DICAR-JP regulates ribosome migration, a new theory of mitochondrial protein production

DICAR, a circular RNA, is known to play a cardioprotective role in diabetic cardiomyopathy (DCM). DICAR-JP is a short fragment of DICAR that represents its active functional domain. We showed that DICAR and DICAR-JP interact with nascent polypeptide–associated complex alpha subunit (NACα) to regulate the expression of the nascent peptide of oxoglutarate dehydrogenase L (OGDHL). Disruption of OGDHL expression reverses the metabolic reprogramming observed in diabetic cardiomyocytes. DICAR-JP facilitates the translocation of nascent OGDHL peptides from the cytoplasm to the mitochondria and plays a key role in regulating the migration of ribosomes from the endoplasmic reticulum to the mitochondria. This mechanism, which we term “ribosome migration,” represents a novel conceptual framework. We also optimized the DICAR-JP RNA sequence and found that DICAR-JP45 exhibits significant cardioprotective effects against heart remodeling in DCM, comparable in efficacy to empagliflozin, a clinically approved inhibitor of sodium–glucose co-transporter-2. In conclusion, we propose a new drug library of endogenous nucleic acids and a new molecular framework, “ribosome migration”, which implicates the DICAR-JP/NAC?/OGDHL nascent peptide axis in metabolic reprogramming associated with DCM. Moreover, DICAR-JP45 shows strong potential as a nucleic acid–based therapeutic candidate for treating DCM.

Dr. Qiong Yuan is a professor of pharmacology, and specialize in cardiovascular pharmacology. She holds a PhD in Pharmacology from Central South University. Dr. Yuan has worked in Wuhan University of Science and Technology and Southwest Medical University on cardiovascular diseases and has published extensively on diabetic cardiomyopathy. She been engaged in the research on the pathogenesis of cardiovascular and cerebrovascular complications in diabetes.