiotics inhibit mitochondrial protein translation, similar to their action in bacteria, resulting in a ‘mitonuclear’ protein imbalance that activates the mitochondrial unfolded protein response (UPR) that is commonly resolved by mitophagy [50,123].”

“Strikingly, neuronal knockdown of OXPHOS components can trigger the UPRmt in the intestine [41].”

“NR350 worms lack rde-1, an essential component of the RNAi machinery encoding a member of the PIWI/STING/Argonaute family, in all tissues except the body wall muscle in which the wild-type rde-1 gene has been rescued using the hlh-1 promoter (Durieux et al., 2011).”

“elegans suggest that the mtUPR is cell-nonautonomous (Durieux et al. 2011).”

“While multiple challenges to mitochondrial proteostasis in neurons can activate cell-nonautonomous UPR, knockdown of the mitochondrial ETC subunit cco-1 in neurons also activates UPR in the peripheral tissue (Durieux et al., 2011).”

“The cell nonautonomous regulation of stress responses by neurons has recently gained support from another study showing that the mitochondrial stress response, central to regulating longevity, is also under cell nonautonomous control (Durieux et al. 2011).”

“…hand, reducing the expression of electron transport chain (ETC) subunits has pro-longevity effects from yeast to mammals (Copeland et al., 2009; Dell’agnello et al., 2007; Dillin et al., 2002; Durieux et al., 2011; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002a; Rea et al., 2007).”

“Neuron-targeted disruption of mitochondrial function can lead to cell-nonautonomous activation of the UPRmt in nonneuronal tissues in C. elegans (Durieux et al., 2011).”

“elegans, in which an induction of the mitochondrial unfolded protein response (UPR) in the neurons is sensed and reacted to by mitochondria within physically distinct, non-innervated tissues (Durieux et al., 2011).”

“Indeed, multiple different ribosome-associated E3 ligases can impact cotranslational degradation in yeast (Duttler et al., 2013).”

“Likewise, we observed the same trend in a human population study (Cohorte Lausannoise [CoLaus] study [Firmann et al., 2008]), in which we recently analyzed the spot urine samples of 835 middle-aged or elderly individuals (Rueedi et al., 2014).”