NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.

Jian Lv, Junmei Wang, Qin Chen, Qianhua Zhong, Hongchao Zhan, Qiuxiao Guo, Jiajie Li, Ningning Guo, Yu Fang, Jingjing Tong, Zhihua Wang

Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Shenzhen Hospital, Chinese Academy of Medical Sciences, Shenzhen 518057, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Shenzhen Hospital, Chinese Academy of Medical Sciences, Shenzhen 518057, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. · pubmed

Paper

Abstract

Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a Nipsnap1/2 double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of Nipsnap1/2 impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, Nipsnap1/2 depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.

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Research summary

The paper claims that NIPSNAP1 and NIPSNAP2 play an anti-aging role by maintaining mitochondrial health independent of mitophagy. This research addresses the underlying mechanisms of aging by exploring mitochondrial dysfunction, which is a key factor in the aging process and age-related diseases.

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