Gerbils of a seizure‐sensitive strain have a mitochondrial inner membrane protein with different isoelectric points from those of a seizure‐resistant strain

Omori, Akira; Ichinose, Sachiyo; Kitajima, Satoko; Shimotohno, K; Murashima, Yoshiya L.; Shimotohno, Kunitada; Seto‐Ohshima, Akiko

doi:10.1002/elps.200290034

Cited by 24 publications

(18 citation statements)

References 18 publications

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“…Only a few studies reported the potential cause about the shift of isoelectric points for mitofilin potential modifications. Omori et al proposed that alternative splicing was involved in consistent differences in the isoelectric point for mitofilin in the cerebral cortex between seizure-sensitive gerbil and seizure-resistant gerbil [35].…”

Section: Discussionmentioning

confidence: 99%

The Hippocampal Proteomic Analysis of Senescence-Accelerated Mouse: Implications of Uchl3 and Mitofilin in Cognitive Disorder and Mitochondria Dysfunction in SAMP8

et al. 2008

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Senescence-accelerated mouse prone 8 (SAMP8) is considered as a useful animal model for age-related learning and memory impairments. Hippocampus, a critical brain region associated with cognitive decline during normal aging and various neurodegenerative diseases, appeared a series of abnormalities in SAMP8. To investigate the molecular mechanisms underlying age-related cognitive disorders, we used 2-DE coupled with MALDI TOF/TOF MS to analyze the differential protein expression of the hippocampus of SAMP8 at 6-month-old compared with the age-matched SAM/resistant 1 (SAMR1) which shows normal aging process. Two proteins were found to be markedly changed in SAMP8 as compared to SAMR1: ubiquitin carboxyl-terminal hydrolase L3 (Uchl3), implicating in cytosolic proteolysis of oxidatively damaged proteins, was down-regulated while mitofilin, a vital protein for normal mitochondria function, exhibited four isoforms with a consistent basic shift of isoelectric point among the soluble hippocampal proteins in SAMP8 compared with SAMR1. The alterations were confirmed by Western blotting analysis. The analysis of their expression changes may shed light on the mechanisms of learning and memory deficits and mitochondrial dysfunction as observed in SAMP8.

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Section: Discussionmentioning

confidence: 99%

The Hippocampal Proteomic Analysis of Senescence-Accelerated Mouse: Implications of Uchl3 and Mitofilin in Cognitive Disorder and Mitochondria Dysfunction in SAMP8

et al. 2008

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“…Our studies suggest that mitofilin is an indispensable part of intramitochondrial morphogenetic machinery. Comparative proteomic analysis of the cerebral cortex of a seizuresensitive strain of gerbil and its seizure-resistant (SR) counterpart revealed that gerbil mitofilin showed consistent differences in their isoelectric point between the two strains (Omori et al, 2002). Sequence analysis of mitofilin cDNAs showed several mutations in the SR strains, including one that resides within a conserved region immediately carboxyl terminal of the membrane-anchoring domain.…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial Inner Membrane Protein Mitofilin Controls Cristae Morphology

John

Shang²,

et al. 2005

MBoC

414

460

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Mitochondria are complex organelles with a highly dynamic distribution and internal organization. Here, we demonstrate that mitofilin, a previously identified mitochondrial protein of unknown function, controls mitochondrial cristae morphology. Mitofilin is enriched in the narrow space between the inner boundary and the outer membranes, where it forms a homotypic interaction and assembles into a large multimeric protein complex. Down-regulation of mitofilin in HeLa cells by using specific small interfering RNA lead to decreased cellular proliferation and increased apoptosis, suggesting abnormal mitochondrial function. Although gross mitochondrial fission and fusion seemed normal, ultrastructural studies revealed disorganized mitochondrial inner membrane. Inner membranes failed to form tubular or vesicular cristae and showed as closely packed stacks of membrane sheets that fused intermittently, resulting in a complex maze of membranous network. Electron microscopic tomography estimated a substantial increase in inner:outer membrane ratio, whereas no cristae junctions were detected. In addition, mitochondria subsequently exhibited increased reactive oxygen species production and membrane potential. Although metabolic flux increased due to mitofilin deficiency, mitochondrial oxidative phosphorylation was not increased accordingly. We propose that mitofilin is a critical organizer of the mitochondrial cristae morphology and thus indispensable for normal mitochondrial function. INTRODUCTIONMitochondria are the center of cellular energy production and essential metabolic reactions. As double membranebound organelles, mitochondria from different species, tissues, and metabolic states are highly polymorphic in nature yet exhibit common structural features. The ultrastructural variations in mitochondrial architecture occur mainly due to the differences in the amount and shape of cristae, which derive from the infolded inner membrane in which protein complexes of oxidative phosphorylation and intermediate metabolism are embedded. Abundant cristae are found in mitochondria from tissues where energy demand is high. For example, mitochondria with densely packed cristae are observed in the flight muscle of the dragonfly, whereas the liver of a winter-starved frog displays mitochondria with sparse cristae (Ghadially, 1997). Furthermore, the inner membranes of isolated mitochondria undergo characteristic morphological changes in response to the metabolic state (Hackenbrock, 1966). Although little is known about the molecular mechanisms regulating cristae biogenesis and architecture, recent studies have implicated proteins resident in both the outer and inner membrane to have roles in this process.The mitochondrial fission and fusion machinery plays an essential role in the dynamics, division, distribution, and morphology of the organelle (Yaffe, 1999;Jensen et al., 2000;Griparic and van der Bliek, 2001;Shaw and Nunnari, 2002). Three evolutionarily conserved large GTPases, Dnm1/ Drp1/Dlp1, Fzo1/mitofusin, and Mgm1/MspI/OPA1, are...

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“…To partially digest the NqrA subunit labeled by PUQ-3, the CBB-stained NqrA band was treated with V8-protease (Roche Applied Science, Penzberg, Germany) in a 15% Tris-EDTA mapping gel using according to the procedures described previously (32)(33)(34). The partial digests were characterized by mass spectrometry or N-terminal sequence analysis.…”

Section: Proteomic Analysismentioning

confidence: 99%

Identification of the binding sites for ubiquinone and inhibitors in the Na+-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae by photoaffinity labeling

Ito

Murai

Ninokura

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeThe Na ؉ -pumping NADH-quinone oxidoreductase (Na ؉ -NQR) is the first enzyme of the respiratory chain and the main ion transporter in many marine and pathogenic bacteria, including Vibrio cholerae. I]PAD-2, rather than being competitively suppressed in the presence of other inhibitors, is enhanced under some experimental conditions. To explain these apparently paradoxical results, we propose models for the catalytic reaction of Na ؉ -NQR and its interactions with inhibitors on the basis of the biochemical and biophysical results reported here and in previous work.The Na ϩ -pumping NADH-quinone oxidoreductase (Na ϩ -NQR) 2 is the first enzyme of the respiratory chain and the main ion transporter in many marine and pathogenic bacteria, such as Vibrio cholerae and Haemophilus influenzae (1, 2). Na ϩ -NQR obtains energy by oxidizing NADH and reducing ubiquinone, which allows it to generate an electrochemical Na ϩ gradient across the inner bacterial membrane. The enzyme is an integral membrane complex consisting of six subunits (NqrA-F) encoded by the nqr operon (2). There is a consensus that the electron transfer takes place through a series of five redox cofactors as follows: a FAD; a 2Fe-2S center; two covalently bound FMN, and a riboflavin (3-5). Different studies have intensively investigated the locations and redox properties of the cofactors of the enzyme (6 -12); however, the exact locations of the ubiquinone-binding site(s) and the Na ϩ transport pathway, as well as the mechanism that couples Na ϩ transport to the electron transfer, still remain elusive.A recently published X-ray crystallographic study provided important information about the structure of V. cholerae Na ϩ -NQR (13), but the model includes several features that are difficult to reconcile with previous biochemical and/or biophysical functional characterizations (11). For instance, the spatial distances between several pairs of redox cofactors in the proposed electron transfer pathway are too large to support physiological rates of electron transfer; for example, the edge-toedge distance between the [2Fe-2S] cluster in NqrF and the Fe(Cys) 4 in NqrD (33.4 Å) and between the FMN and the riboflavin cofactor in NqrB (29.3 Å). The fact that electron transfer between these cofactors takes place indicates that the subunits harboring the cofactors undergo large conformational changes during turnover that decrease these spatial gaps (13).Additionally, the crystallographic model lacks an anticipated tightly bound quinone, which has been reported in the enzyme preparations from different laboratories (4,6,8) and suggested to be located in NqrA on the basis of photoaffinity labeling and NMR studies (7,9). In the crystallographic model, the NqrA subunit includes a deep cavity that is large enough to accommodate a ubiquinone molecule, but the cavity is ϳ20 Å above the predicted membrane surface and the distance between the cavity and the riboflavin in NqrB subunit is too large (Ͼ40 Å) to be consistent with electron transfer during tu...

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Gerbils of a seizure‐sensitive strain have a mitochondrial inner membrane protein with different isoelectric points from those of a seizure‐resistant strain

Cited by 24 publications

References 18 publications

The Hippocampal Proteomic Analysis of Senescence-Accelerated Mouse: Implications of Uchl3 and Mitofilin in Cognitive Disorder and Mitochondria Dysfunction in SAMP8

The Hippocampal Proteomic Analysis of Senescence-Accelerated Mouse: Implications of Uchl3 and Mitofilin in Cognitive Disorder and Mitochondria Dysfunction in SAMP8

The Mitochondrial Inner Membrane Protein Mitofilin Controls Cristae Morphology

Identification of the binding sites for ubiquinone and inhibitors in the Na+-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae by photoaffinity labeling

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