Genetic Mapping of Human Heart-Skeletal Muscle Adenine Nucleotide Translocator and Its Relationship to the Facioscapulohumeral Muscular Dystrophy Locus

Haraguchi, Yoshikura; Chung, Andrew B.; Torroni, Antonio; Stepien, Georges; Shoffner, John M.; Wasmuth, John J.; Costigan, Donal; Polak, Meraida; Altherr, Michael R.; Winokur, Sara T.; Wallace, Douglas C.

doi:10.1006/geno.1993.1214

Cited by 19 publications

(7 citation statements)

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“…It also revealed a 67 % identity and 79 % similarity with a human fibroblast isoform, AAC2 (Ku et al, 1990). The SFEC protein was localized to human chromosome 4q28.1, whereas the other known ADP/ATP carrier proteins localize to chromosome 4q35.1 (AAC1, Haraguchi et al, 1993); chromosome Xp22.32 and Yp (AAC3, Slim et al, 1993;Schiebel et al, 1993), and Xq24 (AAC3, Schiebel et al, 1993), respectively. The mouse SFEC protein localized to chromosome 3B, which is syntenic to locus 4q28.2 in the human (Dehal et al, 2001).…”

Section: Sfec (Aac4) Was Identified In the Purified Fibrous Sheathmentioning

confidence: 99%

Compartmentalization of a unique ADP/ATP carrier protein SFEC (Sperm Flagellar Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece

Kim

Haidl

Schaefer³

et al. 2007

Developmental Biology

102

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The longest part of the sperm flagellum, the principal piece, contains the fibrous sheath, a cytoskeletal element unique to spermiogenesis. We performed mass spectrometry proteomics on isolated human fibrous sheaths identifying a unique ADP/ATP carrier protein, SFEC [AAC4], seven glycolytic enzymes previously unreported in the human sperm fibrous sheath, and sorbitol dehydrogenase. SFEC, pyruvate kinase and aldolase were co-localized by immunofluorescence to the principal piece. A homology model constructed for SFEC predicted unique residues at the entrance to the nucleotide binding pocket of SFEC that are absent in other human ADP/ATP carriers, suggesting opportunities for selective drug targeting. This study provides the first evidence of a role for an ADP/ATP carrier family member in glycolysis. The co-localization of SFEC and glycolytic enzymes in the fibrous sheath supports a growing literature that the principal piece of the flagellum is capable of generating and regulating ATP independently from mitochondrial oxidation in the mid-piece. A model is proposed that the fibrous sheath represents a highly ordered complex, analogous to the electron transport chain, in which adjacent enzymes in the glycolytic pathway are assembled to permit efficient flux of energy substrates and products with SFEC serving to mediate energy generating and energy consuming processes in the distal flagellum, possibly as a nucleotide shuttle between flagellar glycolysis, protein phosphorylation and mechanisms of motility.

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Section: Sfec (Aac4) Was Identified In the Purified Fibrous Sheathmentioning

confidence: 99%

Compartmentalization of a unique ADP/ATP carrier protein SFEC (Sperm Flagellar Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece

Kim

Haidl

Schaefer³

et al. 2007

Developmental Biology

102

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“…There are multiple ANT isoforms derived from different genes. In humans there are three tissue‐specific isoforms [Stepien et al, 1992]: a heart‐muscle specific isoform (ANT1) located at the chromosome 4q35 locus [Neckelmann et al, 1987; Houldsworth and Attardi, 1988; Cozens et al, 1989; Li et al, 1989; Wijmenga et al, 1992, 1993; Haraguchi et al, 1993; Giraud et al, 1998], an inducible isoform (ANT2) located at Xq24 [Battini et al, 1987; Houldsworth and Attardi, 1988; Chen et al, 1990; Ku et al, 1990; Schiebel et al, 1994], and a systemic isoform (ANT3) located in the pseudoautosomal region at Xp22.3 [Houldsworth and Attardi, 1988; Schiebel et al, 1993; Slim et al, 1993; Giraud et al, 1998]. In mice there are only two ANT genes ( Ant1 and Ant2 ), homologues of the human ANT1 and ANT2 proteins [Levy et al, 2000].…”

Section: Mitochondrial Biology and Geneticsmentioning

confidence: 99%

Mouse models for mitochondrial disease

Wallace

2001

Am. J. Med. Genet.

163

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Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.

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“…We also examined a facio-scapulo-humeral muscular dystrophy (FSHMD) muscle sample, because this mutation maps close to ANT1 on the long arm of chromosome 4 (42,43). A summary of the patients and their percentages of heteroplasmy are provided in Table I.…”

Section: Energy Gene Induction In Skeletal Muscle From Patients With mentioning

confidence: 99%

“…Several transcription factors that influence OXPHOS gene expression have been already discovered. These include NRF1 and NRF2 (54,55), the "Mt" element (56,57), the CREB element (58), and the OXBOX-REBOX elements (42,59,60). Some of these elements might be important in compensatory regulation of transcription.…”

Section: Energy Gene Expression In Mitochondrial Diseasesmentioning

confidence: 99%

Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients

Heddi¹,

Stepien²,

Benke³

et al. 1999

Journal of Biological Chemistry

159

100

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We have examined the transcript levels of a variety of oxidative phosphorylation (OXPHOS) and associated bioenergetic genes in tissues of a patient carrying the myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) A3243G mitochondrial DNA (mtDNA) mutation and the skeletal muscles of 14 patients harboring other pathogenic mtDNA mutations. The patients' tissues, which harbored 88% or more mutant mtDNA, had increased levels of mtDNA transcripts, increased nuclear OXPHOS gene transcripts including the ATP synthase ␤ subunit and the heart-muscle isoform of the adenine nucleotide translocator, and increased ancillary gene transcripts including muscle mitochondrial creatine phosphokinase, muscle glycogen phosphorylase, hexokinase I, muscle phosphofructokinase, the E1␣ subunit of pyruvate dehydrogenase, and the ubiquinone oxidoreductase. A similar coordinate induction of bioenergetic genes was observed in the muscle biopsies of severe pathologic mtDNA mutations. The more significant coordinated expression was found in muscle from patients with the MELAS, myoclonic epilepsy with ragged red fibers, and chronic progressive external ophthalmoplegia deletion syndromes, with ragged red muscle fibers and mitochondrial paracrystalline inclusions. High levels of mutant mtDNAs were linked to a high induction of the mtDNA and nuclear OXPHOS genes and of several associated bioenergetic genes. These observations suggest that human tissues attempt to compensate for OXPHOS defects associated with mtDNA mutations by stimulating mitochondrial biogenesis, possibly mediated through redox-sensitive transcription factors.

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Genetic Mapping of Human Heart-Skeletal Muscle Adenine Nucleotide Translocator and Its Relationship to the Facioscapulohumeral Muscular Dystrophy Locus

Cited by 19 publications

References 0 publications

Compartmentalization of a unique ADP/ATP carrier protein SFEC (Sperm Flagellar Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece

Compartmentalization of a unique ADP/ATP carrier protein SFEC (Sperm Flagellar Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece

Mouse models for mitochondrial disease

Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients

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