NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental Pub Date : 2025-06-13 DOI:10.1016/j.metabol.2025.156324

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

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引用次数: 0

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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NIPSNAP1和NIPSNAP2促进独立于线粒体自噬的健康衰老。

线粒体功能障碍是衰老的标志，并与衰老相关疾病有关。NIPSNAP1和NIPSNAP2是参与线粒体质量控制的功能冗余同源物，但它们在健康衰老和长寿中的作用尚不清楚。在这里，我们产生了Nipsnap1/2双敲除（DKO）小鼠系，并研究了其对线粒体生理和自然衰老的影响。我们证明Nipsnap1/2的缺失损害了线粒体功能并增强了糖酵解活性，但它不影响线粒体自噬，尽管Parkin显著积累。与野生型小鼠相比，DKO小鼠在24 月龄时表现出体重减轻、肌肉力量恶化和明显的脆弱性。此外，Nipsnap1/2缺失加剧了心脏、肝脏和肾脏中与衰老相关的纤维化和炎症。RNA-seq揭示了DKO小鼠的促衰老转录组重编程，最终导致恶病质样的不良代谢重塑。我们的研究结果通过监测线粒体健康证明了NIPSNAP1/2的抗衰老作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Metabolism: clinical and experimental 医学-内分泌学与代谢

CiteScore

18.90

自引率

3.10%

发文量

310

审稿时长

16 days

期刊介绍： Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism