MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer

Cui Wang; Kuan Yang; Xiaoqian Liu; Si Wang; Moshi Song; Juan Carlos Izpisua Belmonte; Jing Qu; Guang-Hui Liu; Weiqi Zhang

doi:10.34133/research.0192

MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer

Research (Wash D C). 2023 Jul 27:6:0192. doi: 10.34133/research.0192. eCollection 2023.

Authors

Cui Wang^{1

2}, Kuan Yang^{1

2

3}, Xiaoqian Liu^{4

5

6}, Si Wang⁷, Moshi Song^{2

5

6

8}, Juan Carlos Izpisua Belmonte⁹, Jing Qu^{2

4

5

6}, Guang-Hui Liu^{2

5

6

7

8}, Weiqi Zhang^{1

2

3

5}

Affiliations

¹ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China.
⁴ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
⁵ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
⁷ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
⁸ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
⁹ Altos Labs, Inc., San Diego, CA 94022, USA.

Abstract

Mitochondrial dysfunction is a hallmark feature of cellular senescence and organ aging. Here, we asked whether the mitochondrial antiviral signaling protein (MAVS), which is essential for driving antiviral response, also regulates human stem cell senescence. To answer this question, we used CRISPR/Cas9-mediated gene editing and directed differentiation techniques to generate various MAVS-knockout human stem cell models. We found that human mesenchymal stem cells (hMSCs) were sensitive to MAVS deficiency, as manifested by accelerated senescence phenotypes. We uncovered that the role of MAVS in maintaining mitochondrial structural integrity and functional homeostasis depends on its interaction with the guanosine triphosphatase optic atrophy type 1 (OPA1). Depletion of MAVS or OPA1 led to the dysfunction of mitochondria and cellular senescence, whereas replenishment of MAVS or OPA1 in MAVS-knockout hMSCs alleviated mitochondrial defects and premature senescence phenotypes. Taken together, our data underscore an uncanonical role of MAVS in safeguarding mitochondrial homeostasis and antagonizing human stem cell senescence.