Sains Malaysiana 55(10)(2026): 1681-1689

http://doi.org/10.17576/jsm-2026-5510-07

 

SLIRP at the Interface of Mitochondrial RNA Homeostasis and Translation

(SLIRP pada Antara Muka Homeostasis dan Translasi RNA Mitokondria)

 

JINGUO CAO^1,#, YINING LI^1,#, XIAOHUI HU^2,# & JIANHONG TANG^1,3,*

 

¹Key Laboratory of Mitochondrial Medicine, Department of Basic Medicine, Gannan Medical University, Ganzhou, China

²Department of Basic Medicine, Gannan Healthcare Vocational College, Ganzhou, China

³Laboratory Animal Engineering Research Center of Ganzhou, Science Research Center, Gannan Medical University, Ganzhou, China

 

Diserahkan: 8 Jun 2026/Diterima: 11 September 2026

 

*Pengarang untuk surat-menyurat; email: tangjianhong@gmu.edu.cn

 

#These authors contributed equally to this work

 

Abstract

Mitochondrial gene expression relies on precise coordination between RNA metabolism and protein synthesis, yet how these processes are functionally coupled remains incompletely understood. Stem-loop interacting RNA-binding protein (SLIRP), a conserved component of the LRPPRC-containing ribonucleoprotein complex, has emerged as a key factor in this process. While initially characterized as a stabilizer of mitochondrial mRNAs, accumulating structural, biochemical, and genetic evidence indicates that SLIRP primarily functions to coordinate mitochondrial translation. Rather than being required for transcript production, SLIRP ensures the efficient and selective utilization of mitochondrial mRNAs by the mito-ribosome, thereby maintaining ordered and productive protein synthesis. Disruption of SLIRP results in selective translational defects, tissue-specific vulnerability, and mitochondrial disease phenotypes, despite the persistence of mitochondrial transcripts. We propose a conceptual framework in which SLIRP acts at the interface between RNA homeostasis and translational output, integrating mitochondrial gene expression across molecular, cellular, and organismal scales.

Keywords: LRPPRC; mitochondria; protein translation; RNA homeostasis; SLIRP

Abstrak

Ekspresi gen mitokondria bergantung pada penyelarasan yang tepat antara metabolisme RNA dan sintesis protein, namun bagaimana kedua-dua proses ini digandingkan secara fungsian masih belum difahami sepenuhnya. Gelung batang yang berinteraksi dengan protein pengikat RNA (SLIRP), iaitu komponen terpelihara dalam kompleks ribonukleoprotein yang mengandungi LRPPRC, telah muncul sebagai faktor utama dalam proses ini. Walaupun pada awalnya dicirikan sebagai penstabil mRNA mitokondria, bukti struktur, biokimia dan genetik yang semakin bertambah menunjukkan bahawa SLIRP berfungsi terutamanya untuk menyelaraskan translasi mitokondria. Berbanding berperanan dalam penghasilan transkrip, SLIRP memastikan penggunaan mRNA mitokondria yang cekap dan selektif oleh mitoribosom, sekali gus mengekalkan sintesis protein yang tersusun dan produktif. Gangguan terhadap SLIRP mengakibatkan kecacatan translasi yang selektif, kerentanan tisu yang khusus dan fenotip penyakit mitokondria, walaupun transkrip mitokondria masih wujud. Kami mencadangkan satu kerangka konseptual bahawa SLIRP bertindak pada antara muka antara homeostasis RNA dan output translasi, dengan mengintegrasikan ekspresi gen mitokondria merentasi skala molekul, sel dan organisma.

Kata kunci: Homeostasis RNA; LRPPRC; mitokondria; SLIRP; translasi protein

 

RUJUKAN

Barkan, A., Rojas, M., Fujii, S., Yap, A., Chong, Y.S., Bond, C.S. & Small, I. 2012. A combinatorial amino acid code for RNA recognition by pentatricopeptide repeat proteins. PLoS Genet. 8: e1002910.

Baughman, J.M., Nilsson, R., Gohil, V.M., Arlow, D.H., Gauhar, Z. & Mootha, V.K. 2009. A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis. PLoS Genet. 5: e1000590.

Borowski, L.S., Dziembowski, A., Hejnowicz, M.S., Stepien, P.P. & Szczesny, R.J. 2013. Human mitochondrial RNA decay mediated by PNPase-hSuv3 complex takes place in distinct foci. Nucleic Acids Res. 41: 1223-1240.

Burd, C.G. & Dreyfuss, G. 1994. Conserved structures and diversity of functions of RNA-binding proteins. Science 265: 615-621.

Cao, J., Zhang, J., Wu, Z., Luan, W., Zhou, Y., Huang, H., Li, L. & Hu, W. 2025. Slirp2 modulates oogenesis via regulating mitochondrial protein translation. J. Mol. Cell Biol. 17(12): mjaf047.

Chujo, T., Ohira, T., Sakaguchi, Y., Goshima, N., Nomura, N., Nagao, A. & Suzuki, T. 2012. LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes polyadenylation in human mitochondria. Nucleic Acids Res. 40: 8033-8047.

Colley, S.M., Iyer, K.R. & Leedman, P.J. 2008. The RNA coregulator SRA, its binding proteins and nuclear receptor signaling activity. IUBMB Life 60: 159-164.

Colley, S.M., Wintle, L., Searles, R., Russell, V., Firman, R.C., Smith, S., Deboer, K., Merriner, D.J., Genevieve, B., Bentel, J.M., Stuckey, B.G.A., Phillips, M.R., Simmons, L.W., de Kretser, D.M., O’Bryan, M.K. & Leedman, P.J. 2013. Loss of the nuclear receptor corepressor SLIRP compromises male fertility. PLoS ONE 8: e70700.

Darfarin, G. & Pluth, J. 2025. Mitochondria-nuclear crosstalk: Orchestrating mtDNA maintenance. Environ. Mol. Mutagen. 66: 222-242.

Dong, Y., Yoshitomi, T., Hu, J-F. & Cui, J. 2017. Long noncoding RNAs coordinate functions between mitochondria and the nucleus. Epigenetics Chromatin 10: 41.

Guo, L., Engelen, B.P.H., Hemel, I.M.G.M., de Coo, I.F.M., Vreeburg, M., Sallevelt, S.C.E.H., Hellebrekers, D.M.E.I., Jacobs, E.H., Sadeghi-Niaraki, F., van Tienen, F.H.J., Smeets, H.J.M. & Gerards, M. 2021. Pathogenic SLIRP variants as a novel cause of autosomal recessive mitochondrial encephalomyopathy with complex I and IV deficiency. Eur. J. Hum. Genet. EJHG 29: 1789-1795.

Hatchell, E.C., Colley, S.M., Beveridge, D.J., Epis, M.R., Stuart, L.M., Giles, K.M., Redfern, A.D., Miles, L.E.C., Barker, A., MacDonald, L.M., Arthur, P.G., Lui, J.C.K., Golding, J.L., McCulloch, R.K., Metcalf, C.B., Wilce, J.A., Wilce, M.C.J., Lanz, R.B., O’Malley, B.W. & Leedman, P.J. 2006. SLIRP, a small SRA binding protein, is a nuclear receptor corepressor. Mol. Cell 22: 657-668.

Ku, D., Yang, Y., Park, Y., Jang, D., Lee, N., Lee, Y-K., Lee, K., Lee, J., Han, Y.B., Jang, S., Choi, S.R., Ha, Y-J., Choi, Y.S., Jeong, W-J., Lee, Y.J., Lee, K.J., Cha, S. & Kim, Y. 2024. SLIRP promotes autoimmune diseases by amplifying antiviral signaling via positive feedback regulation. BioRxiv 2024.03.28.587146.

Lagouge, M., Mourier, A., Lee, H.J., Spåhr, H., Wai, T., Kukat, C., Silva Ramos, E., Motori, E., Busch, J.D., Siira, S., German Mouse Clinic Consortium, Kremmer, E., Filipovska, A. & Larsson, N-G. 2015. SLIRP regulates the rate of mitochondrial protein synthesis and protects LRPPRC from degradation. PLoS Genet. 11: e1005423.

Li, L., Miao, W., Williams, P., Guo, C. & Wang, Y. 2019. SLIRP interacts with helicases to facilitate 2’-O-methylation of rRNA and to promote translation. J. Am. Chem. Soc. 141: 10958-10961.

Maris, C., Dominguez, C. & Allain, F.H.-T. 2005. The RNA recognition motif, a plastic RNA-binding platform to regulate post-transcriptional gene expression. FEBS J. 272: 2118-2131.

McShane, E., Couvillion, M., Ietswaart, R., Prakash, G., Smalec, B.M., Soto, I., Baxter-Koenigs, A.R., Choquet, K. & Churchman, L.S. 2024. A kinetic dichotomy between mitochondrial and nuclear gene expression processes. Mol. Cell. 84: 1541-1555.e11.

Muto, Y. & Yokoyama, S. 2012. Structural insight into RNA recognition motifs: Versatile molecular Lego building blocks for biological systems. WIREs RNA 3(2): 229-246.

Ott, M., Amunts, A. & Brown, A. 2016. Organization and regulation of mitochondrial protein synthesis. Annu. Rev. Biochem. 85: 77-101.

Pham, T.C.P., Raun, S.H., Havula, E., Henriquez-Olguín, C., Rubalcava-Gracia, D., Frank, E., Fritzen, A.M., Jannig, P.R., Andersen, N.R., Kruse, R., Ali, M.S., Irazoki, A., Halling, J.F., Ringholm, S., Needham, E.J., Hansen, S., Lemminger, A.K., Schjerling, P., Petersen, M.H., de Almeida, M.E., Jensen, T.E., Kiens, B., Hostrup, M., Larsen, S., Ørtenblad, N., Højlund, K., Kjær, M., Ruas, J.L., Trifunovic, A., Wojtaszewski, J.F.P., Nielsen, J., Qvortrup, K., Pilegaard, H., Richter, E.A. & Sylow, L. 2024. The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms. Nat. Commun. 15: 9826.

Rorbach, J. & Minczuk, M. 2012. The post-transcriptional life of mammalian mitochondrial RNA. Biochem. J. 444: 357-373.

Rubalcava-Gracia, D., Bubb, K., Levander, F., Burr, S.P., August, A.V., Chinnery, P.F., Koolmeister, C. & Larsson, N.G. 2024. LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation. Nucleic Acids Res. 52: 11266-11282.

Ruzzenente, B., Metodiev, M.D., Wredenberg, A., Bratic, A., Park, C.B., Cámara, Y., Milenkovic, D., Zickermann, V., Wibom, R., Hultenby, K., Erdjument-Bromage, H., Tempst, P., Brandt, U., Stewart, J.B., Gustafsson, C.M. & Larsson, N-G. 2012. LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs. EMBO J. 31: 443-456.

Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E.A. & LSFC Consortium. 2010. LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. Mol. Biol. Cell. 21: 1315-1323.

Shan, D., Arhin, S.K., Zhao, J., Xi, H., Zhang, F., Zhu, C. & Hu, Y. 2020. Effects of SLIRP on sperm motility and oxidative stress. BioMed Res. Int. 2020: 9060356.

Siira, S.J., Spåhr, H., Shearwood, A-M.J., Ruzzenente, B., Larsson, N-G., Rackham, O. & Filipovska, A. 2017. LRPPRC-mediated folding of the mitochondrial transcriptome. Nat. Commun. 8: 1532.

Singh, V., Moran, J.C., Itoh, Y., Soto, I.C., Fontanesi, F., Couvillion, M., Huynen, M.A., Churchman, L.S., Barrientos, A. & Amunts, A. 2024. Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome. Nat. Struct. Mol. Biol. 31: 1838-1847.

Spåhr, H., Rozanska, A., Li, X., Atanassov, I., Lightowlers, R.N., Chrzanowska-Lightowlers, Z.M.A., Rackham, O. & Larsson, N-G. 2016. SLIRP stabilizes LRPPRC via an RRM-PPR protein interface. Nucleic Acids Res. 44: 6868-6882.

Suomalainen, A. & Nunnari, J. 2024. Mitochondria at the crossroads of health and disease. Cell 187: 2601-2627.

Temperley, R.J., Wydro, M., Lightowlers, R.N. & Chrzanowska-Lightowlers, Z.M. 2010. Human mitochondrial mRNAs--like members of all families, similar but different. Biochim. Biophys. Acta 1797: 1081-1085.

Trisciuoglio, D., Desideri, M., Farini, V., De Luca, T., Di Martile, M., Tupone, M.G., Urbani, A., D’Aguanno, S. & Del Bufalo, D. 2016. Affinity purification-mass spectrometry analysis of bcl-2 interactome identified SLIRP as a novel interacting protein. Cell Death Dis. 7: e2090.

Williams, P., Li, L., Dong, X. & Wang, Y. 2017. Identification of SLIRP as a G quadruplex-binding protein. J. Am. Chem. Soc. 139: 12426-12429.

Xu, F., Addis, J.B.L., Cameron, J.M. & Robinson, B.H. 2012. LRPPRC mutation suppresses cytochrome oxidase activity by altering mitochondrial RNA transcript stability in a mouse model. Biochem. J. 441: 275-283.