Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James, Margaret O.; Jahn, Stephan C.; Zhong, Guo; Smeltz, Marci; Hu, Zhiwei; Stacpoole, Peter W.

doi:10.1016/j.pharmthera.2016.10.018

Cited by 110 publications

(104 citation statements)

References 154 publications

(237 reference statements)

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“…Mice with knockout of both isoform 2 and 4 of PDK (PDKdKO) mice have increased glucose oxidation rates as well as improved glucose tolerance, but paradoxically at the same time reduced plasma insulin levels (Wu et al, 2018). PDKdKO mice were utilized to evaluate specifically whether increasing the oxidative potential by reducing PDK activity had a similar effect to DCA in intact islets without the off-target effects of DCA (James et al, 2017;; Jeoung et al, 2012). Perifused islets from PDKdKO mice had normal first phase insulin secretion, but the mitochondriadependent second phase was significantly decreased (Figures S1D and S1E).…”

Section: Enhancing Oxidative Metabolism Does Not Improve Islet Functionmentioning

confidence: 99%

Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo

Abulizi

Stark

et al. 2020

Preprint

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Highlights:• Loss of mitochondrial phosphoenolpyruvate (PEP) impairs insulin release in vivo.• Pyruvate kinase (PK) activators stimulate beta-cells in preclinical diabetes models.• PEP cycling in vivo depends on PK and mitochondrial PEPCK (PCK2) for insulin release. • Acute and 3-week oral PK activator amplifies insulin release during hyperglycemia. eTOC Blurb:Abudukadier et al. show that small molecule pyruvate kinase activation in vivo and in vitro increases insulin secretion in rodent and human models of diabetes. The phosphoenolpyruvate (PEP) cycling mechanism and its amplification are dependent on mitochondrial PEPCK (PCK2). SummaryThe mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle is an anaplerotic-cataplerotic mitochondrial shuttle utilizing mitochondrial PEPCK (PCK2) and pyruvate kinase (PK). PEP cycling stimulates insulin secretion via OxPhos-independent lowering of ADP by PK. We assess in vivo whether islet PCK2 is necessary for glucose sensing and if speeding the PEP cycle via pharmacological PK activators amplifies insulin secretion. Pck2 -/mice had severely impaired insulin secretion during islet perifusion, oral glucose tolerance tests and hyperglycemic clamps. Acute and chronic pharmacologic PK activator therapy improved islet insulin secretion from normal, high-fat diet (HFD) fed, or Zucker diabetic fatty (ZDF) rats, and glucolipotoxic or diabetic humans. A similar improvement in insulin secretion was observed in regular chow and HFD rats in vivo.Insulin secretion and cytosolic Ca 2+ during PK activation were dependent on PCK2.These data provide a preclinical rationale for strategies, such as PK activation, that target the PEP cycle to improve glucose homeostasis.

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Section: Enhancing Oxidative Metabolism Does Not Improve Islet Functionmentioning

confidence: 99%

Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo

Abulizi

Stark

et al. 2020

Preprint

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“…Dichloroacetate (DCA) is a small orally available drug with several therapeutic applications including MS, solid tumors and inherited mitochondrial disorders (James et al, ) based on its ability to inhibit the kinase PDK1 and to consequently increase pyruvate dehydrogenase (PDH) activity and the flux of pyruvate into the mitochondria (Gerriets et al, ; Kato, Li, Chuang, & Chuang, ); (Figure ). DCA has been shown to shifts glucose metabolism toward the TCA cycle/oxidative phosphorylation in T cells in mice affected by EAE (Gerriets et al, ) and to promote a pro‐regenerative microglia/macrophages phenotype in vitro and in a peripheral inflammation model (Kato et al, ).…”

Section: Metabolic Drugs and Molecular Pathways Which May Be Exploitementioning

confidence: 99%

How to reprogram microglia toward beneficial functions

Fumagalli

Lombardi

Gressèns

et al. 2018

Glia

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Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

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“…Furthermore, clinical studies with this small molecule resulted in reduced lactate levels in patients with congenital lactic acidosis and sepsis 29, 30 . The influence of DCA on cellular energetics following hemorrhagic shock in the absence of fluid resuscitation has been unclear.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock

Subramani

Warren

et al. 2017

Sci Rep

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Hemorrhagic shock is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. In order to develop a treatment strategy based on potentiating mitochondrial function, we investigated the effect of the orphan drug dichloroacetate (DCA) on survival in an animal model of hemorrhagic shock in the absence of fluid resuscitation. Hemorrhagic shock was induced in rats by withdrawing 60% of the blood volume and maintaining a hypotensive state. The studies demonstrated prolonged survival of rats subjected to hemorrhagic injury (HI) when treated with DCA. In separate experiments, using a fluid resuscitation model we studied mitochondrial functional alterations and changes in metabolic networks connected to mitochondria following HI and treatment with DCA. DCA treatment restored cardiac mitochondrial membrane potential and tissue ATP in the rats following HI. Treatment with DCA resulted in normalization of several metabolic and molecular parameters including plasma lactate and p-AMPK/AMPK, as well as Ach-mediated vascular relaxation. In conclusion we demonstrate that DCA can be successfully used in the treatment of hemorrhagic shock in the absence of fluid resuscitation; therefore DCA may be a good candidate in prolonged field care following severe blood loss.

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Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Cited by 110 publications

References 154 publications

Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo

Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo

How to reprogram microglia toward beneficial functions

Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock

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