SUMMARY Heart failure (HF) is a leading cause of morbidity and mortality affecting nearly 2% of the US population1,2. It has been long appreciated that fuel choice and metabolism of cardiomyocytes is altered in HF, impairing the core function of the organ and contributing to disease progression, but there are no approved therapies to refuel the failing heart. Carbohydrates are known to play an enhanced role in supporting cardiac ATP production in failing hearts, but more recent studies have identified lactate and not glucose as the direct substrate for cardiac metabolism in HF. We discovered using in vivo and in vitro 13C stable isotope tracing approaches that lactate is directly imported into healthy cardiac mitochondria via the monocarboxylate transporter 1 (MCT1/ Slc16a1). Direct mitochondrial import of lactate enables its efficient utilization as an energy substrate without conversion to cytoplasmic pyruvate and transport into mitochondria via the mitochondrial pyruvate carrier. Our preliminary data demonstrates that MCT1iCKO animals undergo hypertrophy in response to trans-aortic constriction (TAC) and rapidly decompensate and suffer heart failure with reduced ejection fraction. 13C tracing suggests these hearts cannot increase the contribution of glucose carbon to total ATP synthesis. In human HF patients, we observed an increase in MCT1 in the mitochondria of their hearts compared to normal donors. Our data suggest a profound paradigm shift in how lactate oxidation occurs in the heart, and reveals a substantial gap in knowledge about the biochemical mechanisms of carbohydrate oxidation in both the healthy and failing heart. Thus, there is a critical need to understand how lactate is metabolized in the mitochondria of failing hearts to guide the design of future therapies to improve cardiac bioenergetics and restore organ function. We hypothesize that direct lactate uptake and oxidation within the mitochondria of cardiomyocytes is a previously unknown protective adaptation for cardiac function. We will test this with the following aims: Aim 1: Quantify direct vs indirect mitochondrial lactate oxidation in health and in models of cardiac hypertrophy and failure; Aim 2: Determine whether mitochondrial localized MCT1 is necessary and sufficient for enhanced lactate metabolism in cardiac injury; Aim 3: Identify the lactate dehydrogenase (LDH) isoform responsible for mitochondrial LDH activity. Completion of the research in this proposal will lead to new knowledge about how cardiomyocyte mitochondria are fueled, the mechanisms by which carbohydrates (lactate) support bioenergetics in HF and provide testable therapeutic approaches for restoring cardiac metabolism in HF.

Narrative Heart failure remains a significant public health problem with few effective therapies. Our proposed research will address how the failing heart acquires and utilizes nutrient fuel and if this can be boosted to improve function. Thus, the proposed research is of high relevance to public health and aligns with the NHLBI mission to support research into the mechanisms and future treatments of cardiovascular disease.