Circulating B Cell‐Derived Small RNA Delivered by Extracellular Vesicles: A Dialogue Mechanism for Long‐Range Targeted Renal Mitochondrial Injury in Obesity

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2024-10, Vol.20 (43), p.e2402526-n/a
• Main Authors: Li, Xiaqing, Yang, Wah, Ma, Ke, Zheng, Zirun, Liu, Xiayun, Hu, Bo, Liu, Huanhuan, Zhao, Qian, Han, Yi, Xiao, Zhangzhang, Chen, Ruichang, Li, Hongyue, Huang, Sibo, Liu, Jinfeng, Wang, Cunchuan, Yin, Lianghong, Meng, Yu
• Format: Article
• Language: English
• Subjects: Animals; B cells; B-Lymphocytes - metabolism; Circulation; Extracellular vesicles; Extracellular Vesicles - metabolism; Gene expression; Humans; Immune system; Injuries; Injury analysis; Kidney - metabolism; Kidney - pathology; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Mitochondria - metabolism; mitochondrial injury; Obesity; Obesity - metabolism; Organs; renal tubular injury; Ribonucleic acid; RNA; Transfer RNA; Vesicles
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.202402526

The intricate processes that govern the interactions between peripatetic immune cells and distal renal injury in obesity are not fully understood. Employing transcriptomic analysis of circulating extracellular vesicles (EVs), a marked amplification of small RNA (miR‐3960) is discerned within CD3−CD19+ B cells. This RNA is found to be preferentially augmented in kidney tissues, contrasting with its subdued expression in other organs. By synthesizing dual‐luciferase reporter assay with co‐immunoprecipitation analysis, it is pinpointed that miR‐3960 specifically targets the nuclear gene TRMT5, a pivotal actor in the methylation of mitochondrial tRNA. This liaison instigates aberrations in the post‐transcriptional modifications of mitochondrial tRNA, engendering deficiencies within the electron respiratory chain, primarily attributable to the diminution of the mitochondrial bioenergetic compound (NDUFA7) complex I. Such perturbations lead to a compromised mitochondrial respiratory capacity in renal tubular cells, thereby exacerbating tubular injury. In contrast, EV blockade or miR‐3960 depletion markedly alleviates renal tubular injury in obesity. This investigation unveils a hitherto unexplored pathway by which obesity‐induced circulating immune cells remotely manipulate mitochondrial metabolism in target organs. The strategic targeting of obese EVs or infiltrative immune cells and their specifically secreted RNAs emerges as a promising therapeutic avenue to forestall obesity‐related renal afflictions. Unraveling the novel mechanisms will address the pressing demand of identifying promising therapeutic avenue for obesity‐related kidney disease. Compared with lean subjects, CD3−CD19+ B cell‐derived miR‐3960 transported by plasma EVs in patients with obesity serve as a circulating pathogenic factor in mediating mitochondrial injury via TRMT5/NDUFA7 axis, ultimately leading to renal tubular injury.