Mitochondrial Transport Processes

Kaplan, Ronald S.

doi:10.1007/978-1-4613-1143-0_15

Cited by 6 publications

(3 citation statements)

References 257 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The gene defective in HHH syndrome is the mitochondrial ornithine transporter (ORNT1) that is localized in the q14.1 region of Ch13 and is a member of the MCF of proteins that includes the uncoupling protein, carnitine/acyl-carnitine translocase, and the ADP/ATP transporter (3,4). The human ORNT1 gene is expressed in the periportal hepatocytes, which contain the urea cycle pathway, and in the pericentral hepatocytes and skin fibroblasts that express the ornithine degradation pathway (1,2).…”

mentioning

confidence: 99%

Clinical and Functional Characterization of a Human ORNT1 Mutation (T32R) in the Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

et al. 2006

View full text Add to dashboard Cite

ABSTRACT:We studied two related families (HHH013 and HHH015) with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, a disorder of the urea cycle and ornithine degradation pathway, who have the same novel ornithine transporter (ORNT1) genotype (T32R) but a variable phenotype. Both HHH015 patients are doing well in school and are clinically stable; conversely, the three affected HHH013 siblings had academic difficulties and one suffered recurrent episodes of hyperammonemia and ultimately died. Overexpression studies revealed that the product of the ORNT1-T32R allele has residual function. Ornithine transport studies in HHH015 fibroblasts, however, showed basal activity similar to fibroblasts carrying nonfunctional ORNT1 alleles. We also examined two potential modifying factors, the ORNT2 gene and the mitochondrial DNA lineage (haplogroup). Haplogroups, associated with specific diseases, are hypothesized to influence mitochondrial function. Results demonstrated that both HHH015 patients are heterozygous for an ORNT2 gain of function polymorphism and belong to haplogroup A whereas the HHH013 siblings carry the wild-type ORNT2 and are haplogroup H. These observations suggest that the ORNT1 genotype cannot predict the phenotype of HHH patients. The reason for the phenotypic variability is unknown, but factors such as redundant transporters and mitochondrial lineage may contribute to the neuropathophysiology of HHH patients. T he HHH syndrome (OMIM #238970) is an autosomal recessive disorder of the urea cycle and ornithine degradation pathway caused by the deficient transport of ornithine across the inner mitochondrial membrane (1,2). The gene defective in HHH syndrome is the mitochondrial ornithine transporter (ORNT1) that is localized in the q14.1 region of Ch13 and is a member of the MCF of proteins that includes the uncoupling protein, carnitine/acyl-carnitine translocase, and the ADP/ATP transporter (3,4). The human ORNT1 gene is expressed in the periportal hepatocytes, which contain the urea cycle pathway, and in the pericentral hepatocytes and skin fibroblasts that express the ornithine degradation pathway (1,2). Physiologically, ORNT1 allows ornithine to serve as a substrate for the ornithine transcarbamylase (OTC) and ornithine amino transferase (OAT) reactions that produce citrulline and the two amino acids, glutamate and proline. In vitro studies have demonstrated that ORNT1 transports ornithine, lysine, and arginine across the inner mitochondrial membrane in exchange for a hydrogen ion and citrulline (5).Biochemically, HHH syndrome is characterized by persistent elevation of plasma ornithine, episodic or postprandial hyperammonemia, and the urinary excretion of homocitrulline and orotic acid (1). The homocitrulline is believed to be the product of transcarbamoylation of lysine whereas the orotic aciduria occurs secondary to decreased OTC activity. Numerous studies have clearly demonstrated a link between hyperammonemia and CNS pathology in urea cycle disorders. However, little is known ...

show abstract

mentioning

confidence: 99%

Clinical and Functional Characterization of a Human ORNT1 Mutation (T32R) in the Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

et al. 2006

View full text Add to dashboard Cite

show abstract

“…8) form structurally large loops (or unordered structures) which can aggregate to form intermolecular b-sheets, making the protein nonfunctional. This is supported by the evidence that the M loops play an important functional role in the protein, being involved in the substrates/inhibitors binding (especially the M2 loop; see Bogner et al, 1986;Dalbon et al, 1988;, substrates transport (Brandolin et al, 1993a;Majima et al, 1994), and perhaps forming a portion of the translocation pathway (Kaplan, 1996;Klingenberg, 1989). Moreover, the M loops contain many conserved residues (Brandolin et al, 1993a), and some of them have been proven to be essential for the protein function as revealed from site-directed mutagenesis (Mu ¨ller et al, 1996(Mu ¨ller et al, , 1997.…”

Section: Discussionmentioning

confidence: 85%

“…Both conformations show particular chemical, immunochemical, and enzymatic reactivities, and their interconversions are probably a key feature of the transport process. For further details, see reviews by Brandolin et al (1993a), Fiore et al (1998), and Kaplan (1996).…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Implications of the Instability of the ADP/ATP Transporter Purified from Mitochondria as Revealed by FTIR Spectroscopy

Lórenz-Fonfrı́a

Villaverde

Trezeguet

et al. 2003

Biophysical Journal

View full text Add to dashboard Cite

The ADP/ATP transporter shows a high instability when solubilized, making it difficult to obtain functional protein with sufficient purity for long-term spectroscopic studies. When solubilized in the detergent dodecyl maltoside the protein is in equilibrium between the so-called CATR and BA conformations and in a few hours it becomes nonfunctional, unable to bind either its inhibitors or its substrates. By Fourier transform infrared spectroscopy, we studied the structural changes involved in this denaturation process. To do so, the carboxyatractyloside-inhibited protein was used as a structural model for the protein in the CATR conformation and its spectrum was compared with that of the unliganded time-inactivated protein. From the difference spectra of the amide I, amide II, and amide A bands combined with dichroism spectra of the carboxyatractyloside-inhibited protein, we concluded that few structural differences exist between both states, affecting as few as 11 amino acids (3.5% of the protein); the structural changes consisted in the disappearance of large loop structure and the appearance of aggregated strands. We hypothesize that some mitochondrial loop (tentatively loop M1) shows a high tendency to aggregate, being responsible for the observed features. The functional consequences of this hypothesis are discussed.

show abstract

Regulation of Fatty Acid Biosynthesis and Lipolysis

Salati

2001

Comprehensive Physiology

View full text Add to dashboard Cite

The sections in this article are: Pathways of De Novo Fatty Acid Biosynthesis and Lipolysis Regulation in the Pathways for Lipogenesis and Lipolysis Cellular Sites of Lipogenesis and Lipolysis Isolated Cell Models for the Study of Lipogenesis and Lipolysis Establishing Insulin and Glucagon as Regulators of Lipogenesis and Lipolysis Molecular Mechanisms Involved in the Regulation of Lipogenesis and Lipolysis Criteria for Evaluating Putative Regulatory Mechanisms Regulated Steps Summary

show abstract

Mitochondrial Transport Processes

Cited by 6 publications

References 257 publications

Clinical and Functional Characterization of a Human ORNT1 Mutation (T32R) in the Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

Clinical and Functional Characterization of a Human ORNT1 Mutation (T32R) in the Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

Structural and Functional Implications of the Instability of the ADP/ATP Transporter Purified from Mitochondria as Revealed by FTIR Spectroscopy

Regulation of Fatty Acid Biosynthesis and Lipolysis

Contact Info

Product

Resources

About