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Mitochondrial Stress Signals Revise an Old Aging Theory
Dong Kyun Woo 1and Gerald S.Shadel 1,2,*
1Department
of Pathology 2Department of Genetics
Yale University School of Medicine,New Haven,CT 06520-8023,USA *Correspondence:gerald.shadel@yale.edu DOI 10.ll.2010.12.023
In this issue,Durieux et al.(2011)describe a tissue-specific signal,originating from mitochondria,that acts cell non-autonomously to regulate life span in the nematode,C.elegans .This new finding
Mitochondrial dysfunction is central to theories of aging,with the production of high levels of reactive oxygen species (ROS)receiving the lion’s share of atten-tion.Durieux et al.(2011)now suggest that mitochondria influence longevity in C.elegans not
only
through the produc-tion of ROS but also via a stress-evoked homeostasis.highlights the need to rethink theories of aging to incorporate mitochondrial signaling events.
As our understanding of mitochondria expands,so too does our appreciation for their diverse contributions to patholo-gies associated with aging and the regulation of life span.Mitochondria do much more than produce ATP via oxida-tive phosphorylation.These dynamic organelles participate in myriad cellular processes including apoptosis,ion homeostasis,and oxygen sensing;and their integrity is safeguarded by multiple quality control mechanisms,including were once thought of only as agents of oxidative damage but are now known to have important signaling functions (Hamanaka and Chandel,2010).Although changes in mitochondrial respiration and ROS are implicated in aging,their relationship with longevity is complicated (Barja,2007).Depending on the circumstance,alterations in mitochondrial respiration can either increase or decrease ROS
production and life span (for instance,see Bonawitz et al.,2007).Mild inhibition of mitochondrial activity extends life span in    C.elegans .This effect is not simply a result of decreased oxidative damage-induced aging by ROS because electron transport chain (ETC)inhibition counteracts aging only when it occurs during a defined developmental period,the L3/L4larval stages.One explanation
for the time dependence of this phenom-enon is that mitochondrial status is sensed during development,somehow programming rates of aging in adulthood.This type of mitochondrial adaptive response is similar to the concept of hormesis,which in the context of aging describes the heightened ability of an organism to respond to a certain condi-tion (such as oxidative stress)following prior exposure to that condition (Gems and Partridge,2008),and implies an underlying epigenetic basis.
Support for a mitochondria-mediated hormetic effect in aging is provided by experiments in which    C.elegans were fed a glucose-restricted diet,which caused an increase in mitochondrial respiration and ROS that,in turn,enhanced stress-resistance pathways and life span (Schulz et al.,2007).The recent discovery of a longevity-pro-moting,ROS-dependent gene expression program that occurs upon ETC inhibition (Lee et al.,2010)may begin to define a mitochondrial retrograde signaling
pathway that could,in principle,promote a hormetic effect,supporting the idea that early exposure to mitochondrial
ROS leads to enhanced oxidative stress resistance later in life (Schulz et al.,2007).The current study by Durieux ibutes novel insight into how early exposure to mitochondrial stress promotes life-span extension while also raising new questions about the identity and transduction of mitochondrial adap-tive signals.
Previous studies have shown that global ETC inhibition can promote longevity,but with a cost to overall fitness,causing decreased fecundity and re-duced motility (Dillin et al.,2002).Durieux
w show that tissue-specific knockdown of mitochondrial ETC compo-nents in either neurons or intestinal cells is
sufficient for life-span extension without any of the deleterious effects associated
perhaps unexpected effect does not appear to involve enhanced overall stress resistance but relies on activation of the mitochondrial UPR pathway (Haynes and Ron,2010).Durieux et al.provide direct support for this idea by showing that the key transcriptional coactivator of
mitochondrial UPR,the ubiquitin-like protein UBL-5,is indispensible for the
increase in life span that results from mild mitochondrial ETC inhibition.Further linking the mitochondria
l UPR and the ETC longevity pathway,the authors demonstrate that UBL-5expression is required during the same developmental window as decreased ETC activity to favor extended life span.Importantly,both UBL-5and ETC inhibition are dis-pensable for life-span extension via the
Cell 144,January 7,2011ª2011Elsevier Inc.11
线虫
幼虫期
毒物兴奋效应
后生的
激效
reactive materials studies倒退的
繁殖力
能动性
神经元
小肠有害效应
oxidative stress
反作用
共激活剂
不可缺少的
well-characterized insulin/IGF-1signaling pathway,providing more evidence that at least two separate pathways regulate longevity.Perhaps the most striking finding from this new study is that the ETC-mediated longevity pathway operates at some level through a cell-non-autonomous mech-anism.The authors show that neuron-specific ETC impairment induces a mito-chondrial UPR response in the intestine and extends life span,a result most easily
explained by an endocrine
signal that relays changes in mitochondrial function/stress in neurons to intestinal
cells.Although the chemical nature of this signal remains unknown,the authors sug-gest that a diffusible mole-cule,a ‘‘mitokine,’’is released from certain tissues,broad-casting a mitochondrial pro-longevity signal to target tissues,such as the intestine (Figure 1).This development adds a completely new layer of regulation to the concept of adaptive mitochondrial
signaling (hormesis)that may explain other observations that link the nervous and
endocrine systems to regula-tion of aging and life span in higher organisms (Russell and Kahn,2007).
The study by Durieux et al.is ground-breaking in many respects,but questions remain.For example,ETC knockdown in body-wall muscle upregulates mitochon-drial UPR in the intestine,but,unlike neuronal ETC inhibition,it does not lead to life-span extension.Thus,although a mitochondrial UPR-mitokine signal can be transmitted to the intestine from at least two different tissues,the tissue of origin matters.How neuronal versus muscular mitokine signaling differs and whether a single systemic mitokine promotes life-span extension remain unclear.Another possibility may be the
need for synergy between cell-autono-mous and cell-non-autonomous mito-chondrial signals (Figure 1)in specific tissues for aging to be delayed.Therefore,elucidating the precise connections between mitochondrial ROS and mito-chondrial UPR in the context of longevity and deciphering the relation-ships between these pro-cesses in various tissues will allow for a more compre-hensive mitochondrial theory of aging.A deeper under-standing of the mechanisms
that activate mitochondrial UPR and the identification of life-span-promoting mito-kine(s)may yield new thera-pies for age-related diseases and contribute to longer,healthier lives for humans.
ACKNOWLEDGMENTS This work was supported by
Program Project Grant ES011163from the NIH.
REFERENCES Barja,G.(2007).Rejuv.Res.10,
215–224.Bonawitz,N.D.,Chatenay-Lapointe,
M.,Pan,Y.,and Shadel,G.S.(2007).Cell Metab.5,265–277.Dillin,  A.,Hsu,  A.-L.,Arantes-Oli-viera,N.,Lehrer-Graiwer,J.,Hsin,
H.,Fraser,  A.G.,Kamath,R.S.,Ahringer,J.,and Kenyon,  C.(2002).Science 298,2398–2401.Durieux,J.,Wolff,S.,and Dillin,A.(2011).Cell 144,this issue,79–91.Gems,D.,and Partridge,L.(2008).Cell Metab.7,200–203.
Hamanaka,R.B.,and Chandel,N.S.(2010).Trends
Biochem.Sci.35,505–513.Haynes,C.M.,and Ron,D.(2010).J.Cell Sci.123,3849–3855.Lee,S.J.,Hwang,A.B.,and Kenyon,C.(2010).
Curr.Biol.20,2131–2136.
Russell,S.J.,and Kahn,C.R.(2007).Nat.Rev.Mol.Cell Biol.8,681–691.
Schulz,T.J.,Zarse,K.,Voigt,  A.,Urban,N.,
Birringer,M.,and Ristow,M.(2007).Cell Metab.6,280–293.
Figure 1.Longevity Is Regulated by Cell-Autonomous and -Non-Autonomous Mitochondrial Stress Pathways
Severe mitochondrial dysfunction,which can include increased production of reactive oxygen species (ROS),promotes aging.However,mild mitochondrial impairment and stress stimulate retrograde signaling and extend life span in C.elegans .Adaptive mitochondrial retrograde pathways relay mitochondrial
stress signals to the nucleus,activating mitochondrial quality control genes.Beyond maintaining mitochondrial integrity and function,both of which are
necessary for maximal life span,Durieux et al.(2011)uncover another arm of this adaptive response,showing that cell-non-autonomous signaling of the
mitochondrial unfolded protein response (UPR)between tissues is involved in
life-span extension.They propose that a diffusible factor,a mitokine,is
released from one tissue in response to mitochondrial stress and relays longevity cues to other tissues.Together,cell-autonomous and -non-auton-omous mitochondrial stress signals likely cooperate to extend life span in
response to mild ETC inhibition.
12Cell 144,January 7,2011ª2011Elsevier Inc.
逆行信号cell non-autonomous 神经元特异性的ETC
损伤诱导了小肠细胞内的线粒体UPR 响应。
这开辟了ETC 介导的
细胞非自主性机制。该分子可能具有组织特异性协同作用阐明
解密ETC inhibition

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