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  • Mitochondria regulate DNA damage and genomic instability induced by high LET radiation. 25072018

    High linear energy transfer (LET) radiation including α particles and heavy ions is the major type of radiation find in space and is considered a potential health risk for astronauts. Even though the chance that these high LET particles traversing through the cytoplasm of cells is higher than that through the nuclei, the contribution of targeted cytoplasmic irradiation, to the induction of genomic instability and other chromosomal damages induced by high LET radiation is not known. In the present study, we investigated whether mitochondria are the potential cytoplasmic target of high LET radiation in mediating cellular damage using a mitochondrial DNA (mtDNA) depleted (ρ(0)) human small airway epithelial (SAE) cell model and a precision charged particle microbeam with a beam width of merely one micron. Targeted cytoplasmic irradiation by high LET α particles induced DNA oxidative damage and double strand breaks in wild type ρ(+) SAE cells. Furthermore, there was a significant increase in autophagy, micronuclei, which is an indication of genomic instability, together with the activation of nuclear factor kappa-B (NF-κB) and mitochondrial inducible nitric oxide synthase (iNOS) signaling pathways in ρ(+) SAE cells. In contrast, ρ(0) SAE cells exhibited a significantly lower response to these same endpoints examined after cytoplasmic irradiation with high LET α particles. The results indicate that mitochondria are essential in mediating cytoplasmic radiation induced genotoxic damage in mammalian cells. Furthermore, the findings may shed some light in the design of countermeasures for space radiation.
    Document Type:
    Reference
    Product Catalog Number:
    05-636
    Product Catalog Name:
    Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301

  • NAMPT regulates mitochondria biogenesis via NAD metabolism and calcium binding proteins during skeletal muscle contraction. 25566462

    The purpose of this study was to investigate the effect that muscle contraction induced NAD metabolism via NAMPT has on mitochondrial biogenesis.Primary skeletal muscle cells were isolated from the gastrocnemius in C57BL/6 mice. The muscle cells were stimulated by electrical current at 1Hz for 3 minutes in conditions of normal or NAD metabolism related inhibitor treatment. NAD/NADH level, Sirt1 and mitochondria biogenesis related signal factor's changes were examined in normal or NAD metabolism related inhibitor treated cells.Electrical stimulation (ES) induced muscle contractions significantly increased NAD/NADH levels, NAMPT inhibitor FK-866 inhibited ES-induced NAD formation, which caused SIRT1 expression and PGC-1α deacetylation to decrease. Moreover, NAMPT inhibition decreased mitochondrial biogenesis related mRNA, COX-1 and Tfam levels. Along with AMPK inhibitor, compound C decreases SIRT1 expression, PGC-1α deacetylation and muscle contraction induced mitochondrial biogenesis related mRNA increment. These results indicated that the AMPK-NAMPT signal is a key player for muscle contraction induced SIRT1 expression and PGC-1α deacetylation, which influences mitochondrial biogenesis. Inhibition of the AMPK upregulator, Camkkβ, STO-609 decreased AMPK phosphorylation and SIRT1 expression but did not decrease PGC-1α deacetylation. However, CAMKII inhibition via AIP decreased PGC-1α deacetylation.In conclusion, the results indicate that NAMPT plays an important role in NAD metabolism and mitochondrial biogenesis. However, mitochondrial biogenesis is also controlled by different calcium binding protein signals including Camkkβ and CAMKII. [Keyword] Muscle contraction, NAD metabolism, SIRT1, PGC-1 α, mitochondria biogenesis.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • New evidence of mitochondria dysfunction in the female Alzheimer's disease brain: deficiency of estrogen receptor-β. 22451324

    Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor β (ERβ) in neuronal mitochondrial (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERβ is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lack of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is associated with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ERβ depletion impairs mitochondrial function in mice, and reduction of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women.
    Document Type:
    Reference
    Product Catalog Number:
    MAB377
    Product Catalog Name:
    Anti-NeuN Antibody, clone A60

  • Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes. 19765776

    Obesity and mild hyperglycemia are characteristic of early or "prediabetes." The associated increase in fatty acid flux is posited to enhance substrate delivery to mitochondria, leading to enhanced superoxide production that results in mitochondrial dysfunction and progressive worsening of the hyperglycemic state. We quantified superoxide production by gastrocnemius muscle, heart, and liver mitochondria in a rodent model that mimics the pathophysiology of prediabetes by administering low-dose streptozotocin to rats fed high fat (HF). Superoxide was rigorously determined indirectly as H(2)O(2) largely released from the matrix and by electron paramagnetic resonance spectroscopy that directly detects superoxide released externally. Both HF and low-dose streptozotocin mildly increased glycemia (P < .05 by 2-way analysis of variance). Matrix and external superoxide production by gastrocnemius mitochondria respiring on the complex II substrate succinate and matrix superoxide production by liver mitochondria respiring on the complex I substrates glutamate plus malate were significantly reduced by HF feeding but not affected by mild hyperglycemia. Superoxide production was not significantly altered by either treatment in heart mitochondria fueled by either complex I or II substrates. The functional status of the mitochondria was assayed as simultaneous respiration and membrane potential that were not affected by HF or mild hyperglycemia. Comparison of substrate and inhibitor effects on superoxide release implied marked differences in the redox mechanisms regulating mitochondrial superoxide production from liver mitochondria compared with muscle and heart. In summary, superoxide production from mitochondria of different insulin-sensitive tissues differs mechanistically. However, in any case, excess superoxide production as an intrinsic property of mitochondria of insulin-sensitive tissues does not result from conditions mimicking the pathophysiology of pre- or early diabetes.
    Document Type:
    Reference
    Product Catalog Number:
    06-984
    Product Catalog Name:
    Anti-Mn-SOD Antibody

  • Translocation of p53 to mitochondria is regulated by its lipid binding property to anionic phospholipids and it participates in cell death control. 20126473

    p53, can regulate cell apoptosis in both transcription-dependent and -independent manners. The transcription-independent pathway was demonstrated by the translocation of p53 to mitochondria. Our study showed that p53 mitochondrial translocation was found in mitomycin C (MMC)-treated HepG2. The p53 C-terminal domain is clustered with potential nuclear leading sequences and showed strong electrostatic ion-ion interactions with cardiolipin, phosphatidylglycerol and phosphatidic acid in vitro. Disruption of cardiolipin biosynthesis by phosphatidylglycero-phosphate synthase (PGS) or CDP-diacylglycerol synthase 2 (CDS-2) short hairpin RNA (shRNA) transfection eliminated the MMC-induced translocation of mitochondrial p53. The elimination of mitochondrial p53 translocation also reduced Bcl-xL and Bcl-2 mitochondrial distribution. In HEK 293T models with saturated p53 expression, the mitochondrial partition of p53, Bcl-xL, and Bcl-2 obviously decreased in their PGS shRNA- or CDS-2 shRNA-expressing stable clones. In p53-null H1299 models, both the mitochondrial partitions of Bcl-xL and Bcl-2 were strongly reduced in relation to the HEK 293T models. The Bcl-xL mitochondrial partition was elevated in H1299 models expressing pCEP4-p53wt suggesting the direct carrier role of p53 in transporting Bcl-xL to the mitochondria. We also found that the cytosolic pool of Bcl-xL and Bcl-2 remained unaffected in the low-dose MMC treatment but decreased in the high-dose MMC treatment. The cytosolic pool of Bcl-2 and Bcl-xL directly regulated their amounts in p53-dependent mitochondrial distribution. In the low-dose MMC treatment, the increased mitochondrial p53, Bcl-xL, and Bcl-2 could attenuate apoptosis. However, in the high-dose MMC treatment, only the p53 translocated to the mitochondria and resulted in apoptosis progression. On the basis of this study, we thought mitochondrial p53 might regulate apoptosis in a biphasic manner.
    Document Type:
    Reference
    Product Catalog Number:
    05-224
    Product Catalog Name:
    Anti-p53 Antibody, clone BP53-12

  • Dual trafficking of Slit3 to mitochondria and cell surface demonstrates novel localization for Slit protein. 11443047

    Drosophila slit is a secreted protein involved in midline patterning. Three vertebrate orthologs of the fly slit gene, Slit1, 2, and 3, have been isolated. Each displays overlapping, but distinct, patterns of expression in the developing vertebrate central nervous system, implying conservation of function. However, vertebrate Slit genes are also expressed in nonneuronal tissues where their cellular locations and functions are unknown. In this study, we characterized the cellular distribution and processing of mammalian Slit3 gene product, the least evolutionarily conserved of the vertebrate Slit genes, in kidney epithelial cells, using both cellular fractionation and immunolabeling. Slit3, but not Slit2, was predominantly localized within the mitochondria. This localization was confirmed using immunoelectron microscopy in cell lines and in mouse kidney proximal tubule cells. In confluent epithelial monolayers, Slit3 was also transported to the cell surface. However, we found no evidence of Slit3 proteolytic processing similar to that seen for Slit2. We demonstrated that Slit3 contains an NH(2)-terminal mitochondrial localization signal that can direct a reporter green fluorescent protein to the mitochondria. The equivalent region from Slit1 cannot elicit mitochondrial targeting. We conclude that Slit3 protein is targeted to and localized at two distinct sites within epithelial cells: the mitochondria, and then, in more confluent cells, the cell surface. Targeting to both locations is driven by specific NH(2)-terminal sequences. This is the first examination of Slit protein localization in nonneuronal cells, and this study implies that Slit3 has potentially unique functions not shared by other Slit proteins.
    Document Type:
    Reference
    Product Catalog Number:
    AB5701

  • Differential subcellular location of mitochondria in rat serotonergic neurons depends on the presence and the absence of monoamine oxidase type B. 12379239

    Monoamine oxidase type A and type B are major neurotransmitter-degrading enzymes in the CNS. The type A is present on mitochondrial outer membranes in the whole extent of noradrenergic and dopaminergic neurons, including their axon terminals. The type B is present in serotonergic neurons, but its subcellular localization has not been elucidated. In the present study, we used both a double-labeling immunofluorescence method and electron microscopic immunohistochemistry to examine the subcellular localization of monoamine oxidase type B in serotonergic neurons projecting from the dorsal raphe nucleus to the suprachiasmatic nucleus in the rat brain. In the dorsal raphe nucleus, serotonin-positive neuronal cell bodies were clustered, and virtually all of these cell bodies were also positive for monoamine oxidase type B. By contrast, serotonin-negative neuronal cell bodies were mostly free of this enzyme. Within the neuronal cell bodies and dendrites that were positive for monoamine oxidase type B, most mitochondria contained this enzyme on their outer membranes, but a substantial proportion of mitochondria lacked this enzyme. In the suprachiasmatic nucleus, serotonin-positive varicosities were concentrated, but none of these varicosities exhibited monoamine oxidase type B. In this nucleus, mitochondria were found in almost all serotonin-positive axon terminals, but monoamine oxidase type B was not observed in any axon terminal that contained mitochondria. Our results show that there are two kinds of mitochondria in serotonergic neuronal cell bodies and dendrites: one containing monoamine oxidase type B on their outer membranes, and the other lacking this enzyme. In addition, mitochondria in serotonergic axon terminals do not possess monoamine oxidase type B. It is suggested in serotonergic neurons that only mitochondria lacking monoamine oxidase type B are transported by axonal flow up to axon terminals. It is also probable that mitochondria containing monoamine oxidase type B are transported along the axons, but that this enzyme undergoes a change, for example, conformational change, decomposition or removal from the membranes.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple