共查询到20条相似文献,搜索用时 0 毫秒
1.
2.
3.
4.
5.
6.
7.
Pacelli C De Rasmo D Signorile A Grattagliano I di Tullio G D'Orazio A Nico B Comi GP Ronchi D Ferranini E Pirolo D Seibel P Schubert S Gaballo A Villani G Cocco T 《Biochimica et biophysica acta》2011,1812(8):1041-1053
Mutations in the parkin gene are expected to play an essential role in autosomal recessive Parkinson's disease. Recent studies have established an impact of parkin mutations on mitochondrial function and autophagy. In primary skin fibroblasts from two patients affected by an early onset Parkinson's disease, we identified a hitherto unreported compound heterozygous mutation del exon2-3/del exon3 in the parkin gene, leading to the complete loss of the full-length protein. In both patients, but not in their heterozygous parental control, we observed severe ultrastructural abnormalities, mainly in mitochondria. This was associated with impaired energy metabolism, deregulated reactive oxygen species (ROS) production, resulting in lipid oxidation, and peroxisomal alteration. In view of the involvement of parkin in the mitochondrial quality control system, we have investigated upstream events in the organelles' biogenesis. The expression of the peroxisome proliferator-activated receptor gamma-coactivator 1-alpha (PGC-1α), a strong stimulator of mitochondrial biogenesis, was remarkably upregulated in both patients. However, the function of PGC-1α was blocked, as revealed by the lack of its downstream target gene induction. In conclusion, our data confirm the role of parkin in mitochondrial homeostasis and suggest a potential involvement of the PGC-1α pathway in the pathogenesis of Parkinson's disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. 相似文献
8.
Zhang Qi Lei Yu-Hong Zhou Jue-Pu Hou Ye-Ye Wan Zheng Wang Hong-Lei Meng Hao 《Neurochemical research》2019,44(9):2031-2043
Neurochemical Research - As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is... 相似文献
9.
Dae Ryoung Park Jeong Seok Kim Chang Keun Kim 《Journal of Exercise Nutrition & Biochemistry》2014,18(1):1-7
[Purpose]
The purpose of this study was to investigate the effect of Sirtuin 1 (SIRT1) and General control nonderepressible 5 (GCN5) knock down on peroxisome proliferator- activated receptor gamma coactivator 1-alpha (PGC-1α) deacetylation during electrical stimulated skeletal muscle contraction.[Methods]
Skeletal muscle primary cell were isolated from C57BL/6 mice gastrocnemius and transfected lentiviral SIRT1 and GCN5 shRNA. Knock downed muscle cell were stimulated by electrical stimulation (1Hz, 3min) and collected for PGC-1α deceatylation assays. Immunoprecipitation performed for PGC-1α deacetylation, acetyl-lysine level was measured.[Results]
Our resulted showed SIRT1 knock down not influenced to PGC-1α deacetylation during electrical stimulation induced muscle contraction while GCN5 knock down decreased PGC-1α deacetylation significantly (p<0.05).[Conclusion]
This study can be concluded that GCN5 is a critical factor for muscle contraction induced PGC-1α deacetylation. 相似文献10.
Skeletal muscles show a high plasticity to cope with various physiological demands. Different muscle types can be distinguished by the force, endurance, contraction/relaxation kinetics (fast-twitch vs. slow-twitch muscles), oxidative/glycolytic capacity, and also with respect to Ca2+-signaling components. Changes in Ca2+ signaling and associated Ca2+-dependent processes are thought to underlie the high adaptive capacity of muscle fibers. Here we investigated the consequences and the involved mechanisms caused by the ectopic expression of the Ca2+-binding protein parvalbumin (PV) in C2C12 myotubes in vitro, and conversely, the effects caused by its absence in in fast-twitch muscles of parvalbumin null-mutant (PV−/−) mice in vivo. The absence of PV in fast-twitch muscle tibialis anterior (TA) resulted in an increase in the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and of its positive regulator, the deacetylase sirtuin 1 (SIRT1). TA muscles from PV−/− mice also have an increased mitochondrial volume. Mild ionophore treatment of control (PV-devoid) C2C12 myotubes causing a moderate elevation in [Ca2+]c resulted in an increase in mitochondrial volume, together with elevated PGC-1α and SIRT1 expression levels, whilst it increased PV expression levels in myotubes stably transfected with PV. In PV-expressing myotubes the mitochondrial volume, PGC-1α and SIRT1 were significantly lower than in control C2C12 myotubes already at basal conditions and application of ionophore had no effect on either one. SIRT1 activation causes a down-regulation of PV in transfected myotubes, whilst SIRT1 inhibition has the opposite effect. We conclude that PV expression and mitochondrial volume in muscle cells are inversely regulated via a SIRT1/PGC-1α signaling axis. 相似文献
11.
Winyoo Chowanadisai Kathryn A. Bauerly Eskouhie Tchaparian Alice Wong Gino A. Cortopassi Robert B. Rucker 《The Journal of biological chemistry》2010,285(1):142-152
Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa1–6 cells to 10–30 μm PQQ for 24–48 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1α, and increased PGC-1α mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1α or CREB expression. Consistent with activation of the PGC-1α pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction. 相似文献
12.
13.
Consiglia PacelliDomenico De Rasmo Anna SignorileIgnazio Grattagliano Giuseppe di TullioAndria D'Orazio Beatrice NicoGiacomo Pietro Comi Dario RonchiErmanno Ferranini Domenico PiroloPeter Seibel Susanna SchubertAntonio Gaballo Gaetano VillaniTiziana Cocco 《生物化学与生物物理学报:疾病的分子基础》2011,1812(8):1041-1053
Mutations in the parkin gene are expected to play an essential role in autosomal recessive Parkinson's disease. Recent studies have established an impact of parkin mutations on mitochondrial function and autophagy. In primary skin fibroblasts from two patients affected by an early onset Parkinson's disease, we identified a hitherto unreported compound heterozygous mutation del exon2-3/del exon3 in the parkin gene, leading to the complete loss of the full-length protein. In both patients, but not in their heterozygous parental control, we observed severe ultrastructural abnormalities, mainly in mitochondria. This was associated with impaired energy metabolism, deregulated reactive oxygen species (ROS) production, resulting in lipid oxidation, and peroxisomal alteration. In view of the involvement of parkin in the mitochondrial quality control system, we have investigated upstream events in the organelles' biogenesis. The expression of the peroxisome proliferator-activated receptor gamma-coactivator 1-alpha (PGC-1α), a strong stimulator of mitochondrial biogenesis, was remarkably upregulated in both patients. However, the function of PGC-1α was blocked, as revealed by the lack of its downstream target gene induction. In conclusion, our data confirm the role of parkin in mitochondrial homeostasis and suggest a potential involvement of the PGC-1α pathway in the pathogenesis of Parkinson's disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. 相似文献
14.
15.
Xingxing Kong Rui Wang Yuan Xue Xiaojun Liu Huabing Zhang Yong Chen Fude Fang Yongsheng Chang 《PloS one》2010,5(7)
Background
Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1α induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.Results
Here we show that PGC-1α strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1α led to decreased Sirt3 gene expression. PGC-1α activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR) binding element (ERRE) (−407/−399) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRα bound to the identified ERRE and PGC-1α co-localized with ERRα in the mSirt3 promoter. Knockdown of ERRα reduced the induction of Sirt3 by PGC-1α in C2C12 myotubes. Furthermore, Sirt3 was essential for PGC-1α-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1α in C2C12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1α on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1α on mitochondrial biogenesis in C2C12 myotubes.Conclusion
Our results indicate that Sirt3 functions as a downstream target gene of PGC-1α and mediates the PGC-1α effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation. The elucidation of the molecular mechanisms of SIRT3 regulation and its physiological functions may provide a novel target for treating ROS-related disease. 相似文献16.
Liu J 《Neurochemical research》2008,33(1):194-203
We have identified a group of nutrients that can directly or indirectly protect mitochondria from oxidative damage and improve
mitochondrial function and named them “mitochondrial nutrients”. The direct protection includes preventing the generation
of oxidants, scavenging free radicals or inhibiting oxidant reactivity, and elevating cofactors of defective mitochondrial
enzymes with increased Michaelis–Menten constant to stimulate enzyme activity, and also protect enzymes from further oxidation,
and the indirect protection includes repairing oxidative damage by enhancing antioxidant defense systems either through activation
of phase 2 enzymes or through increase in mitochondrial biogenesis. In this review, we take α-lipoic acid (LA) as an example
of mitochondrial nutrients by summarizing the protective effects and possible mechanisms of LA and its derivatives on age-associated
cognitive and mitochondrial dysfunction of the brain. LA and its derivatives improve the age-associated decline of memory,
improve mitochondrial structure and function, inhibit the age-associated increase of oxidative damage, elevate the levels
of antioxidants, and restore the activity of key enzymes. In addition, co-administration of LA with other mitochondrial nutrients,
such as acetyl-l-carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial
dysfunction. Therefore, administrating mitochondrial nutrients, such as LA and its derivatives in combination with other mitochondrial
nutrients to aged people and patients suffering from neurodegenerative diseases, may be an effective strategy for improving
mitochondrial and cognitive dysfunction. 相似文献
17.
18.
Alireza Abdanipour Taki Tiraihi Ali Noori-Zadeh Arezo Majdi Ramin Gosaili 《Molecular neurobiology》2014,49(3):1364-1372
Reactive oxygen species and oxidative stress are associated with various cell processes, including cell survival and apoptosis. Oxidative stress has been implicated in the pathogenesis of several neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). In the present study, we evaluated the effects of lovastatin chemoprotection against hydrogen peroxide-induced oxidative stress in bone marrow stromal cell-derived neural stem cells (BMSC-derived NSCs) and whether it has protective effects. BMSC-derived NSCs were pretreated with different doses of lovastatin for 48 h and then exposed to 125 μM H2O2 for 30 min. Using MTT, TUNEL assay, and real-time RT-PCR, we evaluated the effects of lovastatin on cell survival, apoptosis, and PGC-1α and Nrf2 expression rates in pretreated BMSC-derived NSCs compared to control groups. Results showed that apoptosis rate in the lovastatin-pretreated BMSC-derived NSCs was significantly decreased compared to the control group. Our findings suggest that lovastatin protects NSCs against oxidative stress-induced cell death, and therefore, it may be used to promote the survival rate of NSCs and can be a candidate for treatment of oxidative stress-mediated neurological diseases. 相似文献
19.
20.
Christophe M. R. LeMoine Stephen C. Lougheed Christopher D. Moyes 《Journal of molecular evolution》2010,70(5):492-505
In mammals, the peroxisome proliferator activated receptor (PPAR)γ coactivator-1α (PGC-1α) is a central regulator of mitochondrial
gene expression, acting in concert with nuclear respiratory factor-1 (NRF-1) and the PPARs. Its role as a “master regulator”
of oxidative capacity is clear in mammals, but its role in other vertebrates is ambiguous. In lower vertebrates, although
PGC-1α seems to play a role in coordinating the PPARα axis as in mammals, it does not appear to be involved in NRF-1 regulation
of mitochondrial content. To evaluate the evolutionary patterns of this coactivator in fish and mammals, we investigated the
evolutionary trajectories of PGC-1α homologs in representative vertebrate lineages. A phylogeny of the PGC-1 paralogs suggested
that the family diversified through repeated genome duplication events early in vertebrate evolution. Bayesian and maximum
likelihood phylogenetic reconstructions of PGC-1α in representative vertebrate species revealed divergent evolutionary dynamics
across the different functional domains of the protein. Specifically, PGC-1α exhibited strong conservation of the activation/PPAR
interaction domain across vertebrates, whereas the NRF-1 and MEF2c interaction domains experienced accelerated rates of evolution
in actinopterygian (fish lineages) compared to sarcopterygians (tetrapod lineages). Furthermore, analysis of the amino acid
sequence of these variable domains revealed successive serine- and glutamine-rich insertions within the teleost lineages,
with important ramifications for PGC-1α function in these lineages. Collectively, these results suggest modular evolution
of the PGC-1α protein in vertebrates that could allow for lineage-specific divergences in the coactivating capabilities of
this regulator. 相似文献