The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging

Chih-Ling Wang; Rika Ohkubo; Wei-Chieh Mu; Wei Chen; Jiang Lan Fan; Zehan Song; Ayane Maruichi; Peter H Sudmant; Angela O Pisco; Dena B Dubal; Na Ji; Danica Chen

doi:10.1016/j.cmet.2023.04.012

The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging

Cell Metab. 2023 Jun 6;35(6):996-1008.e7. doi: 10.1016/j.cmet.2023.04.012. Epub 2023 May 4.

Authors

Chih-Ling Wang¹, Rika Ohkubo², Wei-Chieh Mu³, Wei Chen⁴, Jiang Lan Fan⁵, Zehan Song², Ayane Maruichi³, Peter H Sudmant⁶, Angela O Pisco⁷, Dena B Dubal⁸, Na Ji⁴, Danica Chen⁹

Affiliations

¹ Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Department of Physics, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
⁵ Joint Graduate Program in Bioengineering, University of California, San Francisco, and University of California, Berkeley, San Francisco, CA 94720, USA.
⁶ Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁷ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁸ Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁹ Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: danicac@berkeley.edu.

PMID: 37146607
PMCID: PMC10330239 (available on 2024-06-06)
DOI: 10.1016/j.cmet.2023.04.012

Abstract

Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.

Keywords: SIRT1; SIRT2; SIRT3; SIRT6; SIRT7; cognitive aging; mitochondrial unfolded protein response; neural stem cell aging; sirtuin; stem cell aging.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aging / physiology
Animals
Cell Proliferation
Hippocampus*
Mice
Neural Stem Cells* / metabolism
Neurogenesis / physiology
Unfolded Protein Response

Abstract

Publication types

MeSH terms

Grants and funding