Abstract
Warm ischemic injury (WII) stems from incorrect energy metabolism and is the main cause of graft dysfunction. Mitochondria, as the center of cellular metabolic activities, may be the key in identifying accurate indicators for evaluating the quality of grafts. Our research focuses on the screening, clinical application, and mechanism of the optimal WII mitochondrion biomarker. Using a 100% hepatic warm ischemia mouse model, without reperfusion, transmission electron microscopy demonstrated evident morphological changes of hepatic mitochondria at 15 min of ischemia. However, all 13 mt-mRNAs could not display continuously up-regulated consistency at 0-15-30-60 min during WII. High throughput analysis of miRNA expression in both purified mitochondria and liver tissues suggested miR-23b-5p was a potential mitochondrial microRNA (mitomiR) biomarker with high sensitivity and 0-15-30-60 min change consistency. Fluorescence in-situ hybridization and RT-qPCR further confirmed the results. Through overexpression and inhibition, the functionality of this mitomiR during WII was identified as a protective regulator in vitro and then verified in Dicer1fl/flAlbCre mice by down-regulation of other miRNAs and supplementation of mature mitomiR-23b-5p. Dual-luciferase reporter assay and the Seahorse XF analyzer determined that mitomiR-23b-5p reduced mitochondrial respiratory function by silencing mtRNR2 (16S). Clinically, mitomiR-23b-5p was positively correlated with serum ALT levels 3 days after the operation (P=0.032), and the C-statistic for 90-day graft survival rate was 0.698. MitomiR-23b-5p plays a protective regulatory role and implements a special mitochondrial regulation mechanism not yet reported in WII. Our clinical results further support the experimental result that the expression of MitomiR-23b-5p is closely related to the prognosis of clinical liver transplantation patients. This is a promising new biomarker for WII evaluation of donor livers.
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