Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fgene.2017.00113/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Takashi K. Ito Takashi K. Ito Takashi K. Ito Chenhao Lu Jacob Khan Quy Nguyen Heather Z. Huang Dayae Kim James Phillips Jo Tan Yenna Lee Tuyet Nguyen Samy Khessib Natalie Lim Surapat Mekvanich Joshua Oh Victor V. Pineda Weirong Wang Weirong Wang Weirong Wang Alessandro Bitto Jonathan Y. An John F. Morton Mitsutoshi Setou Mitsutoshi Setou Warren C. Ladiges Matt Kaeberlein |
| spellingShingle |
Takashi K. Ito Takashi K. Ito Takashi K. Ito Chenhao Lu Jacob Khan Quy Nguyen Heather Z. Huang Dayae Kim James Phillips Jo Tan Yenna Lee Tuyet Nguyen Samy Khessib Natalie Lim Surapat Mekvanich Joshua Oh Victor V. Pineda Weirong Wang Weirong Wang Weirong Wang Alessandro Bitto Jonathan Y. An John F. Morton Mitsutoshi Setou Mitsutoshi Setou Warren C. Ladiges Matt Kaeberlein Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency Frontiers in Genetics S6K1 mTORC1 liver lifespan mitochondrial disease |
| author_facet |
Takashi K. Ito Takashi K. Ito Takashi K. Ito Chenhao Lu Jacob Khan Quy Nguyen Heather Z. Huang Dayae Kim James Phillips Jo Tan Yenna Lee Tuyet Nguyen Samy Khessib Natalie Lim Surapat Mekvanich Joshua Oh Victor V. Pineda Weirong Wang Weirong Wang Weirong Wang Alessandro Bitto Jonathan Y. An John F. Morton Mitsutoshi Setou Mitsutoshi Setou Warren C. Ladiges Matt Kaeberlein |
| author_sort |
Takashi K. Ito |
| title |
Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency |
| title_short |
Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency |
| title_full |
Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency |
| title_fullStr |
Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency |
| title_full_unstemmed |
Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency |
| title_sort |
hepatic s6k1 partially regulates lifespan of mice with mitochondrial complex i deficiency |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Genetics |
| issn |
1664-8021 |
| publishDate |
2017-09-01 |
| description |
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. |
| topic |
S6K1 mTORC1 liver lifespan mitochondrial disease |
| url |
http://journal.frontiersin.org/article/10.3389/fgene.2017.00113/full |
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doaj-b9e4abcd91a34deea0dfa54c43c48b292020-11-24T22:31:52ZengFrontiers Media S.A.Frontiers in Genetics1664-80212017-09-01810.3389/fgene.2017.00113290251Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I DeficiencyTakashi K. Ito0Takashi K. Ito1Takashi K. Ito2Chenhao Lu3Jacob Khan4Quy Nguyen5Heather Z. Huang6Dayae Kim7James Phillips8Jo Tan9Yenna Lee10Tuyet Nguyen11Samy Khessib12Natalie Lim13Surapat Mekvanich14Joshua Oh15Victor V. Pineda16Weirong Wang17Weirong Wang18Weirong Wang19Alessandro Bitto20Jonathan Y. An21John F. Morton22Mitsutoshi Setou23Mitsutoshi Setou24Warren C. Ladiges25Matt Kaeberlein26Department of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Cellular and Molecular Anatomy, Hamamatsu University School of MedicineHamamatsu, JapanInternational Mass Imaging Center, Hamamatsu University School of MedicineHamamatsu, JapanDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesResearch Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research CenterXi'an, ChinaLaboratory Animal Center, Xi'an Jiaotong University Health Science CenterXi'an, ChinaDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesDepartment of Comparative Medicine, University of WashingtonSeattle, WA, United StatesDepartment of Cellular and Molecular Anatomy, Hamamatsu University School of MedicineHamamatsu, JapanInternational Mass Imaging Center, Hamamatsu University School of MedicineHamamatsu, JapanDepartment of Comparative Medicine, University of WashingtonSeattle, WA, United StatesDepartment of Pathology, University of WashingtonSeattle, WA, United StatesThe 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.http://journal.frontiersin.org/article/10.3389/fgene.2017.00113/fullS6K1mTORC1liverlifespanmitochondrial disease |