DICAR-JP Regulates Ribosome Migration, a New Theory of Mitochondrial Protein Production

BackgroundDICAR plays a cardioprotection of diabetic models. DICAR-JP, a short sequence of DICAR, may represent DICAR’s active functional domain. NACα is necessary for the heart tissue development. Addtionally, OGDHL is a metabolism regulator. In this study, we examine a new mechanism of DICAR via NACα/OGDHL on regulating cardiomyocyte metabolism in DCM. We also sought to elucidate the function of DICAR/DICAR-JP in modulating NACα-dependent production of OGDHL nascent peptides and their mitochondrial translocation, and we also aimed to optimize the DICAR-JP sequence to be better therapy on DCM.MethodsSPR was to investigate the binding interaction between DICAR-JP and NACα. The function of DICAR-JP and DICAR-JP45 on OGDHL nascent peptide transfection was detected by in vitro translation approach. Biotin-DICAR-JP was transfected to study the function of DICAR-JP, NACα and OGDHL. Untargeted metabolomics was utilized to characterize the metabolic reprogramming of cardiomyocytes. AAV9-DICAR-JP and DICAR-JP45 were constructed and administered to db/db mice for 1-2 months to assess their cardioprotective effects detected by Echocardiography confirmed mouse cardiac function.ResultsOur findings demonstrated that DICAR-JP be the functional domain that interacts with NACα to regulate OGDHL nascent peptide expression. Disruption of OGDHL expression reversed the metabolic reprogramming observed in diabetic cardiomyocytes, highlighting its crucial role in maintaining cardiac metabolic homeostasis. DICAR-JP facilitated the translocation of OGDHL nascent peptides from the cytoplasm to the mitochondria, leading us to hypothesize that DICAR-JP plays a key role in regulating ribosomal migration from the endoplasmic reticulum to the mitochondria. We refer to this process as the ‘Ribosome Migration’. In our studies using AAV9-mediated DICAR-JP and DICAR-JP45 overexpression in heart tissue. DICAR-JP and DICAR-JP45 both exhibited significant cardioprotective effects against diabetic cardiomyopathy (DCM), comparable to those observed with Empagliflozin.ConclusionsIn a conclusion, we propose a new endogenous nucleic acid candidate drug library, and a new molecular framework, the ‘Ribosome Migration’, which implicates the DICAR-JP/NACα/OGDHL nascent peptide axis in metabolic reprogramming related to DCM. This theory constructs a new mitochondrion protein from nuclear original protein. Moreover, DICAR-JP45 shows strong potential as a nucleic acid-based therapeutic candidate for treating DCM.Novelty and SignificanceWhat Is Known?DICAR is a new protective circular noncoding RNA for diabetic cardiomyopathy. NACα is located in ribosome and regulates new peptide production, which is also a key factor in heart tissue development.OGDHL can regulate different energy metabolism in mitochondria.What New Information Does This Article Contribute?DICAR-JP is the functional domain that interacts with NACα to regulate OGDHL nascent peptide expression.There is an interaction between DICAR-JP and NACα. DICAR-JP sequence is protected by NACα and NACα function is mediated by DICAR-JP. We called this ‘RNA functional domain’.OGDHL expression reversed the metabolic reprogramming observed in diabetic cardiomyocytes, highlighting its crucial role in maintaining cardiac metabolic homeostasis.DICAR-JP takes part in tanscription and translocation of OGDHL nascent peptides from the cytoplasm to the mitochondria via plasma ribosome. We call this process the ‘Ribosome Migration Theory’.DICAR-JP and DICAR-JP45 both exhibited significant cardioprotective effects against diabetic cardiomyopathy (DCM), comparable to those observed with Dapagliflozin (DAPA).Our study revealed a novel molecular framework, the ‘Ribosome Migration Theory’, which implicates the DICAR-JP/NACα/OGDHL nascent peptide axis in metabolic reprogramming related to DCM. Moreover, DICAR-JP45 shows strong potential as a nucleic acid-based therapeutic candidate for treating DCM.