长链非编码RNA（lncRNA）编码的人类微蛋白已经日益被发现，但这些新兴蛋白的完整功能特征分散在各处。在这里，我们展示了LINC00493编码的SMIM26，一种位于线粒体中的未研究微蛋白，趋势性地在透明细胞肾癌（ccRCC）中下调，并与较差的总生存相关。RNA结合蛋白PABPC4识别LINC00493，并将其转移到核糖体上翻译成一个95个氨基酸的蛋白质SMIM26。SMIM26抑制ccRCC的生长和转移性肺结节，但LINC00493则不会，通过其N-末端与酰基甘油激酶（AGK）和谷胱甘肽转运调节蛋白SLC25A11相互作用。这种相互作用增加了AGK的线粒体定位并随后抑制AGK介导的AKT磷酸化。此外，SMIM26-AGK-SCL25A11复合物的形成维持了线粒体谷胱甘肽的入口和呼吸效率，但被AGK过表达或SLC25A11敲除所废除。本研究对LINC00493编码的微蛋白SMIM26进行了功能特征化，建立了其在ccRCC抗转移中的作用，从而阐明了人类癌症中隐藏蛋白质的重要性。© 2023 作者。

Human microproteins encoded by long non-coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493-encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA-binding protein PABPC4 and transferred to ribosomes for translation of a 95-amino-acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N-terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK-mediated AKT phosphorylation. Moreover, the formation of the SMIM26-AGK-SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493-encoded microprotein SMIM26 and establishes its anti-metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers.© 2023 The Authors.