Inhibiting Mitochondrial Calcium Uptake in Heart Failure Secondary to Metabolic Syndrome

As of 2021, 537 million people worldwide had diabetes mellitus (DM), a figure that is projected to reach 643 million by 2030. Diabetes is implicated in many disorders, including heart failure with preserved ejection fraction (HFpEF) which represents ~50% of heart failure patients. Often diagnosed as co-morbidities, the presence of HFpEF - which is characterized by abnormal cardiac relaxation patterns - and metabolic syndrome in the same patient increases expected mortality by 30%-50%. Cardiomyocytes generate up to 95% of their ATP from mitochondria, making mitochondrial metabolism essential for cardiac function. Calcium (Ca 2+ ) modulates mitochondrial ATP production and enters mitochondria primarily via the mitochondrial Ca 2+ uniporter complex. The channel-forming protein MCU and its binding partner Essential MCU Regulator (EMRE) are necessary for uniporter function. Loss of either MCU or EMRE eliminates rapid mitochondrial Ca 2+ (mtCa 2+ ) uptake, and therefore reduces intramitochondrial Ca 2+ levels. Interestingly, in a mouse model of HFpEF induced by high fat, high sucrose (HFHS) diet and L-NAME, we found that the ratio of EMRE to MCU decreased by almost 50% while the phosphorylated PDH (p-PDH) to total PDH ratio increased, suggesting lower mtCa 2+ . These data support the idea that decreased mtCa 2+ in HFpEF leads to a decline in mitochondrial energy production and hence impaired cardiac function. We are currently testing the hypothesis that blocking mtCa 2+ uptake with Emre cardiac-specific knockout (EmrecKO) is detrimental in a HFpEF model. At baseline, 10 weeks, and 15-20 weeks into the HFHS and L-NAME diet, we measure blood pressure, glucose tolerance, fat mass, and perform echocardiography to assess in vivo metabolic and cardiac (systolic and diastolic) function in male and female C57BL/6 mice. We are collecting hearts at 15 or 20 weeks to measure Ca 2+ uptake, ATP production, reactive oxygen species production, and respiration in isolated mitochondria from the right and left ventricles. We will perform histological staining in ventricular, kidney, and liver samples to assess cell morphology and quantify fibrosis. Lastly, we will measure force-work loops on cardiac slices from each ventricle. In this ongoing study, we aim to elucidate the role of impaired mtCa 2+ uptake in driving energetic deficits in HFpEF. 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.