The overarching goal of the laboratory is to identify metabolic mechanisms that link lifestyle factors such as overnutrition and physical inactivity to poor health outcomes. Projects are thematically focused on the interplay between diet, exercise and mitochondrial function; and are co-led by our DMPI faculty colleague, Dr. Tim Koves. In addition to their critical roles in ATP production and cellular bioenergetics, mitochondria are increasingly recognized as a key regulatory hub for processes such as nutrient sensing, retrograde signaling, autophagy, growth and cell survival. Aberrant mitochondrial performance is evident in a broad range of diseases; including diabetes, cardiovascular disease, cancer and numerous age-related disorders. Our work aims to define and understand metabolic networks that maintain mitochondrial integrity and energy stability. Main project areas include: 1) mechanisms that link nutrient oversupply and intramuscular lipid accumulation to mitochondrial stress, muscle insulin resistance and heart failure; 2) mechanisms by which habitual exercise enhances mitochondrial function, energy homeostasis and insulin sensitivity; and 3) translational studies that examine the impact of dietary and/or exercise interventions on metabolic regulation and mitochondrial function in human skeletal muscle.

During the past 18 years our group has worked closely with the Metabolomics and Biomarkers Core Laboratory at the Stedman Center (now housed within DMPI) to develop and apply mass spectrometry-based metabolomics approaches for identifying metabolite signatures of health and disease. We have also collaborated with our DMPI colleagues, Drs. Paul Grimsrud and Guofang Zhang, to build new programs in proteomics and metabolic flux analysis. To complement this powerful suite of molecular profiling tools, our laboratory has developed a sophisticated platform for deep and comprehensive phenotyping of mitochondrial bioenergetics and energy transduction (1). Our goal is to integrate mass spectrometry-based metabolomics, proteomics and metabolic flux analysis with comprehensive bioenergetics to identify and understand molecular signatures that connect mitochondrial performance to disease risk (2). Recent applications of these tools have indeed uncovered new insights into the mechanisms by which mitochondria modulate insulin action and cardiometabolic health (3,4,5,6).

One longstanding focus of the lab centers on understanding how mitochondria resident in specific tissues–under specific circumstances–respond and adapt to a heavy influx of lipid fuel. This topic is relevant to physiological settings such as acute starvation and exercise, as well as pathophysiological conditions such as obesity and diabetes. Our early work in this area identified a cluster of acylcarnitine (AC) metabolites that track with nutrient- and exercise-induced changes in mitochondrial function, insulin action and heart failure (2,7,8,9,10). The significance and clinical implications of this signature were further underscored by subsequent reports identifying AC accumulation as a strong biomarker and predictor of cardiometabolic health in humans (2,9,11,12,13). Most ACs derive from acyl-CoA intermediates of mitochondrial lipid catabolism; and dysregulated fatty acid oxidation (FAO) is a hallmark of cardiometabolic decline and exercise intolerance. Our laboratory has remained keenly committed to delineating the functional and mechanistic relevance of AC accumulation–which, in simple terms, reflects a metabolic bottleneck in the FAO pathway. Emerging findings from new studies that leverage our mitochondrial diagnostics platform reveal a heretofore unrecognized thermodynamic vulnerability in the FAO spiral that might contribute to aging and disease. Ongoing work seeks to determine: a) if/how context-specific vulnerabilities in FAO give rise to skeletal and cardiac muscle dysfunction, b) the role of ketones as an alternative fuel that modulates and/or circumvents the apparent bottleneck in FAO, and c) whether lifestyle interventions such as exercise training and/or time-restricted feeding induce FAO remodeling in a manner that alleviates the bottleneck to improve mitochondrial resilience. These goals will be satisfied using mouse models harboring genetically-engineered lesions or enhancements in mitochondrial fuel metabolism.

Projects are currently supported by grants from NIDDK, NHLBI and Eli Lilly and Company.

NEWS ARTICLES

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