Rtn4ip1, also known as optic atrophy-10 (OPA10), is a mitochondrial NAD(P)H oxidoreductase. It plays a crucial role in coenzyme Q (CoQ) biosynthesis by regulating the O-methylation activity of COQ3, an essential process for maintaining mitochondrial respiration activity in muscle tissue [1].

Rtn4ip1-knockout myoblasts had markedly decreased CoQ9 levels and impaired cellular respiration [1]. Muscle-specific knockdown of dRtn4ip1 in flies resulted in impaired muscle function, which was reversed by dietary supplementation with soluble CoQ [1]. In esophageal squamous cell carcinoma (ESCC), RTN4IP1 depletion impairs cell proliferation, induces apoptosis, abrogates amino acid uptake, and induces amino acid starvation via downregulation of amino acid transporters, demonstrating its role in ESCC carcinogenesis and progression [2]. In breast cancer, high RTN4IP1 expression is associated with poor prognosis, and it is linked to glutamine metabolism, mitoribosome-associated quality control, and immune cell infiltration [3]. Biallelic variants in RTN4IP1 cause syndromic and non-syndromic early-onset autosomal recessive optic neuropathy, often accompanied by rod-cone dystrophy [4]. In thyroid cancer, RTN4IP1 is down-regulated and has a tumor-suppressive function as its knockdown increases cellular proliferation, invasion, migration, and colony formation [5].

In conclusion, Rtn4ip1 is essential for CoQ synthesis and mitochondrial respiration in muscle. Its study through gene knockout and knockdown models has revealed its significant roles in various diseases such as muscle-related disorders, ESCC, breast cancer, optic neuropathies, and thyroid cancer, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Park, Isaac, Kim, Kwang-Eun, Kim, Jeesoo, Suh, Jae Myoung, Rhee, Hyun-Woo. 2023. Mitochondrial matrix RTN4IP1/OPA10 is an oxidoreductase for coenzyme Q synthesis. In Nature chemical biology, 20, 221-233. doi:10.1038/s41589-023-01452-w. https://pubmed.ncbi.nlm.nih.gov/37884807/

2. Wei, Huifang, Zhao, Dengyun, Zhi, Yafei, Dong, Zigang, Liu, Kangdong. 2025. RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12, e2406220. doi:10.1002/advs.202406220. https://pubmed.ncbi.nlm.nih.gov/39757767/

3. Wang, Xiu, Li, Xinyu, Jiang, Wenying. 2023. High expression of RTN4IP1 predicts adverse prognosis for patients with breast cancer. In Translational cancer research, 12, 859-872. doi:10.21037/tcr-22-2350. https://pubmed.ncbi.nlm.nih.gov/37180657/

4. Gupta, Priya R, O'Connell, Kaitlin, Sullivan, Jack M, Huckfeldt, Rachel M. 2024. RTN4IP1-associated non-syndromic optic neuropathy and rod-cone dystrophy. In Ophthalmic genetics, 45, 289-293. doi:10.1080/13816810.2024.2303683. https://pubmed.ncbi.nlm.nih.gov/38224077/

5. Rahbari, Reza, Kitano, Mio, Zhang, Lisa, Bommareddi, Swaroop, Kebebew, Electron. 2013. RTN4IP1 is down-regulated in thyroid cancer and has tumor-suppressive function. In The Journal of clinical endocrinology and metabolism, 98, E446-54. doi:10.1210/jc.2012-3180. https://pubmed.ncbi.nlm.nih.gov/23393170/