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At least 721 records · Page 40Linked to original sources
PubMed2006

A WD40 repeat protein, Arabidopsis Sec13 homolog 1, may play a role in vacuolar trafficking by controlling the membrane association of AtDRP2A.

Dynamin-related protein 2A (AtDRP2A, formally ADL6), a member of the dynamin family, is critical for protein trafficking from the TGN to the central vacuole. However, the mechanism controlling its activity is not well understood in plant cells. We isolated Arabidopsis sec13 homolog1 (AtSeh1) that interacts with AtDRP2A by a yeast two-hybrid screening. AtSeh1 has four WD40 motifs and amino acid sequence homology to Sec13, a component of COPII vesicles. Coimmunoprecipitation and protein pull-down experiments demonstrated specific interaction between AtSeh1 and AtDRP2A. AtSeh1 bound to the pleckstrin homology domain of AtDRP2A in competition with the C-terminal domain of the latter, and this resulted in inhibition of the interaction between AtDRP2A and PtdIns3P in vitro. AtSeh1 localized to multiple locations: the nucleus, the prevacuolar compartment and the Golgi complex. Based on these results we propose that AtSeh1 plays a role in regulating cycling of AtDRP2A between membrane-bound and soluble forms.

Amino Acid Motifs↗
PubMed1994

Calcineurin-mediated protein dephosphorylation in brain nerve terminals regulates the release of glutamate.

In response to Ca2+ entry, several prominent brain nerve terminal phosphoproteins undergo dephosphorylation, but the relation between dephosphorylation and neurotransmitter release is unknown. Using the immunosuppressants cyclosporin A (CsA) and L-683,590 (FK-520) to inhibit specifically the Ca2+/calmodulin-dependent protein phosphatase calcineurin, we demonstrate here that Ca(2+)-dependent dephosphorylation in isolated rat brain nerve terminals (synaptosomes) is mediated by calcineurin. Pretreatment with micromolar CsA resulted in a 76-95% inhibition of stimulation-induced decreases in 32P-labeled dynamin (previously referred to as dephosphin), a phosphoprotein of M(r) = 145,000 (145-kDa protein), and a phosphoprotein of M(r) = 170,000 (170-kDa protein). Pretreatment with FK-520 also inhibited Ca(2+)-dependent dephosphorylation. Using hypotonic lysates of 32P-labeled synaptosomes, the addition of Ca2+ plus calmodulin, but not either agent alone, induced dynamin dephosphorylation. CsA and FK-520 had little to no effect on the release of glutamate induced by either K(+)-depolarization or the Ca2+ ionophore ionomycin. In contrast, calcineurin inhibition led to a substantial enhancement of glutamate release evoked by the K(+)-channel blocker 4-aminopyridine, an agent whose action most closely mimics physiological stimulation. Calcineurin inhibition had no effect on stimulation-induced changes in synaptosomal Ca2+ levels. Based on our findings, we hypothesize that Ca(2+)-dependent protein dephosphorylation resulting from calcineurin activation during physiological stimulation limits neurotransmitter release from brain nerve terminals, perhaps being dependent upon cyclic repolarization of the membrane during stimulation.

4-Aminopyridine↗
PubMed1997

Multiple Grb2-protein complexes in human cancer cells.

Grb2 is an SH2/SH3 domain-containing adaptor protein that links receptor tyrosine kinases to the ras signaling pathway. The Grb2-SH2 domain binds phosphotyrosine sequences on activated tyrosine kinases, and one target of the SH3 domains is the ras-nucleotide-exchange factor Sos1. We have examined Grb2-protein interactions in human cancer cells that over-express the receptor tyrosine kinase erbB2. Our results show that the 2 Grb2-SH3 domains complex with Sos1, dynamin and at least 4 other proteins (p228, p140, p55, p28) in these cells. The 2 Grb2-SH3 domains bind these proteins differently, with the N-terminal SH3 domain interacting preferentially with p228, Sos1, p140 and dynamin. The C-terminal SH3 domain has higher affinity toward p28. The Grb2-SH3 domain interactions appear to be similar in erbB2 over-expressing breast, ovarian and lung cancer cells. Also, the major tyrosine-phosphorylated proteins that associate with Grb2 in erbB2 over-expressing cancer cells appear to be erbB2 and Shc. The multiple Grb2-SH3 domain interactions in these cells may mediate novel cellular functions.

3T3 Cells↗
PubMed2002

Regulators of GTP-binding proteins cause morphological changes in the vacuole system of the filamentous fungus, Pisolithus tinctorius.

Tubule formation is a widespread feature of the endomembrane system of eukaryotic cells, serving as an alternative to the better-known transport process of vesicular shuttling. In filamentous fungi, tubule formation by vacuoles is particularly pronounced, but little is known of its regulation. Using the hyphae of the basidiomycete Pisolithus tinctorius as our test system, we have investigated the effects of four drugs whose modulation, in animal cells, of the tubule/vesicle equilibrium is believed to be due to the altered activity of a GTP-binding protein (GTP gamma S, GDP beta S, aluminium fluoride, and Brefeldin A). In Pisolithus tinctorius, GTP gamma S, a non-hydrolysable form of GTP, strongly promoted vacuolar tubule formation in the tip cell and next four cells. The effects of GTP gamma S could be antagonised by pre-treatment of hyphae with GDP beta S, a non-phosphorylatable form of GDP. These results support the idea that a GTP-binding protein plays a regulatory role in vacuolar tubule formation. This could be a dynamin-like GTP-ase, since GTP gamma S-stimulated tubule formation has only been reported previously in cases where a dynamin is involved. Treatment with aluminium fluoride stimulated vacuolar tubule formation at a distance from the tip cell, but NaF controls indicated that this was not a GTP-binding-protein specific effect. Brefeldin A antagonised GTP gamma S, and inhibited tubule formation in the tip cell. Given that Brefeldin A also affects the ER and Golgi bodies of Pisolithus tinctorius, as shown previously, it is not clear yet whether the effects of Brefeldin A on the vacuole system are direct or indirect.

Aluminum Compounds↗
PubMed2006

Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease).

Over the last 15 years, a number of mutations in a variety of genes have been identified that lead to inherited motor and sensory neuropathies (HMSN), also called Charcot-Marie-Tooth disease (CMT). In this review we will focus on the molecular and cellular mechanisms that cause the Schwann cell pathologies observed in dysmyelinating and demyelinating forms of CMT. In most instances, the underlying gene defects alter primarily myelinating Schwann cells followed by secondary axonal degeneration. The first set of proteins affected by disease-causing mutations includes the myelin components PMP22, P0/MPZ, Cx32/GJB1, and periaxin. A second group contains the regulators of myelin gene transcription EGR2/Krox20 and SOX10. A third group is composed of intracellular Schwann cells proteins that are likely to be involved in the synthesis, transport and degradation of myelin components. These include the myotubularin-related lipid phosphatase MTMR2 and its regulatory binding partner MTMR13/SBF2, SIMPLE, and potentially also dynamin 2. Mutations affecting the mitochondrial fission factor GDAP1 may indicate an important contribution of mitochondria in myelination or myelin maintenance, whereas the functions of other identified genes, including NDRG1, KIAA1985, and the tyrosyl-tRNA synthase YARS, are not yet clear. Mutations in GDAP1, YARS, and the pleckstrin homology domain of dynamin 2 lead to an intermediate form of CMT that is characterized by moderately reduced nerve conduction velocity consistent with minor myelin deficits. Whether these phenotypes originate in Schwann cells or in neurons, or whether both cell types are directly affected, remains a challenging question. However, based on the advances in systematic gene identification in CMT and the analyses of the function and dysfunction of the affected proteins, crucially interconnected pathways in Schwann cells in health and disease have started to emerge. These networks include the control of myelin formation and stability, membrane trafficking, intracellular protein sorting and quality control, and may extend to mitochondrial dynamics and basic protein biosynthesis.

Animals↗
PubMed2003

Adenovirus endocytosis.

Pathogen entry into cells occurs by direct penetration of the plasma membrane, clathrin-mediated endocytosis, caveolar endocytosis, pinocytosis or macropinocytosis. For a particular agent, the infectious pathways are typically restricted, reflecting a tight relationship with the host. Here, we survey the uptake process of human adenovirus (Ad) type 2 and 5 and integrate it into the cell biology of endocytosis. Ad2 and Ad5 naturally infect respiratory epithelial cells. They bind to a primary receptor, the coxsackie virus B Ad receptor (CAR). The CAR-docked particles activate integrin coreceptors and this triggers a variety of cell responses, including endocytosis. Ad2/Ad5 endocytosis is clathrin-mediated and involves the large GTPase dynamin and the adaptor protein 2. A second endocytic process is induced simultaneously with viral uptake, macropinocytosis. Together, these pathways are associated with viral infection. Macropinocytosis requires integrins, F-actin, protein kinase C and small G-proteins of the Rho family, but not dynamin. Macropinocytosis per se is not required for viral uptake into epithelial cells, but it appears to be a productive entry pathway of Ad artificially targeted to the high-affinity Fcgamma receptor CD64 of hematopoietic cells lacking CAR. In epithelial and hematopoietic cells, the macropinosomal contents are released to the cytosol. This requires viral signalling from the surface and coincides with particle escape from endosomes and infection. It emerges that incoming Ad2 and Ad5 distinctly modulate the endocytic trafficking and disrupt selective cellular compartments. These features can be exploited for effective artificial targeting of Ad vectors to cell types of interest.

Adenoviridae↗
PubMed2004

Adenovirus endocytosis.

Pathogen entry into cells occurs by direct penetration of the plasma membrane, clathrin-mediated endocytosis, caveolar endocytosis, pinocytosis or macropinocytosis. For a particular agent, the infectious pathways are typically restricted, reflecting a tight relationship with the host. Here, we survey the uptake process of human adenovirus (Ad) type 2 and 5 and integrate it into the cell biology of endocytosis. Ad2 and Ad5 naturally infect respiratory epithelial cells. They bind to a primary receptor, the coxsackie virus B Ad receptor (CAR). The CAR-docked particles activate integrin coreceptors and this triggers a variety of cell responses, including endocytosis. Ad2/Ad5 endocytosis is clathrin-mediated and involves the large GTPase dynamin and the adaptor protein 2. A second endocytic process is induced simultaneously with viral uptake, macropinocytosis. Together, these pathways are associated with viral infection. Macropinocytosis requires integrins, F-actin, protein kinase C and small G-proteins of the Rho family, but not dynamin. Macropinocytosis per se is not required for viral uptake into epithelial cells, but it appears to be a productive entry pathway of Ad artificially targeted to the high-affinity Fcgamma receptor CD64 of hematopoietic cells lacking CAR. In epithelial and hematopoietic cells, the macropinosomal contents are released to the cytosol. This requires viral signalling from the surface and coincides with particle escape from endosomes and infection. It emerges that incoming Ad2 and Ad5 distinctly modulate the endocytic trafficking and disrupt selective cellular compartments. These features can be exploited for effective artificial targeting of Ad vectors to cell types of interest.

Adenoviridae↗
PubMed2002

Furrow-specific endocytosis during cytokinesis of zebrafish blastomeres.

Mutations affecting endocytosis, such as those in clathrin and dynamin, unexpectedly cause defects in cytokinesis in a number of organisms. To explore the relationship between endocytosis and cytokinesis, we used the relatively large cells of the transparent zebrafish embryo. Using fluorescent markers for fluid-phase as well as plasma membrane uptake, we demonstrate that cytokinesis involves furrow-specific endocytosis. Clathrin-coated pits are visible near the furrow in ultrathin sections, while immunolabeling demonstrates that clathrin and caveolin are localized to the cleavage furrow. Hence, it is likely that both clathrin- and caveolae-mediated endocytosis occurs at the furrow during cytokinesis. Dynamin II is also localized to the furrow and may mediate furrow-specific endocytosis. Treatment of embryos with chlorpromazine or with methyl-beta-cyclodextrin, both of which inhibit endocytosis, prevents the normal completion of cytokinesis. These data suggest that furrow-specific endocytosis is an integral part of cytokinesis.

Animals↗
PubMed1998

Two isoforms of a human intersectin (ITSN) protein are produced by brain-specific alternative splicing in a stop codon.

Using selected trapped exons with homology to specific protein domains, we identified a new full-length cDNA encoding a protein containing many motifs for protein-protein interactions. There are two major mRNA transcripts, a ubiquitously expressed mRNA of 5.3 kb and a brain-specific transcript of approximately 15 kb, encoding proteins of 1220 and 1721 amino acids, respectively. The stop codon of the ORF of the shorter transcript is split between adjacent exons. In brain tissues the last exon of the short transcript is skipped, and an alternative downstream exon, the first of several additional, is used to produce the 15-kb mRNA. The putative human protein is highly homologous to Xenopus intersectin (81% identical) and to Drosophila dynamin-associated protein, Dap160 (31% identical) and was termed intersectin (ITSN). Both human proteins contain five SH3 (Src homology 3) domains, two EH (Eps15 homology) domains, and an alpha-helix-forming region. The brain-specific long transcript encodes for three additional domains: a GEF (guanine-nucleotide exchange factors), a PH (pleckstrin homology), and a C2 domain. The Drosophila homologue is associated with dynamin, a protein family involved in the endocytic pathway and/or synaptic vesicle recycling. The structure of the human ITSN protein is consistent with its involvement in membrane-associated molecular trafficking and signal transduction pathways. The human ITSN gene has been mapped to 21q22. 1-q22.2 between markers D21S319 and D21S65, and its importance in Down syndrome and monogenic disorders is currently unknown.

Adaptor Proteins, Vesicular Transport↗
PubMed1993

Mx proteins: GTPases with antiviral activity.

Mx proteins are synthesized in interferon-treated vertebrate cells. They have attracted much attention because some of them can block the multiplication of influenza A virus and certain other negative-stranded RNA viruses. Recently, Mx proteins have been shown to be GTPases with significant homology to dynamins and yeast VPS1, enzymes involved in intracellular protein trafficking. Several biochemical properties of dynamin and VPS1 are similar to those of Mx, promoting new speculation about how Mx proteins might interfere with virus multiplication.

Journal Article↗
PubMed2005

Demonstration of differential quantitative requirements for NSF among multiple vesicle fusion pathways of GLUT4 using a dominant-negative ATPase-deficient NSF.

In this study, we investigated the relative participation of N-ethylmaleimide-sensitive factor (NSF) in vivo in a complex multistep vesicle trafficking system, the translocation response of GLUT4 to insulin in rat adipose cells. Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total, or basal and insulin-stimulated cell-surface expression of HA-tagged GLUT4. In contrast, a dominant-negative NSF (NSF-D1EQ) can be expressed at a low enough level that it has little effect on total HA-GLUT4, but does reduce both basal and insulin-stimulated cell-surface HA-GLUT4 by approximately 50% without affecting the GLUT4 fold-translocation response to insulin. However, high expression levels of NSF-D1EQ decrease total HA-GLUT4. The inhibitory effect of NSF-D1EQ on cell-surface HA-GLUT4 is reversed when endocytosis is inhibited by co-expression of a dominant-negative dynamin (dynamin-K44A). Moreover, NSF-D1EQ does not affect cell-surface levels of constitutively recycling GLUT1 and TfR, suggesting a predominant effect of low-level NSF-D1EQ on the trafficking of GLUT4 from the endocytic recycling compared to the intracellular GLUT4-specific compartment. Thus, our data demonstrate that the multiple fusion steps in GLUT4 trafficking have differential quantitative requirements for NSF activity. This indicates that the rates of plasma and intracellular membrane fusion reactions vary, leading to differential needs for the turnover of the SNARE proteins.

Adenosine Triphosphatases↗
PubMed2005

Analysis of functional domains of rat mitochondrial Fis1, the mitochondrial fission-stimulating protein.

In yeast, mitochondrial-fission is regulated by the cytosolic dynamin-like GTPase (Dnm1p) in conjunction with a peripheral protein, Mdv1p, and a C-tail-anchored outer membrane protein, Fis1p. In mammals, a dynamin-related protein (Drp1) and Fis1 are involved in the mitochondrial-fission reaction as Dnm1 and Fis1 orthologues, respectively. The involvement of other component(s), such as the Mdv1 homologue, and the mechanisms regulating mitochondrial-fission remain unclear. Here, we identified rat Fis1 (rFis1) and analyzed its structure-function relationship. Blue-native-polyacrylamide gel electrophoresis revealed that rFis1 formed a approximately 200-kDa complex in the outer mitochondrial membrane. Its expression in HeLa cells promoted extensive mitochondrial fragmentation, and gene knock-down by RNAi induced extension of the mitochondrial networks. Taking advantage of these properties, we analyzed functional domains of rFis1. These experiments revealed that the N-terminal and C-terminal segments are both essential for oligomeric rFis1 interaction, and the middle TPR-like domains regulate proper oligomer assembly. Any mutations that disturb the proper oligomeric assembly compromise mitochondrial division-stimulating activity of rFis1.

Amino Acid Sequence↗
PubMed2003

Mitochondrial fission in apoptosis, neurodegeneration and aging.

A decline in mitochondrial function is well recognized in neurodegenerative diseases and aging, and is thought to play a causal role in their biology. Unfortunately, the molecular basis underlying this detrimental loss in mitochondrial function remains mysterious. Interestingly, mitochondria undergo frequent fission and fusion. This process is regulated by molecular machinery that has been highly conserved during evolution, including dynamin-related GTPases that manifest opposing effects. A balance between mitochondrial fission and fusion events is required for normal mitochondrial and cellular function. Emerging evidence indicates that mitochondria undergo rapid and extensive fission at an early stage during apoptosis. A clue that these new findings are of significance for the pathogenesis of neurodegenerative disease is provided by the observation that OPA-1, a dynamin-related GTPase regulating mitochondrial fusion, is mutated in humans with dominant optic atrophy, which is characterized by degeneration of retinal ganglion cells and childhood blindness. Loss of function of OPA-1, analogous to deficiency of its yeast homologue, Mgm1p, is expected to lead to mitochondrial fission, loss of mitochondrial DNA, respiratory deficits and an increase in reactive oxygen species. Here we review the molecular mediators controlling mitochondrial fission and fusion, and how death effector molecules may hijack this ancient machinery. A shift in the rate of mitochondrial fission or fusion may provide a new mechanistic explanation for the mitochondrial dysfunction in neurodegenerative diseases and normal aging, and may offer a new target for therapeutic intervention.

Aging↗
PubMed2004

Cloning and characterization of an Mx gene and its corresponding promoter from the zebrafish, Danio rerio.

Type I interferons (IFNs) represent a crucial component of the innate immune response to viruses. An important downstream effector of IFN is the Mx gene, which is activated solely through this pathway. Mx proteins are characterized by a tripartite GTP-binding domain, dynamin family signature, and leucine zipper motif. Mx genes are transcribed upon activation of an interferon-stimulated response element (ISRE) located in the Mx promoter region. In this article, we describe the cloning and analysis of an Mx gene and its corresponding promoter from the zebrafish (Danio rerio). The deduced amino acid sequence of zebrafish Mx contains the conserved GTP-binding domain, dynamin family signature, and leucine zipper motif common to Mx proteins, and shows a 50% identity to human MxA and 69% identity both to rainbow trout and to Atlantic salmon. Zebrafish liver cells produced high levels of Mx mRNA in response to induction by the known IFN-inducer polyinosinic-polycytidylic acid (Poly[I:C]). The zebrafish Mx promoter contains two ISREs homologous to those found in the promoter regions of many IFN-inducible genes, and was able to drive transcription of a luciferase reporter gene when induced by either purified zebrafish IFN or Poly[I:C].

Amino Acid Sequence↗
PubMed2006

Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy.

Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 (OPA1), a second locus is linked to 18q12.2-q12.3 (OPA4) and a third locus on 22q12.1-q13.1 (OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14-15years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2-q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438.

Adolescent↗
PubMed2006

First report of invertebrate Mx: cloning, characterization and expression analysis of Mx cDNA in disk abalone (Haliotis discus discus).

Myxovirus resistance (Mx) protein is one of the most studied antiviral proteins. It is induced by the type I interferon system (IFN alpha/beta) in various vertebrates, but its expression has not been identified or characterized in mollusks or other multi-cellular invertebrates to date. In this study, we isolated the Mx gene from a disk abalone (Haliotis discus discus) normalized cDNA library. Mx cDNA was sequenced, cloned and compared to other known Mx proteins. The full-length 1664 bp of abalone Mx cDNA contained a 1533-bp open reading frame that codes for 511 amino acids. Within the coding sequence of abalone Mx, characteristic features were found, such as a tripartite guanosine-5'-triphosphate (GTP)-binding motif and a dynamin family signature. In addition, leucine residues in the C-terminal region displayed a special leucine domain at L(468), L(475), L(489) and L(510), suggesting that abalone Mx may have a similar oligomerization function as other leucine zipper motifs. Abalone Mx protein exhibited 44% amino acid similarity with channel catfish Mx1, rainbow trout Mx2 and Atlantic halibut Mx. Abalones were injected intramuscularly with the known IFN inducer poly I:C and RT-PCR was performed for Mx mRNA analysis. The results showed enhanced Mx expression in abalone gill and digestive tissues 24h as well as 48 h after injection of poly I:C. Mx mRNA was expressed in gill, digestive gland, mantle and foot tissues in healthy abalone, suggesting that the basal level of Mx expressed is tissue-specific. There is no known Mx protein closely related to abalone Mx according to phylogenetic analysis. Abalone Mx may have diverged from a common gene ancestor of fish and mammalian Mx proteins, since abalone Mx showed high similarity in terms of conserved tripartite GTP-binding, dynamin family signature motifs and poly I:C enhancement of Mx mRNA expression.

Amino Acid Sequence↗
PubMed2004

PKC modulation of GABAA receptor endocytosis and function is inhibited by mutation of a dileucine motif within the receptor beta 2 subunit.

The modulation of GABAA receptors by protein kinase C is complex and involves effects on both ion channel function and receptor trafficking. Although PKC regulates receptor cell surface expression the mechanism is not well understood. Using immunofluorescence studies in HEK 293 cells, we demonstrate that activation of PKC by the phorbol ester PMA promotes receptor endocytosis and is dependent on the presence of a gamma subunit. This endocytosis is blocked by the dominant negative dynamin mutant K44A indicating that PKC-induced receptor endocytosis involves the dynamin endocytic pathway. Mutation of a dileucine motif within the receptor beta2 subunit inhibits the effect of PKC activation on receptor endocytosis. Using patch clamp analysis, we show that PKC activation produces a robust inhibition of GABA-gated chloride currents in cells expressing wildtype GABAA receptors, but it is ineffective in modulating receptors lacking the dileucine motif. Furthermore, the introduction into the patch pipette of a 10-amino acid peptide corresponding to the dileucine motif present in the receptor beta2 subunit prevents PKC modulation of wildtype recombinant receptors. Furthermore, in cerebral cortical neuronal slices inclusion of this peptide in the patch pipette prevents PKC modulation of native GABAA receptors. Using limited chymotrypsin digestion assays, we also show that PKC increases receptor internalization in primary cultures of cerebral cortical neurons. Lastly, PKC inhibitors do not block constitutive receptor endocytosis or affect GABA-gated chloride currents suggesting that PKC-dependent phosphorylation is not required for GABAA receptor endocytosis but plays a modulatory role in the process.

Animals↗
PubMed2006

Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture.

Mitochondria have many roles critical to the function of neurons including the generation of ATP and regulation of intracellular Ca2+. Mitochondrial movement is highly dynamic in neurons and is thought to direct mitochondria to specific cellular regions of increased need and to transport damaged or old mitochondria to autophagosomes. Morphology also varies between individual mitochondria and is modulated by fusion and fission proteins such as mitofusin-1 and dynamin-related protein-1, respectively. Although mitochondrial movement and morphology are thought to be modulated to best meet cellular demands, few regulatory signals have been identified. In this study, we examined how the different cellular environments of synaptically immature and mature rat cortical neurons affect mitochondrial movement, morphology, distribution and function. In younger cells, mitochondria were more mobile, were shorter, occupied a smaller percentage of neuronal processes, and expressed greater mitofusin-1 and lower dynamin-related protein-1 protein levels compared with older cells. However, the number of mitochondria per mum of neuronal process, mitochondrial membrane potential and the amount of basally sequestered mitochondrial Ca2+ were similar. Our results suggest that while mitochondria in young neurons are functionally similar to mature neurons, their enhanced motility may permit faster energy dispersal for cellular demands, such as synaptogenesis. As cells mature, mitochondria in the processes may then elongate and reduce their motility for long-term support of synaptic structures.

Animals↗