Rejection-associated Mitochondrial Impairment After Heart Transplantation

Abstract

Background. Mitochondrial dysfunction is associated with poor allograft prognosis. Mitochondrial-related gene expression (GE) in endomyocardial biopsies (EMBs) could be useful as a nonimmune functional marker of rejection. We hypothesize that acute cardiac allograft rejection is associated with decreased mitochondrial-related GE in EMBs. Methods. We collected 64 routines or clinically indicated EMB from 47 patients after heart transplant. The EMBs were subjected to mRNA sequencing. We conducted weighted gene coexpression network analysis to construct module-derived eigengenes. The modules were assessed by gene ontology enrichment and hub gene analysis. Modules were correlated with the EMBs following the International Society of Heart and Lung Transplantation histology-based criteria and a classification based on GE alone; we also correlated with clinical parameters. Results. The modules enriched with mitochondria-related and immune-response genes showed the strongest correlation to the clinical traits. Compared with the no-rejection samples, rejection samples had a decreased activity of mitochondrial-related genes and an increased activity of immune-response genes. Biologic processes and hub genes in the mitochondria-related modules were primarily involved with energy generation, substrate metabolism, and regulation of oxidative stress. Compared with International Society of Heart and Lung Transplantation criteria, GE-based classification had stronger correlation to the weighted gene coexpression network analysis–derived functional modules. The brain natriuretic peptide level, ImmuKnow, and Allomap scores had negative relationships with the expression of mitochondria-related modules and positive relationships with immune-response modules. Conclusions. During acute cardiac allograft rejection, there was a decreased activity of mitochondrial-related genes, related to an increased activity of immune-response genes, and depressed allograft function manifested by brain natriuretic peptide elevation. This suggests a rejection-associated mitochondrial impairment.

Human myocardial mitochondrial oxidative capacity is impaired in mild acute heart transplant rejection

“…Romero et al . described a decreased activity of mitochondrial‐related genes in ACR 20 . Our results complement these findings and suggest the translation of alterations in mitochondrial gene regulation in functional alterations.…”

“…[30][31][32] Romero et al described a decreased activity of mitochondrial-related genes in ACR. 20 Our results complement these findings and suggest the translation of alterations in mitochondrial gene regulation in functional alterations. These findings expose mitochondrial dysfunction as a potential therapeutic target in ACR, especially considering promising effects of dietary interventions on mitochondrial bioenergetics.…”

“…19 Just recently, Romero et al described a decreased activity of mitochondrial-related genes in ACR, suggesting a rejection-associated mitochondrial impairment. 20 We thought to extend these findings, by providing a comprehensive functional, clinical, and immunohistochemical characterization of HTX recipients and cardiac tissue specimens.…”

Microvesicular Steatosis and Severe Cardiac Allograft Dysfunction

“…16 Gene expression profiling studies have shown that myocardial samples obtained during an episode of rejection have decreased activity of mitochondrial-related genes and increased activity of immune response genes. 17 Chronic tumour necrosis factor-alpha exposure alters mitochondrial function through the activation of nuclear factor-kappa B. 18 Anticardiac antibodies directed against ATP synthase have been reported in end-stage heart failure.…”

Transcriptomics in transplantation: More than just biomarkers of allograft rejection

“…For example, proteomic analysis of allograft tissue identified downregulation of mitochondrial energy generation, particularly TCA enzymes such as aconitate hydrase in ACR 5 . Transcriptomic analysis of rejecting allograft tissue also identified significant disruption of the mitochondria‐related genes implicated in substrate metabolism, energetics, and regulation of oxidative stress 6 . These studies point to a more critical role of the mitochondrion in rejection.…”