A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging

Mary Mohrin; Jiyung Shin; Yufei Liu; Katharine Brown; Hanzhi Luo; Yannan Xi; Cole M. Haynes; Danica Chen

doi:10.1126/science.aaa2361

A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging

Mary Mohrin, Jiyung Shin, Yufei Liu, Katharine Brown, Hanzhi Luo, Yannan Xi, Cole M. Haynes, Danica Chen

Research output: Contribution to journal › Article › peer-review

424 Scopus citations

Abstract

Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPR^mt), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFS^mt), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPR^mt-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.

Original language	English
Pages (from-to)	1374-1377
Number of pages	4
Journal	Science
Volume	347
Issue number	6228
DOIs	https://doi.org/10.1126/science.aaa2361
State	Published - Mar 20 2015

Bibliographical note

Publisher Copyright:
© 2015 American Association for the Advancement of Science. All rights reserved.

Funding

Funders	Funder number
Ellison Medical Foundation
National Institutes of Health (NIH)	R01 AG040990, T32 AG000266
National Stroke Foundation
National Institute on Aging	R01AG040061
National Institute on Aging

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abstract = "Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPRmt), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFSmt), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPRmt-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.",

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AU - Mohrin, Mary

AU - Shin, Jiyung

AU - Liu, Yufei

AU - Brown, Katharine

AU - Luo, Hanzhi

AU - Xi, Yannan

AU - Haynes, Cole M.

AU - Chen, Danica

PY - 2015/3/20

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AB - Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPRmt), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFSmt), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPRmt-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.

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A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging

Abstract

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