Circulating mitochondrial genes detect acute cardiac allograft rejection: Role of the mitochondrial calcium uniporter complex

Abstract

Acute rejection after heart transplantation increases the risk of chronic dysfunction. Disturbances in mitochondrial function may play a contributory role, however, the relationship between histological signs of rejection in the human transplanted heart and expression levels of circulating mitochondrial genes, such as the mitochondrial Ca2+ uniporter (MCU) complex, remains unexplored. We conducted an RNA‐sequencing analysis to identify altered mitochondrial genes in serum and to evaluate their diagnostic accuracy for rejection episodes. We included 40 consecutive samples from transplant recipients undergoing routine endomyocardial biopsies. In total, 112 mitochondrial genes were identified in the serum of posttransplant patients, of which 28 were differentially expressed in patients with acute rejection (p < .05). Considering the receiver operating characteristic analysis with an area under the curve (AUC) >0.900 to discriminate patients with moderate or severe degrees of rejection, we found that the MCU system showed a strong capability for detection: MCU (AUC = 0.944, p < .0001), MCU/MCUR1 ratio (AUC = 0.972, p < .0001), MCU/MCUB ratio (AUC = 0.970, p < .0001), and MCU/MICU1 ratio (AUC = 0.970, p < .0001). Mitochondrial alterations are reflected in peripheral blood and are capable of discriminating between patients with allograft rejection and those not experiencing rejection with excellent accuracy. The dysregulation of the MCU complex was found to be the most relevant finding.

Diagnostic value of serum miR-144-3p for the detection of acute cellular rejection in heart transplant patients

“…Although the gold standard of the diagnosis of cardiac allograft rejection is EMB 28,29 , this procedure has negative consequences for patients 2 and is subject to sampling error and interobserver variability 30 . Due to these important risks and limitations, numerous studies have focused on identifying a method of noninvasive monitoring of acute and chronic rejection after cardiac transplantation [3][4][5][6][7][8][9][10][11][12][13] . It is crucial to develop complementary methods for the present tools, as well as provide a non-invasive alternative to EMB, to achieve an optimal diagnostic approach to diagnose cardiac allograft rejection, especially in its early phase.…”

“…Therefore, it is essential to identify noninvasive methods to improve the rejection diagnosis and surveillance of transplanted patients. Numerous studies have been carried out based on this topic [3][4][5][6][7][8][9][10][11][12][13] .…”

Alpha-cardiac Actin Serum Expression Levels Detect Acute Cellular Rejection in Heart Transplant Patients

“…RNA sequencing analysis has been extensively described by Tarazón et al 24 Briefly, RNA extraction was performed using NucleoSpin miRNA Plasma of Macherey Nagel, following the protocol and instructions provided by the manufacturer. RNA quantification was performed using a NanoDrop 1000 spectrophotometer and the Qubit 3.0 fluorometer (Thermo Fisher Scientific).…”

Noninvasive biomarkers in heart transplant: 2020–2021 year in review

“…There is a growing interest to define changes of mitochondrial energetics and mitochondrial gene expression in rejection. Tarazon et al investigated the role of circulating mitochondrial genes as biomarkers of ACR in a single-center cohort of 40 heart transplant patients [29]. They performed RNA-sequencing of 112 mitochondrial genes and identified several genes which were differentially expressed during ACR.…”