RISP Deficiency Impairs Cardiac Function: Echocardiographic Assessment of RISP Knockout and Heterozygous Mice

The integrity of the mitochondrial electron-transport chain is essential for myocardial energy production. Mitochondrial dysfunction is a key contributor to cardiovascular diseases, like heart failure and pulmonary hypertension, yet the role of individual protein subunits in cardiac performance remains poorly defined. The Rieske iron-sulfur protein (RISP), a subunit of mitochondrial complex III, is involved with calcium handling. In this study, we aimed to determine how deficiency of the RISP protein impacts in vivo cardiac function. We hypothesized that full or partial loss of RISP would impair left ventricular (LV) systolic function in vivo. Echocardiography data of adult RISP knockout and RISP heterozygous mice were compared to control mice. From short axis M-mode recordings, trace-derived measurements of ejection fraction (EF), fractional shortening (FS), end-systolic volume (LV Vol;s), and stroke volume (SV) were obtained to quantify systolic function. Our findings revealed that RISP knockout mice exhibited systolic dysfunction. EF and FS declined, suggesting impairments in contractile performance. LV Vol;s was elevated, which is consistent with incomplete systolic emptying of blood. RISP heterozygous mice exhibited similar impairments in systolic performance. Despite these reductions in contractile function, SV in both genotypes remained comparable to control mice, suggesting the presence of compensatory mechanisms that may temporarily preserve overall cardiac output even while systolic function is impaired. We also observed reduced mitochondrial reactive oxygen species (ROS) production in RISP knockout mice. Such reductions can impair calcium handling and electron transport chain signaling, which could contribute to the systolic abnormalities seen in echocardiography. These findings suggest that RISP is crucial to maintaining normal systolic performance, as even partial loss of RISP contributes to significant cardiac abnormalities. More broadly, this study suggests how important mitochondrial complex III integrity is to sustaining normal cardiac function. Further investigation on the role of RISP within the mitochondrial electron transport chain may reveal new therapeutic targets for mitochondrial cardiomyopathy. Funding: This work was supported by the NIH (R01HL164941, to Yun-Min Zheng). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.