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SUMMARY: Mitochondrial mediated aging is modulated by CEP-1\, the C. elega
 ns homolog of p53
DTSTART:20130304T140000
DTEND:20130304T150000
DTSTAMP:20260510T013124Z
UID:83b457d670ddc74cd90680c2f0ed1f9c86ca493b4d0b25ab02f6f283
CATEGORIES:Conferences - Seminars
DESCRIPTION:Aiswarya Baruah\nDept. Molecular Biology & Genetics\, Cornell 
 University\, Ithaca\, NY\, USA\nIn this study we investigated how mitochon
 drial electron transport chain (ETC) dysfunction modulates longevity by en
 gaging CEP-1\, the C. elegans homolog of mammalian p53. Previous findings 
 indicated that ETC complex III mutant isp-1(qm150) is long-lived due to a 
 mild elevation of mitochondrial superoxide (02-) levels(1). This mechanism
  is distinct from that of the long-lived coenzyme Q biosynthesis enzyme mu
 tant clk-1(e2519)\, which is thought to have a general increase in antioxi
 dant response. Our double mutant analysis showed that cep-1 is required to
  mediate the longevity of isp-1 but not that of clk-1\, suggesting that CE
 P-1 might sense a slight increase in mitochondrial ROS in order to promote
  longevity. Also\, inactivation of cep-1 by RNAi suppressed the longevity 
 of mitochondrial superoxide dismutase mutant sod-2(ok1030) and ETC complex
  I mutants nuo-6(qm200). Both sod-2 and nuo-6 mutants have been shown to b
 e long-lived due to increased mitochondrial 02- (1\,2). While a slight inc
 rease in mitochondrial 02- is thought to promote longevity\, a large eleva
 tion of mitochondrial 02-stress is detrimental. The complex I missense mut
 ant gas-1(fc21) and the complex II missense mutant mev-1(kn1) are both tho
 ught to be short lived because of a severe block in ETC leading to a high 
 increase in 02- levels. Double mutant analysis showed that inactivation of
  cep-1 is able to rescue short-lived mev-1 and gas-1 mutants\, suggesting 
 that CEP-1/p53 is able to respond to a high elevation in mitochondrial ROS
  to shorten lifespan. In addition to lifespan modulation CEP-1/p53 is also
  involved in mitochondrial mediated growth and reproduction in worm.\nTo d
 issect the transcriptional response of CEP-1/p53 to different mitochondria
 l dysfunctions\, we compared the expression profiles of isp-1 and mev-1 mu
 tants with or without cep-1. Despite the opposite effect of cep-1 inactiva
 tion on the longevity of isp-1 and mev-1 mutants\, the transcriptional out
 comes of cep-1 inactivation in these mutants were quite similar. We furthe
 r compared CEP-1 regulated genes in response to mitochondrial dysfunction 
 to CEP-1 regulated genes in response to UV irradiation(3). Results show th
 at CEP-1 regulates a similar set of genes upon mitochondrial dysfunction a
 nd UV irradiation. Since UV irradiation is known to induce ROS production\
 , this finding is consistent with our model that elevation of mitochondria
 l ROS engages CEP-1/p53.\nAn intriguing observation from the expression pr
 ofiling was the differential regulation of ftn-1 (ferritin-1) in mitochond
 rial ETC mutants. A quantitative PCR analysis confirmed that ftn-1 is indu
 ced both in isp-1 and mev-1 in a cep-1 dependent manner. Similar results w
 ere observed using Pftn-1::GFP. Ferritin regulates iron availability impor
 tant in the context of mitochondrial dysfunction. Functional studies are u
 nderway to demonstrate the importance of ftn-1 in affecting longevity of m
 itochondrial ETC mutants.  \n1. Yang W\, Hekimi S. A mitochondrial super
 oxide signal triggers increased longevity in C. elegans. PLoS Biol. 2010 D
 ec 7\;8(12):e1000556.\n2. Van Raamsdonk JM\, Hekimi S. Superoxide dismutas
 e is dispensable for normal animal lifespan. Proc Natl Acad Sci U S A. 201
 2 Apr 10\;109(15):5785-90.\n3. Derry WB\, Bierings R\, van Iersel M\, Satk
 unendran T\, Reinke V\, Rothman JH. Regulation of developmental rate and g
 erm cell proliferation in C. elegans by the p53 gene network. Cell Death D
 iffer. 2007 Apr\;14(4):662-70.
LOCATION:SV 1717A
STATUS:CONFIRMED
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