Search Results (3)

Mitochondrial ATP synthase (Complex V) catalyzes the last step of oxidative phosphorylation and provides most of the energy (ATP) required by human cells. The mitochondrial genes MT-ATP6 and MT-ATP8 encode two subunits of the multi-subunit Complex V. Since the discovery of the first MT-ATP6 variant in the year 1990 as the cause of Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome, a large and continuously increasing number of inborn variants in the MT-ATP6 and MT-ATP8 genes have been identified as pathogenic. Variants in these genes correlate with various clinical phenotypes, which include several neurodegenerative and multisystemic disorders. In the present review, we report the pathogenic variants in mitochondrial ATP synthase genes and highlight the molecular mechanisms underlying ATP synthase deficiency that promote biochemical dysfunctions. We discuss the possible structural changes induced by the most common variants found in patients by considering the recent cryo-electron microscopy structure of human ATP synthase. Finally, we provide the state-of-the-art of all therapeutic proposals reported in the literature, including drug interventions targeting mitochondrial dysfunctions, allotopic gene expression- and nuclease-based strategies, and discuss their potential translation into clinical trials. Full article

Guillain-Barré syndrome (GBS) can occur at all stages of human immunodeficiency virus (HIV) infection. HIV, cytomegalovirus (CMV), and varicella zoster virus (VZV) are the main infectious agents in HIV-positive GBS cases. These cases include acute and chronic HIV infection, immune reconstitution inflammatory syndrome (IRIS) shortly after anti-retroviral therapy (ART), those with ART interruption, or those with cerebrospinal fluids (CSF) HIV escape. The mechanisms are involved in both humoral and cellular immunities. Demyelinating and axonal neuropathies are the main pathological mechanisms in GBS. Presentation and prognosis are identical to those in patients without HIV infection. Typical or atypical clinical manifestations, CSF analysis, electrophysiological and pathological examination, and antiganglioside antibody detection can help diagnose GBS and classify its various subtypes. Intravenous immunoglobulin and plasma exchange have been used to treat GBS in HIV-positive patients with a necessary ART, while ganciclovir or foscarnet sodium should be used to treat ongoing CMV- or VZV-associated GBS. Steroids may be beneficial for patients with IRIS-related GBS. We reviewed HIV-positive cases with GBS published since 2000 and summarized their features to highlight the necessity of HIV testing among patients with GBS. Moreover, the establishment of a multidisciplinary team will guarantee diagnostic and therapeutic advantages. Full article

Phosphoribosyl pyrophosphate synthetase (PRS EC 2.7.6.1) is a rate-limiting enzyme that irreversibly catalyzes the formation of phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate (ATP). This key metabolite is required for the synthesis of purine and pyrimidine nucleotides, the two aromatic amino acids histidine and tryptophan, the cofactors nicotinamide adenine dinucleotide (NAD⁺) and nicotinamide adenine dinucleotide phosphate (NADP⁺), all of which are essential for various life processes. Despite its ubiquity and essential nature across the plant and animal kingdoms, PRPP synthetase displays species-specific characteristics regarding the number of gene copies and architecture permitting interaction with other areas of cellular metabolism. The impact of mutated PRS genes in the model eukaryote Saccharomyces cerevisiae on cell signalling and metabolism may be relevant to the human neuropathies associated with PRPS mutations. Human PRPS1 and PRPS2 gene products are implicated in drug resistance associated with recurrent acute lymphoblastic leukaemia and progression of colorectal cancer and hepatocellular carcinoma. The investigation of PRPP metabolism in accepted model organisms, e.g., yeast and zebrafish, has the potential to reveal novel drug targets for treating at least some of the diseases, often characterized by overlapping symptoms, such as Arts syndrome and respiratory infections, and uncover the significance and relevance of human PRPS in disease diagnosis, management, and treatment. Full article