Abstract
While numerous life-extending manipulations have been discovered in the nematode Caenorhabditis elegans, one that remains most enigmatic is disruption of oxidative phosphorylation. In order to unravel how such an ostensibly deleterious manipulation can extend lifespan, we sought to identify the ensemble of nuclear transcription factors that are activated in response to defective mitochondrial electron transport chain (ETC) function. Using a feeding RNAi approach, we targeted over 400 transcription factors and identified 15 that, when reduced in function, reproducibly and differentially altered the development, stress response, and/or fecundity of isp-1(qm150) Mit mutants relative to wild-type animals. Seven of these transcription factors--AHA-1, CEH-18, HIF-1, JUN-1, NHR-27, NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein TAF-4--were also essential for isp-1 life extension. When we tested the involvement of these seven transcription factors in the life extension of two other Mit mutants, namely clk-1(qm30) and tpk-1(qm162), TAF-4 and HIF-1 were consistently required. Our findings suggest that the Mit phenotype is under the control of multiple transcriptional responses, and that TAF-4 and HIF-1 may be part of a general signaling axis that specifies Mit mutant life extension.
Highlights
In humans, many mutations that disrupt the mitochondrial electron transport chain (ETC) result in pathogenesis; several are the cause of debilitating childhood illnesses [1]
To expedite discovery of transcription factors required for Mit mutant life extension we monitored several surrogate phenotypes that co-segregate with increased lifespan in isp-1(qm150); Pgst-4::GFP mutants
The six additional RNAi clones that we identified targeted genes encoding two homeodomaincontaining proteins (CEH-18 and CEH-24), the GATArecognizing zinc-finger protein ELT-3, the T-box containing transcription factor TBX-2, TBP-associated factors (TAFs)-4 which is a component of the TFIID complex that forms part of the general RNA Pol II transcriptional machinery, and an unnamed transcription factor (Y62E10A.17) belonging to the activating protein 2 (AP-2) family of transcription factors
Summary
Many mutations that disrupt the mitochondrial electron transport chain (ETC) result in pathogenesis; several are the cause of debilitating childhood illnesses [1]. Altered mitochondrial function has been implicated in various late-onset diseases, including Alzheimer’s, Parkinson’s and Huntington’s Diseases [2]. Mutations that reduce mitochondrial ETC function can sometimes extend life rather than shorten it. In the nematode Caenorhabditis elegans, for example, when any of several components of the ETC are disrupted, either by mutation or RNAitreatment, lifespan is increased anywhere from 10% to 3-fold over wild-type [3]. RNAi knockdown of subunits in complex I, III, IV or V can extend the lifespan of Drosophila melanogaster as well [4].
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