MicroRNA 29 modulates β-cell mitochondrial metabolism and insulin secretion via underlying miR-29-OXPHOS complex pathways
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MicroRNAs (miRNAs) regulate β-cell function, and β-cell mitochondria and insulin secretion are perturbed in diabetes. We aimed to identify key miRNAs regulating β-cell mitochondrial metabolism and novel β-cell miRNA-mitochondrial pathways.
Methods
TargetScan (http://www.targetscan.org/) was used to predict if 16 miRNAs implicated in β-cell function target 27 cis-eGenes implicated in mitochondrial activity. The expression of candidate miRNAs and insulin secretion after 24 and 1 h pre-incubation in 2.8, 11.1- and 16.7-mM glucose was measured in clonal INS-1 832/13 β-cells. MiR-29 silenced INS-1 832/13 cells were assessed for insulin secretion (glucose, pyruvate, and K+), target cis-eGene expression (Ndufv3 and Ndufa10 components of mitochondrial complex I (CI)), OXPHOS (CI-V) protein expression, and mitochondrial OXPHOS respiration/activity. The expression of differentially expressed miR-29 miRNAs was evaluated in Goto-Kakizaki (GK) rat, db/db mouse and type 2 diabetic (T2D) human islets, as well as NMRI mouse islets cultured under glucolipotoxic conditions.
Results
MiR-29, miR-15 and miR-124 were predicted to regulate ~20 cis-eGenes, while miR-29 alone was predicted to regulate ≥12 of these in rat and human species. MiR-29 expression and insulin secretion were reduced in INS-1 832/13 cells after 24 h in elevated glucose. MiR-29 knockdown increased all tested insulin secretory responses, Nudfv3, Ndufa10, complex I and II expression, and cellular mitochondrial OXPHOS. MiR-29 expression was reduced in db/db islets but increased in GK rat and T2D human islets.
Conclusion
We conclude miR-29 is a key miRNA in regulating β-cell mitochondrial metabolism and insulin secretion via underlying miR-29-OXPHOS complex pathways. Furthermore, we infer reduced miR-29 expression compensatorily enhances insulin secretion under glucotoxicity.
Originalsprog | Engelsk |
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Artikelnummer | e14180 |
Tidsskrift | Acta Physiologica |
Vol/bind | 240 |
Udgave nummer | 8 |
Antal sider | 17 |
ISSN | 1748-1708 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
The work was supported by a grant from the Swedish Foundation for Strategic Research (IRC\u2010LUDC; DnrIRC15\u20100067) and the Swedish Research Council through an SRA grant SFO\u2010EXODIAB (Dnr2009\u20101039). Furthermore, L.E. was supported by project grants from the Swedish Research Council (Dnr 2019\u201001406), Region Sk\u00E5ne\u2010ALF (ALFSKANE\u2010450661) and the Swedish Diabetes Foundation (DIA2019\u2010454 and DIA2022\u2010723) and E.C. was supported by the Nilsson\u2010Ehle Endowments award from the Royal Physiographic Society of Lund. E.F. PhD\u2010student position was supported by CF\u2010Trust (SRC CFRD\u2010019) Some images from https://smart.servier.com/ were used to produce the Graphical abstract.
Publisher Copyright:
© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.
ID: 394479886