10.3389/fgene.2017.00113.s001
Takashi K. Ito
Takashi
K. Ito
Chenhao Lu
Chenhao
Lu
Jacob Khan
Jacob
Khan
Quy Nguyen
Quy
Nguyen
Heather Z. Huang
Heather Z.
Huang
Dayae Kim
Dayae
Kim
James Phillips
James
Phillips
Jo Tan
Jo
Tan
Yenna Lee
Yenna
Lee
Tuyet Nguyen
Tuyet
Nguyen
Samy Khessib
Samy
Khessib
Natalie Lim
Natalie
Lim
Surapat Mekvanich
Surapat
Mekvanich
Joshua Oh
Joshua
Oh
Victor V. Pineda
Victor
V. Pineda
Weirong Wang
Weirong
Wang
Alessandro Bitto
Alessandro
Bitto
Jonathan Y. An
Jonathan Y.
An
John F. Morton
John
F. Morton
Mitsutoshi Setou
Mitsutoshi
Setou
Warren C. Ladiges
Warren
C. Ladiges
Matt Kaeberlein
Matt
Kaeberlein
Image1.JPEG
Frontiers
2017
S6K1
mTORC1
liver
lifespan
mitochondrial disease
2017-12-22 09:31:15
Figure
https://frontiersin.figshare.com/articles/figure/Image1_JPEG/5729088
<p>The inactivation of ribosomal protein S6 kinase 1 (S6K1) recapitulates aspects of caloric restriction and mTORC1 inhibition to achieve prolonged longevity in invertebrate and mouse models. In addition to delaying normative aging, inhibition of mTORC1 extends the shortened lifespan of yeast, fly, and mouse models with severe mitochondrial disease. Here we tested whether disruption of S6K1 can recapitulate the beneficial effects of mTORC1 inhibition in the Ndufs4 knockout (NKO) mouse model of Leigh Syndrome caused by Complex I deficiency. These NKO mice develop profound neurodegeneration resulting in brain lesions and death around 50–60 days of age. Our results show that liver-specific, as well as whole body, S6K1 deletion modestly prolongs survival and delays onset of neurological symptoms in NKO mice. In contrast, we observed no survival benefit in NKO mice specifically disrupted for S6K1 in neurons or adipocytes. Body weight was reduced in WT mice upon disruption of S6K1 in adipocytes or whole body, but not altered when S6K1 was disrupted only in neurons or liver. Taken together, these data indicate that decreased S6K1 activity in liver is sufficient to delay the neurological and survival defects caused by deficiency of Complex I and suggest that mTOR signaling can modulate mitochondrial disease and metabolism via cell non-autonomous mechanisms.</p>