Nipsnap1, also known as 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1, is a protein involved in multiple biological processes. It localizes to the mitochondrial matrix and is associated with pathways like non-shivering thermogenesis, mitophagy, and cellular senescence regulation, which are crucial for maintaining normal cellular and organismal functions [1,3,4]. Gene knockout mouse models have been valuable in studying its functions.

In Nipsnap1 knockout (N1-KO) mice, they are unable to sustain activated energy expenditure and have lower body temperature during extended cold challenges, indicating its role in long-term thermogenic maintenance in brown adipose tissue (BAT) [1]. Mechanistically, Nipsnap1 integrates with lipid metabolism, and its BAT-specific ablation leads to beta-oxidation capacity defects [1]. In cancer cells, Nipsnap1 promotes proliferation and inhibits P27-dependent senescence through dual mechanisms: maintaining c-Myc levels and modulating ROS levels [2]. In liver fibrosis models, SIRT3 regulates mitophagy by deacetylating Nipsnap1, and its overexpression improves mitophagy and attenuates extracellular matrix production [3]. Zebrafish lacking functional Nipsnap1 display reduced mitophagy in the brain and parkinsonian phenotypes [4]. In addition, Nipsnap1-deficient mice show exacerbated inflammatory pain, suggesting its role in pain regulation [5].

In summary, Nipsnap1 is essential for maintaining long-term non-shivering thermogenesis in BAT, regulating cellular senescence in cancer cells, modulating mitophagy in liver fibrosis, and influencing pain perception. Studies using Nipsnap1 KO mouse models and other loss-of-function experiments have significantly advanced our understanding of its functions in these disease-related biological processes.