NIPSNAP protein family emerges as a sensor of mitochondrial health

Abstract

Since their discovery over two decades ago, the molecular and cellular functions of the NIPSNAP family of proteins (NIPSNAPs) have remained elusive until recently. NIP-SNAPs interact with a variety of mitochondrial and cytoplasmic proteins. They have been implicated in multiple cellular processes and associated with different physiologic and pathologic conditions, including pain transmission, Parkinson's disease, and cancer. Recent evidence demonstrated a direct role for NIPSNAP1 and NIPSNAP2 proteins in regulation of mitophagy, a process that is critical for cellular health and maintenance. Importantly, NIPSNAPs contain a 110 amino acid domain that is evolutionary conserved from mammals to bacteria. However, the molecular function of the conserved NIPSNAP domain and its potential role in mitophagy have not been explored.It stands to reason that the highly conserved NIPSNAP domain interacts with a substrate that is ubiquitously present across all species and can perhaps act as a sensor for mitochondrial health.

Nipsnap1—A Regulatory Factor Required For Long-Term Maintenance of Non-Shivering Thermogenesis

“…Nipsnap1 protein induction was then verified by western blot, confirming a significant increase in mice exposed to chronic cold conditions similar to UCP1—the classical marker of thermogenic activation, indicating that the Nipsnap1 expression pattern strongly correlates with other thermogenic proteins (Figure 1E and 1F). The thermogenic properties were specific to only BAT, as there was no increase in inguinal white adipose tissue (iWAT) or in other tissues such as the brain and liver that are reported to have high expression of Nipsnap1 (Fathi, Yarbro and Homayouni, 2021) (Figure S1A-D). Moreover, there was also no increase in Nipsnap2, which shares strong homology with Nipsnap1 (Figure S1E).…”

“…Nipsnap1 is an evolutionarily conserved protein from fly to humans that is expressed predominantly in highly energetic tissues such as the brain and liver (Seroussi et al ., 1998; Satoh et al ., 2002; Nautiyal et al ., 2010; Tummala, Li and Homayouni, 2010; Morgenstern et al ., 2021). It possesses an N-terminal mitochondrial targeting sequence (MTS) that directs it to the mitochondrial matrix, and previous studies have determined that Nipsnap1 plays a critical role in mitophagy where it functions as a sensor of mitochondrial health and recruits autophagy proteins when mitochondria become damaged (Abudu et al ., 2019; Fathi, Yarbro and Homayouni, 2021). Other reported functions include its role in pyruvate and branched chain amino acid metabolism (Manisha Nautiyal et al ., 2008; Ghoshal, Jones and Homayouni, 2014), pain transmission signaling, neurological disorders, carcinogenesis, and the immune response (Okuda-Ashitaka et al ., 2012; Yamamoto et al ., 2017).…”

Genomic, transcriptomic, and metabolomic analysis of Oldenlandia corymbosa reveals the biosynthesis and mode of action of anti‐cancer metabolites

“…In addition, it might interact with BRCA1 (Hill et al, 2014) and BRCA2 (Malik et al, 2016). The third protein, NIPSNAP homolog 1, is involved in removal of damaged mitochondria and was shown to be upregulated upon treatment with anti‐tumor drugs (Khaghanzadeh et al, 2016; Abudu et al, 2019; Fathi et al, 2021).…”

Genomic, transcriptomic, and metabolomic analysis of Traditional Chinese Medicine plantOldenlandia corymbosareveals the biosynthesis and mode of action of anti-cancer metabolites

“…In addition, it might interact with BRCA1 90 and BRCA2 91 . The third protein, NIPSNAP homolog 1, is involved in removal of damaged mitochondria and was shown to be upregulated upon treatment with anti-tumor drugs [92][93][94] .…”