TY - JOUR
T1 - Epigenetic silencing mediates mitochondria stress-induced longevity
AU - Schroeder, Elizabeth A.
AU - Raimundo, Nuno
AU - Shadel, Gerald S.
N1 - Funding Information:
This work was supported by grant W911NF-11-1-0376 from the Army Research Office to G.S.S. E.A.S. was supported by NIH Genetics Training Grant T32 GM07499 and is currently supported by NIH predoctoral fellowship F31 AG043242. N.R. was supported by a postdoctoral fellowship from the United Mitochondrial Disease Foundation. We thank Drs. Megan King, Patrick Lusk, and David Stern for reagents used in the study and insightful discussions.
PY - 2013/6/4
Y1 - 2013/6/4
N2 - Reactive oxygen species (ROS) play complex roles in aging, having both damaging effects and signaling functions. Transiently elevating mitochondrial stress, including mitochondrial ROS (mtROS), elicits beneficial responses that extend lifespan. However, these adaptive, longevity-signaling pathways remain poorly understood. We show here that Tel1p and Rad53p, homologs of the mammalian DNA damage response kinases ATM and Chk2, mediate a hormetic mtROS longevity signal that extends yeast chronological lifespan. This pathway senses mtROS in a manner distinct from the nuclear DNA damage response and ultimately imparts longevity by inactivating the histone demethylase Rph1p specifically at subtelomeric heterochromatin, enhancing binding of the silencing protein Sir3p, and repressing subtelomeric transcription. These results demonstrate the existence of conserved mitochondria-to-nucleus stress-signaling pathways that regulate aging through epigenetic modulation of nuclear gene expression.
AB - Reactive oxygen species (ROS) play complex roles in aging, having both damaging effects and signaling functions. Transiently elevating mitochondrial stress, including mitochondrial ROS (mtROS), elicits beneficial responses that extend lifespan. However, these adaptive, longevity-signaling pathways remain poorly understood. We show here that Tel1p and Rad53p, homologs of the mammalian DNA damage response kinases ATM and Chk2, mediate a hormetic mtROS longevity signal that extends yeast chronological lifespan. This pathway senses mtROS in a manner distinct from the nuclear DNA damage response and ultimately imparts longevity by inactivating the histone demethylase Rph1p specifically at subtelomeric heterochromatin, enhancing binding of the silencing protein Sir3p, and repressing subtelomeric transcription. These results demonstrate the existence of conserved mitochondria-to-nucleus stress-signaling pathways that regulate aging through epigenetic modulation of nuclear gene expression.
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U2 - 10.1016/j.cmet.2013.04.003
DO - 10.1016/j.cmet.2013.04.003
M3 - Article
C2 - 23747251
AN - SCOPUS:84878797603
SN - 1550-4131
VL - 17
SP - 954
EP - 964
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -