Jacovetti 2024 Mol Metab

Jacovetti C, Donnelly C, Menoud V, Suleiman M, Cosentino C, Sobel J, Wu K, Bouzakri K, Marchetti P, Guay C, Kayser B, Regazzi R (2024) The mitochondrial tRNA-derived fragment, mt-tRF-LeuTAA, couples mitochondrial metabolism to insulin secretion. Mol Metab 84:101955. https://doi.org/10.1016/j.molmet.2024.101955

» PMID: 38704026 Open Access

Jacovetti Cecile, Donnelly Chris, Menoud Veronique, Suleiman Mara, Cosentino Cristina, Sobel Jonathan, Wu Kejing, Bouzakri Karim, Marchetti Piero, Guay Claudiane, Kayser Bengt, Regazzi Romano (2024) Mol Metab

Abstract: The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-Leu^TAA) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-Leu^TAA, on mitochondrial metabolism and pancreatic islet functions.

We used antisense oligonucleotides to reduce mt-tRF-Leu^TAA levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-Leu^TAA inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-Leu^TAA silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays.

Our study unveils a modulation of mt-tRF-Leu^TAA levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-Leu^TAA interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-Leu^TAA in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-Leu^TAA impairs insulin secretion of rat and human pancreatic ß-cells.

Our findings indicate that mt-tRF-Leu^TAA interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion. • Keywords: Insulin secretion, Mitochondrial OXPHOS, Mitochondrial tRNA-derived fragments • Bioblast editor: Plangger M • O2k-Network Lab: CH Lausanne Place N

Labels: MiParea: Respiration, mtDNA;mt-genetics  Pathology: Diabetes 

Organism: Rat  Tissue;cell: Islet cell;pancreas;thymus  Preparation: Permeabilized cells 

Regulation: mt-Membrane potential  Coupling state: LEAK, OXPHOS  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k 

2024-05