A new circular RNA–encoded protein BIRC6-236aa inhibits transmissible gastroenteritis virus (TGEV)–induced mitochondrial dysfunction

Transmissible gastroenteritis virus (TGEV), a member of the coronavirus family, is the pathogen responsible for transmissible gastroenteritis, which results in mitochondrial dysfunction in host cells. Previously, we identified 123 differentially expressed circular RNAs (cRNA)from the TGEV-infected porcine intestinal epithelial cell line jejunum 2 (IPEC-J2). Previous bioinformatics analysis suggested that, of these, circBIRC6 had the potential to regulate mitochondrial function. Furthermore, mitochondrial permeability transition, a key step in the process of mitochondrial dysfunction, is known to be caused by abnormal opening of mitochondrial permeability transition pores (mPTPs) regulated by the voltage-dependent anion-selective channel protein 1 (VDAC)–Cyclophilin D (CypD) complex. Therefore, in the present study, we investigated the effects of circBIRC6-2 on mitochondrial dysfunction and opening of mPTPs. We found that TGEV infection reduced circBIRC6-2 levels, which in turn reduced mitochondrial calcium (Ca2+) levels, the decrease of mitochondrial membrane potential, and opening of mPTPs. In addition, we also identified ORFs and internal ribosomal entrance sites within the circBIRC6-2 RNA. We demonstrate circBIRC6-2 encodes a novel protein, BIRC6-236aa, which we show inhibits TGEV-induced opening of mPTPs during TGEV infection. Mechanistically, we identified an interaction between BIRC6-236aa and VDAC1, suggesting that BIRC6-236aa destabilizes the VDAC1–CypD complex. Taken together, the results suggest that the novel protein BIRC6-236aa encoded by cRNA circBIRC6-2 inhibits mPTP opening and subsequent mitochondrial dysfunction by interacting with VDAC1. Transmissible gastroenteritis virus (TGEV), a member of the coronavirus family, is the pathogen responsible for transmissible gastroenteritis, which results in mitochondrial dysfunction in host cells. Previously, we identified 123 differentially expressed circular RNAs (cRNA)from the TGEV-infected porcine intestinal epithelial cell line jejunum 2 (IPEC-J2). Previous bioinformatics analysis suggested that, of these, circBIRC6 had the potential to regulate mitochondrial function. Furthermore, mitochondrial permeability transition, a key step in the process of mitochondrial dysfunction, is known to be caused by abnormal opening of mitochondrial permeability transition pores (mPTPs) regulated by the voltage-dependent anion-selective channel protein 1 (VDAC)–Cyclophilin D (CypD) complex. Therefore, in the present study, we investigated the effects of circBIRC6-2 on mitochondrial dysfunction and opening of mPTPs. We found that TGEV infection reduced circBIRC6-2 levels, which in turn reduced mitochondrial calcium (Ca2+) levels, the decrease of mitochondrial membrane potential, and opening of mPTPs. In addition, we also identified ORFs and internal ribosomal entrance sites within the circBIRC6-2 RNA. We demonstrate circBIRC6-2 encodes a novel protein, BIRC6-236aa, which we show inhibits TGEV-induced opening of mPTPs during TGEV infection. Mechanistically, we identified an interaction between BIRC6-236aa and VDAC1, suggesting that BIRC6-236aa destabilizes the VDAC1–CypD complex. Taken together, the results suggest that the novel protein BIRC6-236aa encoded by cRNA circBIRC6-2 inhibits mPTP opening and subsequent mitochondrial dysfunction by interacting with VDAC1. The mitochondrion, an organelle of eukaryotic cells, plays a pivotal role in maintaining normal cellular function (1Anzell A.R. Maizy R. Przyklenk K. Sanderson T.H. Mitochondrial Quality control and disease: insights into ischemia-reperfusion injury.Mol. Neurobiol. 2018; 55: 2547-2564Crossref PubMed Scopus (265) Google Scholar). Mitochondria are sensitive to various stimuli, including viral infection, leading to potential dysfunction. Dysfunctional mitochondria release signals that induce cell death. Mitochondrial permeability transition pores (mPTPs) are located on the inner mitochondrial membrane (IMM). Normally these pores are closed; prolonged opening of mPTPs results in apoptosis and cell death (2Xu T. Ding W. Ao X. Chu X.M. Wan Q.G. Wang Y. et al.ARC regulates programmed necrosis and myocardial ischemia/reperfusion injury through the inhibition of mPTP opening.Redox Biol. 2019; 20: 414-426Crossref PubMed Scopus (83) Google Scholar, 3Zorov D.B. Juhaszova M. Sollott S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.Physiol. Rev. 2014; 94: 909-950Crossref PubMed Scopus (3155) Google Scholar). Persistent opening of mPTPs can occur in response to virus infections or to oxidative or chemical-induced stress (4Mehrbod P. Ande S.R. Alizadeh J. Rahimizadeh S. Shariati A. 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Therefore, we that circBIRC6-2 the potential to regulate mitochondrial function. we demonstrate that TGEV the of mitochondrial permeability transition to circBIRC6-2 encodes a protein BIRC6-236aa that is located the of the mitochondria including In addition, BIRC6-236aa a on mPTP opening by interacting with VDAC1. TGEV infection mitochondrial dysfunction (12Zhao X. Ma X. Guo J. Mi M. Wang K. Zhang C. et al.Circular RNA CircEZH2 suppresses transmissible gastroenteritis coronavirus-induced opening of mitochondrial permeability transition pore via targeting MiR-22 in IPEC-J2.Int. J. Biol. Sci. 2019; 15: 2051-2064Crossref PubMed Scopus (23) Google Scholar, 13Zhu L. Mou C. Yang X. Lin J. Yang Q. Mitophagy in TGEV infection counteracts oxidative stress and apoptosis.Oncotarget. 2016; 7: 27122-27141Crossref PubMed Scopus (68) Google Scholar). we in the mitochondria of the intestinal epithelial cell line jejunum 2 infection with TGEV that the mitochondria in had and of swelling and rupture of the mitochondrial membrane TGEV in TGEV-infected show that mitochondrial mitochondrial dysfunction and cell death J. P. and mitochondrial damage in R. Biol. Sci. 2016; PubMed Scopus Google Scholar). Therefore, we mitochondrial to mitochondrial mitochondrial of with and of with of of mitochondria that are with mitochondrial that is with The results that mitochondrial by TGEV and of mitochondrial membrane potential mitochondrial the of TGEV infection, with an in by a for the of which to with a formation of of mitochondrial is by a decrease in the the of and is with is an of is as the We an in the of and a decrease in the of suggesting a decrease in the TGEV infection reduced the signal suggesting that TGEV the leading to mitochondrial in cells. we a to opening of mPTPs. The of the as by TGEV infection and suggesting that TGEV opening of leading to mitochondrial In to the of on we the of to cell The results that on cell We also the of TGEV-induced mPTP opening on cell and the results that TGEV-induced mPTP opening reduced cell Previously, we that is TGEV infection (12Zhao X. Ma X. Guo J. Mi M. Wang K. Zhang C. et al.Circular RNA CircEZH2 suppresses transmissible gastroenteritis coronavirus-induced opening of mitochondrial permeability transition pore via targeting MiR-22 in IPEC-J2.Int. J. Biol. Sci. 2019; 15: 2051-2064Crossref PubMed Scopus (23) Google Scholar, X. X. Zhang Guo J. L. 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PubMed Scopus Google K. H. T. a for internal in mitochondrial Chem. 2021; PubMed Scopus Google and The results show that BIRC6-236aa a potential for targeting mitochondria We the of BIRC6-236aa, including signal and The of BIRC6-236aa protein the E. A. J.C. et al.Protein and analysis in the Mol. Biol. Google Scholar). The results that the BIRC6-236aa protein is of with the molecular of and and with a of The is BIRC6-236aa is and and signal with 1 to as signal The function of BIRC6-236aa protein that BIRC6-236aa protein function is with a of signal and to the and of The protein results that and The results of that the of BIRC6-236aa protein had with which with the results of we investigated the effects of BIRC6-236aa on mitochondrial and mPTPs. to mitochondrial Mitochondrial in and cells, as by than in control the in and cells, as by the results to The by of in and with TGEV infection and that BIRC6-236aa inhibits the decrease in by In addition, the of the as by in and and as cell Mitochondrial opening of mPTP and cell between and control cells. Taken together, these suggest that BIRC6-236aa inhibits mPTP with TGEV for by to that with BIRC6-236aa in and potential the of the we identified with BIRC6-236aa and analysis of and analysis and analysis that located in the in mitochondria to process as and and and The results suggest that BIRC6-236aa plays a role in mPTP opening by interacting with host VDAC1 and member channel during mPTP opening E. A. R. VDAC1, mitochondrial dysfunction, and Res. 2018; PubMed Scopus Google and the potential to with we an with The results that with VDAC1 and and the interaction with VDAC1 and in cells, and the interaction between by and we a to R. S. on and to demonstrate 2017; PubMed Google Scholar). and as in the signal in with suggesting that BIRC6-236aa interacts with VDAC1. Taken together, the suggest that BIRC6-236aa interacts with VDAC1 to a in cells. VDAC1, and 1 is essential for mPTP opening (16Bernardi P. Rasola A. Forte M. Lippe G. The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology.Physiol. Rev. 2015; 95: 1111-1155Crossref PubMed Scopus (476) Google Scholar). BIRC6-236aa interacts with VDAC1, we the of BIRC6-236aa on the formation of complex. an that VDAC1, and a the signal in the of BIRC6-236aa, that of BIRC6-236aa the interaction between VDAC1 and that BIRC6-236aa the interaction between VDAC1 and that between VDAC1 and The interaction between VDAC1 and by of circBIRC6-2 and by inhibition of circBIRC6-2 D and these show that circBIRC6-2 encodes a protein, BIRC6-236aa, that destabilizes the interaction between VDAC1 and mPTP opening Previously, we that TGEV cell death via and L. X. Huang Y. Zhang K. G. et gastroenteritis virus infection apoptosis through and PubMed Scopus Google Scholar). The a pore in the is to be a key to mitochondrial damage and cell death. Previously, we that of circBIRC6-2 is reduced by TGEV we that circBIRC6-2 plays a role in TGEV-induced mitochondrial damage by regulating mPTPs. The demonstrate that circBIRC6-2 inhibits TGEV-induced opening of mPTPs. In study, TGEV can induce mPTP that mPTP opening to cell death, which can cell Y. J. Yang M. L. H. Wang Q. et of mitochondrial permeability transition pore opening caused by leading to in Biol. Med. 2021; PubMed Scopus Google Scholar, N. A. J. S.J. et of oxidative on the mitochondrial permeability transition pore and necrosis in a of 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). we found that TGEV mPTP opening and cell suggesting that mPTP opening cell in the In addition, BIRC6-236aa the cell by mPTP TGEV-induced mPTP opening to cell necrosis and the between TGEV-induced necrosis and cell to be by are a of circular RNA that various and by as to and A. roles and function of circular RNAs in eukaryotic Mol. Sci. 2018; PubMed Scopus Google Scholar, S. M. T. 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The interaction between VDAC1 and is for formation of the for mPTP In study, we found that circBIRC6-2 plays a role in regulating mPTP opening by we that BIRC6-236aa interacts with the complex. we found that BIRC6-236aa interacts with VDAC1 and the interaction between and VDAC1 to opening of that BIRC6-236aa and VDAC1 for is a pathogenic mechanism underlying mPTP In we that circBIRC6-2 encodes a protein, BIRC6-236aa, that suppresses TGEV-induced mPTP opening by with for to VDAC1 suggest that TGEV-induced mPTP opening is a novel potential to TGEV-induced cell death. and Cell The The The and The and and the and The The and and and The cell line a in with and The TGEV TGEV-infected L. and of porcine transmissible gastroenteritis virus and analysis of its J. Med. 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F. N. S. et of and in the PubMed Scopus Google Scholar, L. P. P. G. et for the of to the Mol. Med. 2021; PubMed Scopus Google Scholar). The of by the in the well that is the of the with the of mPTP Cell into well of the of to which 1 the a of by a RNA and and into in a and of by to and the of and the PubMed Scopus Google Scholar). The of the for are in The circBIRC6-2 into to the of J. J. 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M. by and Cell 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). by by The protein and with a and The into and The on a and a The to a by a in line with the in the a of and for as in the a of that between by to the a ion of in the with The control to of the ion to the the to as the and into for of the ion and of ion the in for the a by with a and the protein of The as The of to The for to and that for to on as a as on the protein as a for and sites to the the and the identified to The of the of as the in protein to the of the in protein BIRC6-236aa in cells. in as and on a for in and with an for 1 by a protein for for with and by for in and with for in in for with in with an for with for with to a and a as with and with for a The as R. S. on and to demonstrate 2017; PubMed Google Scholar). or into cells. for with 1 TGEV and with for with for with a of and by an and to and with a to and The with of the TGEV with of TGEV of and the for RNA. in with the of the of with the on of by the of and and had the of are as the of an of as and as and to and of BIRC6-236aa to the via the Y. A. J.W. M. S. et al.The and and in for Res. 2019; PubMed Scopus Google the The that of with the of We for the cell of and for with for with and Wang and for with and by the of and X. J. and T. J. G. X. X. and J. L. X. J. X. and J. L. X. and T. X. J. and L. T. C. X. and with 1 with 2 with 1 with 2 with with with