The metabolic activity of the brain is extraordinary, accounting for nearly 20% of the body's energy demand. As such, it is perhaps unsurprising that a deficit in energy metabolism is associated with multiple forms of chronic neurodegenerative disease. In Alzheimer's Disease (AD), for example, the earliest detectable defect in patients is diminished glucose utilization by the brain. Epidemiological data reinforces the link between dysregulated glucose metabolism, as type 2 diabetes is a significant risk factor for development of AD and cognitive impairment. In fact, the two diseases share several noteworthy features, including insulin resistance (the inability of tissues to properly transport and metabolize glucose in response to insulin), oxidative stress, amyloidosis, cognitive dysfunction, and atrophy of neural tissues. This shared pathogenesis has led to clinical trials which re-purpose medications used to treat type 2 diabetes [including intranasal insulin, incretin analogues, and thiazolidinediones (TZDs)] to treat AD and other neurodegenerative diseases. Unfortunately, each of these approaches suffer from the same drawbacks that limit their use in diabetes, including significant side effects from TZDs mediated by transcriptional nuclear receptor PPAR?. We recently reported that TZDs have a previously undiscovered, pleiotropic effect in which they specifically modulate the activity of an important metabolite transporter - the mitochondrial pyruvate carrier (MPC, Divakaruni et al. 2013). The MPC transports pyruvate from the cytoplasm into mitochondria, and as such is a crucial branch point in cellular metabolism. Mild inhibition of the MPC by TZDs can acutely stimulate glucose uptake into human myocytes, and this effect can be reproduced by the specific MPC inhibitor UK5099. We have extended our work into neurodegenerative disease with promising early data. A low concentration of UK5099 also acutely stimulates glucose uptake in primary rat cortical neurons, and 24 h treatment enhances their ability to oxidize alternative metabolic fuels (such as ketone bodies) and withstand excitotoxic stress. We therefore propose a novel strategy for the treatment of AD: identify drug-like compounds that mildly inhibit the MPC to (i) stimulate cellular glucose uptake and (ii) promote the oxidation of alternative fuels. To achieve this goal, we propose the following:
Aim 1 : Characterize the response of primary neurons and astrocytes to mild MPC inhibition with further studies of glucose uptake, resistance to excitotoxic death, ROS production, and metabolic flexibility using 13C flux analysis.
Aim 2 : Determine the high-resolution structures of the human MPC protein complex and functionally important mutants as well as with UK5099 to provide a detailed framework to support drug development efforts.
Aim 3 : Conduct a chemical screen to identify mild MPC inhibitors, using a battery of follow-on assays in neurons and astrocytes to further optimize a potential lead compound. This Multi-PI project on a novel mitochondrial target merges expertise in bioenergetics, drug discovery, and structural biology into a synergistic program for the treatment of neurodegenerative disease.

Public Health Relevance

Effective therapies for Alzheimer's Disease (AD) are desperately needed for the increasing portion of our population suffering from this devastating disease. The brain requires an enormous amount of energy in order to function properly, and it is clear that there is a defect in energy metabolism in the brains of AD patients. The proposed project will pursue the discovery of new candidate compounds for the treatment of Alzheimer's Disease by targeting a recently discovered transporter in mitochondria, the mitochondrial pyruvate carrier, which acts as a central hub of metabolism. This transporter is unlike any others that have been described previously, therefore we propose to also fully characterize the structure of the complex to enable better understanding of how it functions and how potential drugs could interact with it.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Corriveau, Roderick A
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Divakaruni, Ajit S; Andreyev, Alexander Y; Rogers, George W et al. (2018) In situ measurements of mitochondrial matrix enzyme activities using plasma and mitochondrial membrane permeabilization agents. Anal Biochem 552:60-65
Sessions, Ayla O; Min, Peter; Cordes, Thekla et al. (2018) Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span. APL Bioeng 2:
Barros, L Felipe; Bolaños, Juan P; Bonvento, Gilles et al. (2018) Current technical approaches to brain energy metabolism. Glia 66:1138-1159
Divakaruni, Ajit S; Hsieh, Wei Yuan; Minarrieta, Lucía et al. (2018) Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis. Cell Metab 28:490-503.e7
Parker, Seth J; Svensson, Robert U; Divakaruni, Ajit S et al. (2017) LKB1 promotes metabolic flexibility in response to energy stress. Metab Eng 43:208-217
Divakaruni, Ajit S; Wallace, Martina; Buren, Caodu et al. (2017) Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death. J Cell Biol 216:1091-1105
Zhang, Hui; Badur, Mehmet G; Divakaruni, Ajit S et al. (2016) Distinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions. Cell Rep 16:1536-1547
Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia et al. (2016) HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders. Neurobiol Dis 86:154-69
Green, Courtney R; Wallace, Martina; Divakaruni, Ajit S et al. (2016) Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat Chem Biol 12:15-21
Cordes, Thekla; Wallace, Martina; Michelucci, Alessandro et al. (2016) Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels. J Biol Chem 291:14274-84

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