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Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.

Baker BM, Nargund AM, Sun T, Haynes CM - PLoS Genet. (2012)

Bottom Line: During mitochondrial dysfunction, GCN-2-dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans.Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2α phosphorylation but not ATFS-1 activation.These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPR(mt).

View Article: PubMed Central - PubMed

Affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT
Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1. During mitochondrial dysfunction, GCN-2-dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2α phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPR(mt).

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GCN-2 Is Required for the Lifespan Extension Associated with Mitochondrial Dysfunction.(A) Lifespan analysis of clk-1(qm30) animals fed vector (median survival 27.0 days) or gcn-2(RNAi) (median survival 17.0 days); p<0.0001, log-rank test. (B) Lifespan analysis of wild-type animals fed vector(RNAi) (median survival 21.0 days) or gcn-2(RNAi) (median survival 20.0 days); p = 0.6019 log-rank test.
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pgen-1002760-g006: GCN-2 Is Required for the Lifespan Extension Associated with Mitochondrial Dysfunction.(A) Lifespan analysis of clk-1(qm30) animals fed vector (median survival 27.0 days) or gcn-2(RNAi) (median survival 17.0 days); p<0.0001, log-rank test. (B) Lifespan analysis of wild-type animals fed vector(RNAi) (median survival 21.0 days) or gcn-2(RNAi) (median survival 20.0 days); p = 0.6019 log-rank test.

Mentions: Additionally, cytosolic translation attenuation also contributes to longevity in several animal models [15], [16], [17]. As GCN-2 slows cytosolic translation [51] in response to mitochondrial dysfunction, we examined the role of GCN-2 in lifespan extension associated with mitochondrial dysfunction. Interestingly, GCN-2 knockdown in clk-1(qm30) animals reduced their lifespan to that of wild-type worms (Figure 6A) consistent with a role for GCN-2 in lifespan extension associated with mitochondrial dysfunction. gcn-2(RNAi) was not generally toxic, as it did not affect lifespan or development in the absence of stress (Figure 6B and Figure S4). gcn-2(RNAi) also shortened the lifespan of isp-1(qm150) animals, but because the animals were very sick with considerable developmental defects, we were unable to determine a role for GCN-2 in longevity of these animals (data not shown). These data are consistent with GCN-2 and increased eIF2α phosphorylation contributing to the lifespan extension observed in mitochondrial mutants and further emphasizes the importance of protein homeostasis in aging.


Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.

Baker BM, Nargund AM, Sun T, Haynes CM - PLoS Genet. (2012)

GCN-2 Is Required for the Lifespan Extension Associated with Mitochondrial Dysfunction.(A) Lifespan analysis of clk-1(qm30) animals fed vector (median survival 27.0 days) or gcn-2(RNAi) (median survival 17.0 days); p<0.0001, log-rank test. (B) Lifespan analysis of wild-type animals fed vector(RNAi) (median survival 21.0 days) or gcn-2(RNAi) (median survival 20.0 days); p = 0.6019 log-rank test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375257&req=5

pgen-1002760-g006: GCN-2 Is Required for the Lifespan Extension Associated with Mitochondrial Dysfunction.(A) Lifespan analysis of clk-1(qm30) animals fed vector (median survival 27.0 days) or gcn-2(RNAi) (median survival 17.0 days); p<0.0001, log-rank test. (B) Lifespan analysis of wild-type animals fed vector(RNAi) (median survival 21.0 days) or gcn-2(RNAi) (median survival 20.0 days); p = 0.6019 log-rank test.
Mentions: Additionally, cytosolic translation attenuation also contributes to longevity in several animal models [15], [16], [17]. As GCN-2 slows cytosolic translation [51] in response to mitochondrial dysfunction, we examined the role of GCN-2 in lifespan extension associated with mitochondrial dysfunction. Interestingly, GCN-2 knockdown in clk-1(qm30) animals reduced their lifespan to that of wild-type worms (Figure 6A) consistent with a role for GCN-2 in lifespan extension associated with mitochondrial dysfunction. gcn-2(RNAi) was not generally toxic, as it did not affect lifespan or development in the absence of stress (Figure 6B and Figure S4). gcn-2(RNAi) also shortened the lifespan of isp-1(qm150) animals, but because the animals were very sick with considerable developmental defects, we were unable to determine a role for GCN-2 in longevity of these animals (data not shown). These data are consistent with GCN-2 and increased eIF2α phosphorylation contributing to the lifespan extension observed in mitochondrial mutants and further emphasizes the importance of protein homeostasis in aging.

Bottom Line: During mitochondrial dysfunction, GCN-2-dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans.Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2α phosphorylation but not ATFS-1 activation.These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPR(mt).

View Article: PubMed Central - PubMed

Affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT
Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1. During mitochondrial dysfunction, GCN-2-dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2α phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPR(mt).

Show MeSH
Related in: MedlinePlus