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The Metabolic Cart
Published in Michael M. Rothkopf, Jennifer C. Johnson, Optimizing Metabolic Status for the Hospitalized Patient, 2023
Michael M. Rothkopf, Jennifer C. Johnson
For example, when we eat carbohydrates, the gastrointestinal (GI) tract digests them into glucose, which is absorbed and delivered to the bloodstream. The cells then transport the glucose into the cytoplasm, where the Embden–Meyerhoff (cytosolic) pathway converts glucose into pyruvate. The pyruvate dehydrogenase complex then makes pyruvate into acetyl CoA. This pathway produces energy, but the net gain from the cytosolic process is only two molecules of ATP.
Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Subacute necrotizing encephalomyelopathy (Leigh's syndrome) can be produced by nDNA and mtDNA mutations of genes encoding for enzymes involved in energy production, such as mitochondrial respiratory chain complexes I–V, and components of the pyruvate dehydrogenase complex. Leigh's syndrome is therefore more than one disease with similar phenotypes.
Neurodegeneration, ataxia, and retinitis pigmentosa (NARP)
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Of seven patients with typical Leigh spongiform changes on neuropathology or the characteristic appearance on MRI, the classic NARP mutation was found in all [15]. In each, there was heteroplasmy, but the mutation was in high proportion in blood and muscle. It was found in four asymptomatic mothers and two asymptomatic siblings. This series was expanded to 12 patients in ten families, all with the same mutation [3]. Consistent with the observations of Tatuch et al. [2], the Leigh phenotype was associated with a high percentage of abnormal mitochondrial DNA. The heterogeneity of Leigh syndrome is pointed up by the fact that the 12 patients of Santorelli et al. [3] were found in the study of 50 patients with typical Leigh syndrome. These authors compared 18 patients reported with the NARP mutation and Leigh syndrome with 34 and 64 in whom the underlying disease was cytochrome oxidase deficiency or pyruvate dehydrogenase complex deficiency (Chapter 50), respectively. Smaller numbers had biotinidase or complex I deficiency. Among the features of the clinical picture, only retinitis pigmentosa and positive family history seemed to distinguish the patients with NARP. An earlier-onset, more rapid course or propensity for seizures was more common among the NARP patients. Patients with the classic NARP mutation and Leigh syndrome were also reported by Ciafaloni and colleagues [11], Shoffner and colleagues [8], and Mäkelä-Bengs and colleagues [9]. Thus, it is clear that the 8993 mutation in mitochondrial DNA is a common cause of Leigh syndrome.
Advances in pharmacotherapy for acute kidney injury
Published in Expert Opinion on Pharmacotherapy, 2022
Yali Xu, Ping Zou, Xiaojing Cao
α-Lipoic Acid (ALA) is an organic sulfur compound derived from bitter acid synthesized from mitochondria widely known for its physiological function as a cofactor in the pyruvate dehydrogenase complex [31]. ALA is conducive to the treatment of diabetes, cardiovascular disease, and cancer. Meanwhile, as a natural antioxidant, ALA can effectively improve the damage caused by oxidative stress [32]. So far, it has been demonstrated that ALA treatment can effectively protect kidney from oxidative stress-induced damage in AKI animal models, including ischemia/reperfusion injury and cisplatin-induced renal injury. Furthermore, ALA ameliorates kidney injury by inhibiting apoptosis and reducing lipopolysaccharide-induced inflammatory response via reducing TNF-α, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), and inhibiting the infiltration of CD11b-positive macrophages [33]. In addition, ALA treatment could also improve renal function via relieving tubule dysfunction, as well as regulating sodium transporter and aquaporin [34,35]. One phase IV clinical trial was performed to evaluate whether ALA treatment could prevent contrast-induced AKI and endothelial dysfunction in patients with type 2 diabetes, but the result is still unavailable (NCT01978405) [36]. Although ALA showed good antioxidant activity, it was characterized by its unpleasant odor, poor bioavailability and stability. Nanotechnology was used to improve its physical properties and biological activities, but so far there have been no reports of AKI.
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
Pyruvate dehydrogenase complex (PDC) is a 9.5 million Da multi-enzyme complex located in mitochondrial matrix and consisting of four major enzyme components: pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2), dihydrolipoamide dehydrogenase (E3), and E3-binding protein (E3BP), as well as the two kinds of dedicated regulatory enzymes: PDKs and pyruvate dehydrogenase phosphatase [47]. The detailed structure and function of PDC have been well reviewed [48]. As an important gatekeeper enzyme that links pyruvate to the TCA cycle, PDC catalyzes the conversion of pyruvate to acetyl-CoA coupled with the reduction of NAD+ to NADH. The modulation of PDC activities depends on the reversible phosphorylation and dephosphorylation [49]. Phosphorylation of E1α component, regardless of which one of the three serine residues, is enough to switch off PDC activity. Thus, phosphorylation of PDC by PDKs will downregulate its activity, and subsequently reduce the flux of pyruvate into the TCA cycle. In human, phosphorylation of PDC is catalyzed by any of four isoforms of pyruvate dehydrogenase kinase (PDK1-4) which are expressed differently in specific tissues. In particular, PDK1 is closely associated with cancer malignancy and serves as the only PDK isoform that could phosphorylate all serine sites of PDC [50]. To sum up, inhibiting PDKs has been one of the recognized strategies to fight against cancer by increasing OXPHOS and reversing Warburg effect.
Pyruvate dehydrogenase complex deficiency mimicking congenital cytomegalovirus infection on imaging
Published in Baylor University Medical Center Proceedings, 2022
Jasmin Rahesh, Rohan Anand, Victor Mendiola, Roy Jacob
Pyruvate dehydrogenase complex deficiency is secondary to absence of the mitochondrial enzyme that converts pyruvate into acetyl coenzyme A and links the glycolytic pathway with the citric acid cycle. Pyruvate accumulation leads to lactate increase by lactate dehydrogenase. Alanine can result directly from accumulation of pyruvate or indirectly from lactate. The deficiency presents with neurological defects including motor delay, seizures, ataxia, dystonia, growth problems, and visual deficiencies.1 While the most common inheritance pattern is X-linked due to abnormal PDHA1 function, there are other genes, such as PDHB and PDHX, of autosomal recessive inheritance responsible for the other subunits. The signs and symptoms of this disease can present at any time between birth and late childhood and most commonly appear in infancy. Postnatal imaging findings include elevated lactate peak on magnetic resonance imaging (MRI) spectroscopy and diffuse increased T2 signal in the periventricular white matter.