Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Research of progress of pyruvate dehydrogenase complex in sepsis metabolism / 中华危重病急救医学

Sepsis is a critical illness with high morbidity and mortality. Anaerobic glycolysis plays an important role in the pathogenesis of sepsis. Pyruvate dehydrogenase complex (PDHC) serves as a key regulator during sepsis. With PDHC dephosphorylation and deacetylation, PDHC activity is upregulated, allowing pyruvate translocate to mitochondria in aerobic condition, preceding the production of acetyl-CoA to accelerate aerobic oxidation. Activation of PDHC improves the prognosis of sepsis through regulating the balance of lactate, release of inflammatory factors and energy metabolism. A variety of remedies can improve the prognosis of patients with sepsis by up-regulating the activity of PDHC, including dichloroacetate (DCA), vitamin B1, milrinone, tumor necrosis factor binding protein, and ciprofloxacin.This article reviews the role and the regulatory mechanism of PDHC and signal pathway in the sepsis metabolism, in order to innovate treatment for sepsis and multiple organ dysfunction.

Research progress on pyruvate dehydrogenase kinase inhibitors / 药学学报

Tumor cells can metabolize glucose through glycolysis to intermediates for biomacromolecule synthesis by inhibiting the activity of the pyruvate dehydrogenase complex (PDC) in mitochondria. In this process, pyruvate dehydrogenase kinases (PDKs) play a key role. The inhibition of the activity of PDKs can effectively block this metabolic pathway, activate mitochondrial oxidative metabolism, and induce tumor cell apoptosis. PDK inhibitors have become a research hotspot in medicinal chemistry, and novel structures targeting classical binding sites have been synthesized. In this paper, recent research progress on PDK inhibitors is reviewed to provide information on these latest entities and to explore their clinical applicability.

Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers

Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.

Current status of pyruvate dehydrogenase complex deficiency / 国际儿科学杂志

Pyruvate dehydrogenase complex (PDHc)deficiency is a genetic disorder of mitochondrial energy metabolism.Most cases result from mutations in gene encoded PDHc.The clinical presentation of patients with PDHc deficiency is extremely variable.Diagnosis of PDHc deficiency remains challenging,which depends on definitive enzymatic assays and DNA analysis.We review the relevant literature of recent domestic and international research results,in order to enhance our awareness of this disease and reduce misdiagnosis and missed diagnosis.It is helpful to improve prognosis and quality of life of patients by earlier and essential treatment.

Role of Pyruvate Dehydrogenase Kinase 4 in Regulation of Blood Glucose Levels / 당뇨병

In the well-fed state a relatively high activity of the pyruvate dehydrogenase complex (PDC) reduces blood glucose levels by directing the carbon of pyruvate into the citric acid cycle. In the fasted state a relatively low activity of the PDC helps maintain blood glucose levels by conserving pyruvate and other three carbon compounds for gluconeogenesis. The relative activities of the pyruvate dehydrogenase kinases (PDKs) and the opposing pyruvate dehydrogenase phosphatases determine the activity of PDC in the fed and fasted states. Up regulation of PDK4 is largely responsible for inactivation of PDC in the fasted state. PDK4 knockout mice have lower fasting blood glucose levels than wild type mice, proving that up regulation of PDK4 is important for normal glucose homeostasis. In type 2 diabetes, up regulation of PDK4 also inactivates PDC, which promotes gluconeogenesis and thereby contributes to the hyperglycemia characteristic of this disease. When fed a high fat diet, wild type mice develop fasting hyperglycemia but PDK4 knockout mice remain euglycemic, proving that up regulation of PDK4 contributes to hyperglycemia in diabetes. These finding suggest PDK4 inhibitors might prove useful in the treatment of type 2 diabetes.

Anesthetic experience in a pediatric patient with pyruvate dehydrogenase complex (PDHC) deficiency: A case report / 대한마취과학회지

Mitochondrial dysfunction represents a biochemically and clinically diverse group of conditions that can affect any organs with high energy requirement such as brain and muscle being particularly vulnerable. Pyruvate dehydrogenase complex (PDHC) deficiency is one type of mitochondrial dysfuntion that is anesthetically associated with lactic acidosis, muscle hypotonia, malignant hyperthermia, and postoperative respiratory failure. We report a case of general anesthetic management during ventriculoperitoneal shunt in a pediatric patient with PDHC deficiency and its possible considerations.

Anesthetic experience in a pediatric patient with pyruvate dehydrogenase complex (PDHC) deficiency: A case report / 대한마취과학회지

Mitochondrial dysfunction represents a biochemically and clinically diverse group of conditions that can affect any organs with high energy requirement such as brain and muscle being particularly vulnerable. Pyruvate dehydrogenase complex (PDHC) deficiency is one type of mitochondrial dysfuntion that is anesthetically associated with lactic acidosis, muscle hypotonia, malignant hyperthermia, and postoperative respiratory failure. We report a case of general anesthetic management during ventriculoperitoneal shunt in a pediatric patient with PDHC deficiency and its possible considerations.

A Korean Female Patient with Thiamine-responsive Pyruvate Dehydrogenase Complex Deficiency Due to a Novel Point Mutation (Y161C)in the PDHA1 Gene

Pyruvate dehydrogenase complex (PDHC) deficiency is mostly due to mutations in the X-linked E1alpha subunit gene (PDHA1). Some of the patients with PDHC deficiency showed clinical improvements with thiamine treatment. We report the results of biochemical and molecular analysis in a female patient with lactic acidemia. The PDHC activity was assayed at different concentrations of thiamine pyrophosphate (TPP). The PDHC activity showed null activity at low TPP concentration (1 x 10(-3) mM), but significantly increased at a high TPP concentration (1 mM). Sequencing analysis of PDHA1 gene of the patient revealed a substitution of cysteine for tyrosine at position 161 (Y161C). Thiamine treatment resulted in reduction of the patient's serum lactate concentration and dramatic clinical improvement. Biochemical, molecular, and clinical data suggest that this patient has a thiamine-responsive PDHC deficiency due to a novel mutation, Y161C. Therefore, to detect the thiamine responsiveness it is necessary to measure activities of PDHC not only at high but also at low concentration of TPP.

Research progresses on pyruvate dehydrogenase kinases / 基础医学与临床

Pyruvate dehydrogenase kinases(PDKs 1-4) can regulate the activity of mitochondrial pyruvate dehydrogenase complex(PDC) to catalyse the oxidative decarboxylation of pyruvate,and then to link glycolysis to the tricarboxylic acid cycle and ATP production.In this review,we summarize up-to-date information of mechanisms regulating PDKs and the function of PDKs inhibitors in lowering blood glucose level,alleviate damage during heart ischemia and also triggering apoptosis in cancer cells.PDKs will be a possible pharmacological targets in diabetes,heart ischemia and cancer therapy.