Metabolic Biology of Cellular Fuel Usage and Fuel Flexibility
Different cell states have anabolic and catabolic requirements that are fulfilled by metabolism
of specific nutrients/fuel substrates. These alter cellular energy, reductive power and biosynthetic intermediates, thereby influencing homeostatic processes. What are the molecular determinants of cellular fuel preferences? How does processing of fuel substrates translate
into metabolic signals that shape cellular and systemic physiology? The answer to these questions will advance basic understanding of metabolic regulation and unveil translational insights into metabolic contributions to disease pathogenesis. The following lines
of investigation showcase our current research efforts in this area.
Metabolic Crosstalks and Regulation
of Cellular Inflammation
Chronic inflammation is linked to diverse diseases. While the immune cell
component of inflammation has been well-studied, cell-intrinsic mechanisms that determine the response of target cells to inflammation are incompletely understood. We have recently identified a link between glucose, mitochondrial pyruvate handling and arginine metabolism through the urea cycle as a cell-intrinsic anti-inflammatory mechanism. Pyruvate entry into the TCA cycle via pyruvate carboxylase (PC) leads to increased aspartate synthesis, which supports the aspartate-argininosuccinate
shunt to fuel ureagenesis from arginine. This in turn diminishes arginine use for generation of nitric oxide, a chief mediator of inflammatory cytotoxicity. The ureagenic effect of PC sheds new insights into metabolic biology of this enzyme
and may have implications for diseases where alterations in PC are observed, including diabetes, cancer and inborn errors of metabolism. Our current research
in this area is focused on understanding the physiological functions of this
PC-directed pathway in inflammatory immune cells and their target tissues,
and its relevance for immunomodulation in the context autoimmune
and other chronic inflammatory diseases.
Contribution of Mitochondrial Pathways to
Metabolic Heterogeneity In Cancer
Increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis (the Warburg effect), including varied contribution of mitochondria to tumor metabolism. This metabolic heterogeneity is not only relevant across different cancers but also manifests within distinct subtypes of heterogeneous tumors that otherwise share a common initial diagnosis. A clear example of the latter is functional distinctions in mitochondrial bioenergetic efficiency and fuel utilization patterns, including fatty acid oxidation (FAO), which we have previously reported in B-cell receptor (BCR)-dependent vs –independent/OXPHOS subtypes of Diffuse Large B-Cell Lymphoma (DLBCL). What are cell-autonomous and non-cell autonomous mechanisms underlying fuel preferences in non-Warburg type cancers? How does FAO influence tumor growth? Our recent studies indicate that mitochondrial network architecture selectively regulates fuel access and metabolism. We are using multidisciplinary approaches such as metabolomics and quantitative proteomics, coupled with biochemical and loss-of-function studies to determine the contributions of mitochondria to fuel utilization patterns and identify the specific anabolic outputs of fatty acid consumption required for tumor growth and survival.
Neuronal Fuel Substrate Switching and the Excitable Brain
Glucose is the predominant fuel in the brain, however, neural cells can utilize alternate fuels such as ketone bodies (KBs) with important implication in neuronal excitability and seizure responses. This is also evident from the protective effects of low glycemic or ketogenic diets in pharmacoresistant epilepsy. However, given the systemic effects of diets, it has been difficult to home in on cell-autonomous mechanisms that control the choice and direct consequences of glucose vs KB utilization in the brain. In earlier work, we characterized a diet independent, cell autonomous genetic model that recapitulates this glucose-to-KB fuel switch in neurons and produces anti-seizure effects, in effect “reverse engineering” the ketogenic diet. Recently, we have utilized this model for unbiased discovery of the minimal metabolic mechanism that is necessary and sufficient to trigger this fuel switch. We are currently investigating the top candidates that have emerged from these studies for their role in neuronal metabolism and excitability.
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