Sarcoplasmic reticulum (SR)-mitochondria tethering is lost in human heart failure

Abstract

Sarcoplasmic reticulum (SR)-mitochondria (SR-mito) tethering facilitates communication between these organelles and regulates many physiological processes critical for cardiomyocyte function. Recent evidence suggests that alterations in SR-mito tethering impacts cardiac metabolism and calcium handling which contributes to cardiovascular pathologies, such as heart failure (HF). To characterize SR-mito apposition in cardiac disease we obtained electron microscopy (EM) images of individual cardiomyocytes freshly isolated from failing hearts explanted from ischemic (ICM), ischemic-dilated (ICM-DCM) and dilated cardiomyopathy (DCM) patients undergoing transplantation and nonfailing control hearts. Topographical EM analysis revealed a significant increase in the mean SR-Mito distance, as well as an increase in the minimum SR-mito distance (closest approximation of any single mitochondrion to SR) in ICM, ICM-DCM and DCM cardiomyocytes, compared to nonfailing controls. Results from the EM analysis also revealed that in DCM there was a decrease in mean mitochondrion perimeter in contact with the SR, as well as a decrease in SR in approximation with mitochondria at a distance <50-nm. In agreement, nonfailing hearts had a greater length of outer mitochondrial membrane in close contact (<20-nM) with the SR, as compared to failing cardiomyocytes. ICM and DCM cardiomyocytes displayed an overall reduction in mitochondrion perimeter and circularity, suggesting smaller and more fragmented mitochondria. Surprisingly, failing cardiomyocytes exhibited an overall increase in mitochondrial area compared to nonfailing controls. To define the molecular changes that may underlie loss of SR-mito tethering, we evaluated the expression of several proposed linkers. qPCR analysis of left ventricular samples revealed that mRNA expression of mitofusin 2 is significantly decreased in both hypertrophic cardiomyopathy (HCM) and DCM. Further, other proposed tethering components including FUNDC1, BAP31, DJ-1 and VAPB demonstrated decreased mRNA expression in HCM, DCM and ischemic HF samples, compared to nonfailing controls. IP3R1 displayed increased mRNA expression in HCM and DCM human HF samples, whereas IP3R2 and VDAC1 displayed increases in expression in HCM and ICM. These results highlight that transcriptional remodeling of the components mediating SR-mito tethering and communication may contribute to the observed structural changes in inter-organelle approximation in cardiomyocytes. These studies provide rationale for causal interrogation of the structural mechanisms regulating SR-mito communication in the context of HF progression. Fellowship in Biomedical Sciences, Lewis Katz School of Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.