1,722,092 research outputs found
Mitochondrial carriers and related diseases
No full textSince the end of nineties numerous mitochondrial diseases have been found to be related to mutations in nuclear genes encoding mitochondrial carriers, a family of proteins that shuttle a variety of metabolites across the mitochondrial membrane. To date eleven disorders are known to be caused by defects of mitochondrial carriers. Mutations of mitochondrial carrier genes are responsible for carnitine/acylcarnitine carrier deficiency, ornithine carrier deficiency (HHH syndrome), aspartate/glutamate isoform 1 deficiency (global cerebral hypomyelination), aspartate/glutamate isoform 2 deficiency (CTLN2 and NICCD), amish microcephaly, neonatal myoclonic epilepsy, congenital sideroblastic anemia, PiC deficiency, ADP/ATP carrier isoform 1 deficiency and involved in neuropathy and bilateral striatal necrosis and adPEO (autosomal dominant progressive external ophthalmoplegia). We propose un updated overview of these diseases. We shall also discuss the role of missense mutations in impairing mitochondrial carrier function and the consequent severe damage to the mitochondrial matrix supply with substrates destined to specific metabolic pathways. Despite the substantial progress that has been made in our understanding of the molecular bases of mitochondrial carrier associated diseases, specific pharmacological therapies are not yet available. Current therapies are symptomatic and usually based on specific dietary measures. New therapeutic approaches are under investigation for some of these diseases.
For further reading
Palmieri F. (2008) Diseases caused by defects of mitochondrial carriers: a review. Biochim Biophys Acta; 1777:564-78.
Palmieri F, Pierri CL (2010) Structure and function of mitochondrial carriers - Role of the transmembrane helix P and G residues in the gating and transport mechanism. FEBS Lett. 584:1931-9.
Tessa A, Fiermonte G, Dionisi-Vici C, Paradies E, Baumgartner MR, Chien YH,Loguercio C, de Baulny HO, Nassogne MC, Schiff M, Deodato F, Parenti G, Rutledge SL, Vilaseca MA, Melone MA, Scarano G, Aldamiz-Echevarría L, Besley G, Walter J, Martinez-Hernandez E, Hernandez JM, Pierri CL, Palmieri F, Santorelli FM. (2009) Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Human Mutation; 30:741-8.
Wibom R, Lasorsa FM, Töhönen V, Barbaro M, Sterky FH, Kucinski T, Naess K, Jonsson M, Pierri CL, Palmieri F, Wedell A. (2009) AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med.; 361:489-95.
Iacobazzi V, Convertini P, Infantino V, Scarcia P, Todisco S, Palmieri F. (2009) Statins, fibrates and retinoic acid upregulate mitochondrial acylcarinitine carrier gene expression. Biochem Biophys Res Commun.; 388:643-7
Transport mechanism of mitochondrial carriers
No full textThe inner mitochondrial membrane contains a superfamily of proteins, called mitochondrial carriers (MCs), which transport several metabolites into and out of the mitochondrial matrix. As observed in the ADP/ATP carrier structure, crystallized in complex with its powerful inhibitor carboxyatractyloside, the main structural fold of the MCs consists of a barrel of six transmembrane α-helices whose charged surfaces form the wall of a water-filled cavity. Multiple sequence alignment and 3D comparative models of mitochondrial carriers of known function have recently allowed the identification of i) a similarly located binding site located in the carrier cavity, ii) two ion pair networks or gates that are on the matrix or the cytosolic side of the carrier molecules, and iii) two Pro-Gly levels above and below the substrate binding site. As a result of the substrate–protein interactions, ‘hinged helix movements’ consisting of a tilt of the entire helical segments and a kink/swivel of the helical termini at the level of their Pro and Gly have been proposed to be fundamental for the alternative opening and closure of the gates on the matrix or the cytosolic side and thus for the translocation mechanism. The key role of residues of the binding site, gates and Pro-Gly levels in substrate translocation is supported by the localization of most missense mutations found in patients affected by diseases associated to mitochondrial carriers.
References
Klingenberg M (2007 ) Transport viewed as a catalytic process. Biochimie. 89:1042-8.
Palmieri F (2008) Diseases caused by defects of mitochondrial carriers: a review. Biochim Biophys Acta 1777: 564-57
Palmieri F, Pierri CL (2010) Structure and function of mitochondrial carriers - Role of the transmembrane helix P and G residues in the gating and transport mechanism. FEBS Lett. 584:1931-9
Pebay-Peyroula E, Dahout-Gonzalez C, Kahn R, Trézéguet V, Lauquin GJ, Brandolin G. (2003) Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature. 426:39-44
Robinson AJ, Kunji ER. (2006) Mitochondrial carriers in the cytoplasmic state have a common substrate binding site. Proc Natl Acad Sci U S A. 103:2617-22
Robinson AJ, Overy C, Kunji ER. (2008) The mechanism of transport by mitochondrial carriers based on analysis of symmetry. Proc Natl Acad Sci U S A. 105:17766-71
Wibom R, Lasorsa F, Töhönen V, Barbaro M, Sterky F, Kucinski T, Naess K, Jonsson M, Pierri CL, Palmieri F, Wedell A (2009) AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med 361: 489-49
Turbocharger speed monitoring based on vibration measurements for diesel engine management
No full text
A Reliability and latency-aware routing framework for 5G transport infrastructures
No full textThe 5G technology is providing totally new opportunities to mobile communications and their related applications, fostering the creation of service ecosystems and business models that will significantly revolutionize our daily life. With its massive scalability, resiliency and time-sensitive performance demands it will significantly increase the footprint of the underlying transport infrastructure by requiring new control plane facilities capable of supporting the specific needs characterizing end-to-end connections between mobile devices and their targets. Such facilities, built on top of an optical backhaul/fronthaul layer must rely on new routing mechanisms able to meet 5G Ultra-Reliable Low-Latency Communication requirements. Accordingly, this work presents a novel multi-objective distributed online routing scheme for converged fiber-radio transport infrastructures. Such scheme is able to guarantee the 5G reliability and delay optimization needs, while simultaneously taking into account the more traditional network engineering objectives, aiming at satisfying the maximum number of communication requests by taking the best from the already made infrastructural investments. Its effectiveness has been demonstrated through extensive simulation experiments that resulted in quite promising outcomes, enforcing confidence in future industrial developments
On the performance of optical direct-detection DPSK in the presence of receiver impairments
No full textKINETIC DISCRIMINATION OF 2 SUBSTRATE BINDING-SITES OF THE RECONSTITUTED DICARBOXYLATE CARRIER FROM RAT-LIVER MITOCHONDRIA
No full textINDIVERI C, Dierks T, KRAMER R, PALMIERI F. KINETIC DISCRIMINATION OF 2 SUBSTRATE BINDING-SITES OF THE RECONSTITUTED DICARBOXYLATE CARRIER FROM RAT-LIVER MITOCHONDRIA. BIOCHIMICA ET BIOPHYSICA ACTA. 1989;977(2):194-199
A MOLECULAR EXPLANATION OF SLC25A1 DEFICIENCY RESULTING IN AGENESIS OF CORPUS CALLOSUM AND OPTIC NERVE HYPOPLASIA
No full textMitochondrial carriers (MCs) form a large family of nuclear-encoded transporters embedded in the inner mitochondrial membrane and in a few cases in other organelle membranes (Palmieri, 2013). The members of this superfamily are widespread in eukaryotes and involved in numerous metabolic pathways and cell functions. They can be easily recognized by their striking sequence features, i.e., a tripartite structure, six transmembrane α-helices and a 3-fold repeated signature motifs. Members of the family vary greatly in the nature and size of their transported substrates, modes of transport (i.e., uniport, symport or antiport) and driving forces, although the molecular mechanism of substrate translocation may be basically the same. In recent years mutations in the MC genes have been shown to be responsible for 11 diseases (Palmieri, 2013), highlighting the important role of MCs in metabolism. MC impairing mutations affect three main regions crucial for substrate translocation. A first group of mutations affects MC conformational changes and locates at PG levels or at the aromatic belts (Pierri et al., 2013). A second group of mutations affects substrate specificity and locates at the common substrate binding site (Robinson et al., 2008) and at the substrate binding area (Pierri et al., 2013). A further group of mutations locate at residues of the m-/c-gates (Palmieri et al., 2013; Robinson et al., 2008) and at residues of the m-gate area (Pierri et al. 2013). For this last group of mutations, it appears difficult to establish if the impaired function is due to the lack of substrate specificity (or substrate recognition) or to the wrong triggering of conformational changes. Two mutations, one at the PG level 1 and one at the common substrate binding site, impairing citrate translocation within SLC25A1_CTP protein are presented. The two mutations are found to be responsible of agenesis of corpus callosum and optic nerve hypoplasia (Edvardson et al., 2013).
References
1. Palmieri F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Aspects Med. 2013;34:465.
2. Pierri CL, Palmieri F, De Grassi A. Single-nucleotide evolution quantifies the importance of each site along the structure of mitochondrial carriers. Cell Mol Life Sci. 2013.
3. Robinson AJ, Overy C, Kunji ER. The mechanism of transport by mitochondrial carriers based on analysis of symmetry. Proc Natl Acad Sci U S A. 2008;105:17766.
4. Edvardson S, Porcelli V, Jalas C, Soiferman D, Kellner Y, Shaag A, Korman SH, Pierri CL, Scarcia P, Fraenkel ND, Segel R, Schechter A, Frumkin A, Pines O, Saada A, Palmieri L, Elpeleg O. Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter. J Med Genet. 2013;50:240
- …
