Mitochondrial transport and metabolism of the vitamin B-derived cofactors thiamine pyrophosphate, coenzyme A, FAD and NAD+, and related diseases: A review

Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner membrane, these cofactors need to be synthesized within the mitochondria or be imported, themselves or one of their precursors, into the organelles. Transporters belonging to the protein family of mitochondrial carriers have been identified to transport the coenzymes: thiamine pyrophosphate, coenzyme A, FAD and NAD+, which are all structurally similar to nucleotides and derived from different B-vitamins. These mitochondrial cofactors bind more or less tightly to their enzymes and, after having been involved in a specific reaction step, are regenerated, spontaneously or by other enzymes, to return to their active form, ready for the next catalysis round. Disease-causing mutations in the mitochondrial cofactor carrier genes compromise not only the transport reaction but also the activity of all mitochondrial enzymes using that particular cofactor and the metabolic pathways in which the cofactor-dependent enzymes are involved. The mitochondrial transport, metabolism and diseases of the cofactors thiamine pyrophosphate, coenzyme A, FAD and NAD+ are the focus of this review

Official cartography and / or collaborative maps: what is the future?

In linea di massima, potremmo affermare che OpenStreetMap (OSM) è “il progetto che crea e distribuisce dati geografici gratuiti per il mondo”. Forse il tutto è iniziato semplicemente “perché la maggior parte delle mappe che si considerano libere in realtà hanno restrizioni legali o tecniche sul loro utilizzo, trattenendo le persone dal loro utilizzo in modi creativi, produttivi o inaspettati” . Negli ultimi anni, la crescita di OSM ha generato un potente flusso di conoscenza che ha cambiato il modo di creare e utilizzare la cartografia. Da una semplice raccolta di informazioni, è stato creato un database molto complesso e i dati geo-localizzati hanno acquisito una nuova dimensione: da una semplice posizione su una mappa siamo passati ad una nuova entità collaborativa e libera (forse potremmo dire, un nuovo “sistema di informazione geografica”). Questo perché è molto facile collaborare al progetto. Ad esempio, è possibile contribuire con una piccola donazione; digitalizzando forme mancanti o inserendo etichette di testo, caricando foto; creare eventi correlati (mapping party) o, ultimo ma non meno importante, impegnandosi semplicemente a diffondere la notizia tra colleghi, amici e studenti. Una volta salvati i dati e le informazioni queste sono immediatamente disponibili su una piattaforma comune che li condivide e che consente di scaricare e (ri) utilizzare i dati (nel rispetto delle condizioni di licenza) per una varietà di applicazioni, anche commerciali. Dalle sfide sociali (Wheelmap), al routing (OpenRouteService), da Piattaforma collaborativa per immagini di livello stradale e dati cartografici (Mapillary) a Azione umanitaria e sviluppo della comunità attraverso la mappatura aperta (HOT): questi sono solo alcuni esempi di possibili applicazioni. Oggi OSM rappresenta - senza dubbio - una grande risorsa. Anche se OSM enfatizza la conoscenza locale per la mappatura, la comunità garantisce (e ci fidiamo di essa) per l’output finale che contribuisce e si nutre dell’ambiente di mappatura è anche vero che i contributori possono usare diverse mappe di base (antenna immagini...), strumenti (mappe dei campi a bassa tecnologia...) e strumenti (dispositivi GPS...) per confrontarsi con la piattaforma, e questo è valido in tutto il mondo. Ma questo è accurato? Quanto queste informazioni sono comparabili con una mappa tecnica o un database geo-topografico (che provengono da un comune, una regione o uno stato)? Questo contributo cercherà di offrire alcuni spunti di riflessione utilizzando alcune esperienze tratte dalle nostre attività e ricerche sviluppate nei nostri studi di laurea triennale o magistrale

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspar-tate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the as-partate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention

The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia

An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases

none8noNeuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcomeopenMarra Federica, Lunetti Paola, Curcio Rosita, Lasorsa Francesco Massimo, Capobianco Loredana, Porcelli Vito, Dolce Vincenza, Fiermonte Giuseppe and Scarcia PasqualeMarra, Federica; Lunetti, Paola; Curcio, Rosita; Lasorsa Francesco, Massimo; Capobianco, Loredana; Porcelli, Vito; Dolce, Vincenza; Fiermonte Giuseppe and Scarcia, Pasqual

CUGC for hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome

From 1999 to date, 50 affecting function variants have been identified and associated to HHH syndrome [1–5]. As it is not available in the literature a complete up-to-date list of disease-causing variants for SLC25A15 gene, we included this information as a Supplementary Excel sheet (See Supplementary Material File #1): this list was created by using LOVD and ClinVar databases and liked to the relevant literature reference. Reported variants consist of: 29 missense variants, 4 frameshift, 11 nonsense, 2 splicing, 2 small deletion, 1 in frame insertion, 1 gross deletion