MITOP, the mitochondrial proteome database: 2000 update

Scharfe, Curt; Zaccaria, Paolo; Hoertnagel, Konstanze; Jaksch, Michaela; Klopstock, Thomas; Dembowski, Markus; Lill, Roland; Prokisch, Holger; Gerbitz, Klaus-Dieter; Neupert, Walter; Mewes, Hans‐Werner; Meitinger, Thomas

doi:10.1093/nar/28.1.155

Cited by 68 publications

(27 citation statements)

References 19 publications

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“…This finding appears to rule out complementation of the auxotrophy by an indirect effect of the expressed gene. Overall, this manuscript describes the first human protein identified to transport folates or, to our knowledge, any vitamin across the inner mitochondrial membrane (32).…”

Section: Resultsmentioning

confidence: 99%

Retrovirally Mediated Complementation of the glyBPhenotype

Titus

Moran

2000

Journal of Biological Chemistry

118

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The transduction of a human placental cDNA retroviral library into glyB cells, a Chinese hamster ovary K1 subline that is deficient in the transport of folates into mitochondria, resulted in the complementation of glycine auxotrophy of these cells. A 2.6-kilobase pair cDNA insert flanked by retroviral sequences had integrated into genomic DNA in rescued cells. An open reading frame in this cDNA encoded a 35-kDa protein homologous to several inner mitochondrial wall transporters for intermediate metabolites. The subcloned cDNA complemented the glycine auxotrophy of glyB cells and reinstated folate accumulation in the mitochondria of transfected cells. The human origin, chromosomal location, and intron-exon organization of the isolated mitochondrial folate transporter gene were deduced from the expressed sequence tag database and human genome project data.In mammalian cells, the processes of folate metabolism are distributed between the cytosolic and mitochondrial compartments (1). Mitochondrial folates amount to about 35% of the total cellular pool (2, 3) and are used as cofactors for a mitochondrial serine hydroxymethyltransferase (SHMT) 1 by the glycine cleavage system and for the synthesis of the formylmethionine initiator of mitochondrial protein synthesis.The transport of folates through the plasma membrane into the cytosol has been extensively studied (4 -6), and two of the transport systems have been cloned (7,8). In contrast, the mechanism of the transfer of folates into mitochondria, presumably from the cytosol, is largely unknown as is the release of folates back into the cytosol from the mitochondria. Once the folate monoglutamates, the form of folate found in the circulation, enter the mammalian cells they are quickly metabolized to poly-␥-glutamate derivatives by cytosolic folylpoly-␥-glutamate synthetase (FPGS), a process needed to promote the retention of folate cofactors in cells (9). FPGS is also present in the mitochondrial compartment of mammalian cells (10) translated from transcripts from the FPGS gene, which add a mitochondrial leader sequence to the coding region of the protein found in the cytosol (11,12). Two studies (13,14) have demonstrated the penetration into isolated mitochondria by folates in a process that was saturable and temperature-dependent. These studies would support the existence of a transporter responsible for the entry of folates into the mitochondria as does the fact that cells that either lack mitochondrial FPGS (11) or are incapable of accumulation of mitochondrial folates (15) are glycine auxotrophs.Early studies by Puck and coworkers (16, 17) selected somatic cells that were auxotrophic for glycine and demonstrated that these cells fell into four complementation groups named glyA, glyB, glyC, and glyD. glyA was found to be attributed to a deficiency in mitochondrial SHMT (17,18). The glyC and glyD mutations have not to our knowledge been assigned to any functions. glyB cells had normal cytosolic folate metabolism and enzymes and had the same mitochondrial SHMT and...

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Section: Resultsmentioning

confidence: 99%

Retrovirally Mediated Complementation of the glyBPhenotype

Titus

Moran

2000

Journal of Biological Chemistry

118

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“…Since mitochondrial FSR, as measured in our study, represents [ 2 H]alanine incorporation in both nuclear-and mtDNA-encoded proteins over a 24-h period, any defects in the replication, transcription, or translation of either genome could theoretically have attributed to a blunted anabolic response in the obese phenotype. Considering that the vast majority of mitochondrial matrix and membrane proteins are encoded by nuclear DNA [only 13 of ϳ1,000 -2,000 proteins are encoded by the organelle's own genome (55)], in addition to the fact that replication, transcription, and translation of mtDNA are controlled ultimately by nuclear-encoded proteins (19), we believe that insulin resistance syndrome is associated with multiple dysfunctions in the manufacture and/or import of nuclear proteins, leading to an attenuated anabolic response of mitochondria following acute contractile activity. Because of the necessity of a 24-h 2 H 2 O enrichment period, the signal transduction events underlying this phenomenon remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Insulin resistance syndrome blunts the mitochondrial anabolic response following resistance exercise

Nilsson

Greene

Dobson

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Metabolic risk factors associated with insulin resistance syndrome may attenuate augmentations in skeletal muscle protein anabolism following contractile activity. The purpose of this study was to investigate whether or not the anabolic response, as defined by an increase in cumulative fractional protein synthesis rates (24-h FSR) following resistance exercise (RE), is blunted in skeletal muscle of a well-established rodent model of insulin resistance syndrome. Four-month-old lean ( Fa/?) and obese ( fa/fa) Zucker rats engaged in four lower body RE sessions over 8 days, with the last bout occurring 16 h prior to muscle harvest. A priming dose of deuterium oxide (2H2O) and 2H2O-enriched drinking water were administered 24 h prior to euthanization for assessment of cumulative FSR. Fractional synthesis rates of mixed (−5%), mitochondrial (−1%), and cytosolic (+15%), but not myofibrillar, proteins (−16%, P = 0.012) were normal or elevated in gastrocnemius muscle of unexercised obese rats. No statistical differences were found in the anabolic response of cytosolic and myofibrillar subfractions between phenotypes, but obese rats were not able to augment 24-h FSR of mitochondria to the same extent as lean rats following RE (+14% vs. +28%, respectively). We conclude that the mature obese Zucker rat exhibits a mild, myofibrillar-specific suppression in basal FSR and a blunted mitochondrial response to contractile activity in mixed gastrocnemius muscle. These findings underscore the importance of assessing synthesis rates of specific myocellular subfractions to fully elucidate perturbations in basal protein turnover rates and differential adaptations to exercise stimuli in metabolic disease.

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“…The exact number of mitochondrial proteins is not known but is believed to be ϳ1,000 proteins (43). Most of the proteomic analyses performed to date have identified mitochondrial proteins using high-throughput experiments.…”

Section: Discussionmentioning

confidence: 99%