Peroxisome Proliferator-activated Receptor γ Up-regulates the Bcl-2 Anti-apoptotic Protein in Neurons and Induces Mitochondrial Stabilization and Protection against Oxidative Stress and Apoptosis

Fuenzalida, Karen; Quintanilla, Rodrigo A.; Ramos, Patricio; Piderit, Daniela; Fuentealba, Rodrigo A.; Martinez, Gabriela R.; Inestrosa, Nibaldo C.; Bronfman, Miguel

doi:10.1074/jbc.m700447200

Cited by 224 publications

(206 citation statements)

References 74 publications

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“…This is important because increased levels of nitrated proteins have been reported in AD brains and cerebrospinal fluid of AD patients, 43 and numerous proteins in AD have been shown to be nitrated by peroxynitrite. 44 For example, peroxisome proliferator-activated receptor gamma expression protects neurons from Abmediated toxicity; 45 however, its nitration prevents its translocation to the nucleus, thereby preventing mitochondrial biogenesis. 46 We also found that nanoceria blocked Ab-mediated mitochondrial fragmentation via a mechanism that involved reduction of DRP1 S616 hyperphosphorylation (Figure 5b).…”

Section: Discussionmentioning

confidence: 99%

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

et al. 2014

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Evidence indicates that nitrosative stress and mitochondrial dysfunction participate in the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Ab) and peroxynitrite induce mitochondrial fragmentation and neuronal cell death by abnormal activation of dynamin-related protein 1 (DRP1), a large GTPase that regulates mitochondrial fission. The exact mechanisms of mitochondrial fragmentation and DRP1 overactivation in AD remain unknown; however, DRP1 serine 616 (S616) phosphorylation is likely involved. Although it is clear that nitrosative stress caused by peroxynitrite has a role in AD, effective antioxidant therapies are lacking. Cerium oxide nanoparticles, or nanoceria, switch between their Ce 3 þ and Ce 4 þ states and are able to scavenge superoxide anions, hydrogen peroxide and peroxynitrite. Therefore, nanoceria might protect against neurodegeneration. Here we report that nanoceria are internalized by neurons and accumulate at the mitochondrial outer membrane and plasma membrane. Furthermore, nanoceria reduce levels of reactive nitrogen species and protein tyrosine nitration in neurons exposed to peroxynitrite. Importantly, nanoceria reduce endogenous peroxynitrite and Ab-induced mitochondrial fragmentation, DRP1 S616 hyperphosphorylation and neuronal cell death.

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Section: Discussionmentioning

confidence: 99%

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

et al. 2014

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“…28 Based on the observation that Aldo-induced ROS originated from mt, we investigated if Aldo induced MtD. The mt ultrastructure morphology of Aldo-treated cells displayed mt vacuolization and decreased distribution in podocytes ( Figure 4A).…”

Section: Aldo-induced Mtd In Podocytes Via Mrmentioning

confidence: 99%

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Zhu

Huang

Yuan

et al. 2011

The American Journal of Pathology

108

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Aldosterone (Aldo) causes podocyte damage by an unknown mechanism. We examined the role of mitochondrial dysfunction (MtD) in Aldo-treated podocytes in vitro and in vivo. Exposure of podocytes to Aldo reduced nephrin expression dose dependently, accompanied by increased production of reactive oxygen species (ROS). The ROS generation and podocyte damage were abolished by the mitochondrial (mt) respiratory chain complex I inhibitor rotenone. Pronounced MtD, including reduced mt membrane potential, ATP levels, and mtDNA copy number were seen in Aldo-treated podocytes and in the glomeruli of Aldo-infused mice. The mineralocorticoid receptor antagonist eplerenone significantly inhibited Aldo-induced MtD. The MtD was associated with higher levels of ROS, reduction in the activity of complexes I, III, and IV, and expression of the peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator-1␣ and mt transcription factor A. Both the PPAR␥ agonist rosiglitazone and PPAR␥ overexpression protected against podocyte injury by preventing MtD and oxidative stress, as evidenced by reduced ROS production, by maintenance of mt morphology, by restoration of mtDNA copy number, by decrease in mt membrane potential loss, and by recovery of mt electron transport function. The protective effect of rosiglitazone was abrogated by the specific PPAR␥ small interference RNA, but not a control small interference RNA. We conclude that MtD is involved in Aldo-induced podocyte injury, and that the PPAR␥ agonist rosiglitazone may protect podocytes from this injury by The mineralocorticoid aldosterone (Aldo) is a key component of the renin-angiotensin-aldosterone system and is increasingly recognized as an important player in the development and progression of kidney disease. Patients with chronic kidney disease have markedly elevated plasma Aldo concentrations. Animal studies suggest that Aldo is a pathogenic factor in renal injury in the remnant kidney of hypertensive rats, 1 and in renal fibrosis. Moreover, exogenous infusion of Aldo reverses the renoprotective effects of angiotensin-converting enzyme inhibitors in hypertensive remnant kidney rats, and in stroke-prone, spontaneously hypertensive rats. 2 In vitro studies show that Aldo exerts a direct deleterious influence on kidney cells, including podocytes, 3-5 mesangial cells, proximal tubular epithelial cells, 6 and fibroblasts. In particular, Aldo causes podocyte injury in vivo and in vitro, and Aldo blockade is therapeutic in renal injury. 5,[7][8][9] However, the underlying mechanism for Aldoinduced injury in the kidney (in general) and in the podocytes (in particular) is not well understood.Podocytes are terminally differentiated, high-energy required cells that have lost mitotic activity, and typically do not proliferate after injury. 10 Mitochondria (mt) dysfunction (MtD) is involved in several diseases and progressive disease processes, including glomerulosclerosis, in which podocyte injury is a crucial event in sclerosis formation. 11,12 We hypothesized that preserving mt func...

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“…The images were analyzed with LCS Leica confocal software and recorded as mean MitoRed or TMRM fluorescence signal per live cell. Estimation of fluorescence intensities were presented as the pseudoratio (⌬F/F o ), which was calculated using the following formula: ⌬F/F o ϭ (F Ϫ F base )/(F base Ϫ B), where F is the measured fluorescence intensity of the indicator, F base is the fluorescence intensity before the stimulation, and B is the background signal determined from the average of areas adjacent to the cells (22,28,30).…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial Potential Determination in Live CellsMitochondria membrane potential was determined using Mitotracker Red CM-H 2 XRos (MitoRed) or TMRM (22,28,30). Striatal cells were grown on poly-L-lysine-coated plates and cultured for 4 days.…”

Section: Methodsmentioning

confidence: 99%

“…However, activation of PPAR␥ by three different TZDs protected rat hippocampal neurons against ␤-amyloid (A␤)-induced damage (20), and the TZD rosiglitazone protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity (21). In addition, PPAR␥ activation by rosiglitazone up-regulates the Bcl-2 protective pathway and prevents neuronal degeneration induced by both oxidative stress and treatment with A␤ fibrils, with a concomitant increase in mitochondrial viability (22). Recent studies have also provided evidence that the expression of PGC-1␣, a potent co-activator of PPAR␥, is repressed by mutant huntingtin expression, and when PGC-1␣ knock-out (KO) mice are crossed with HD knockin mice, this resulted in increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice (2).…”

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confidence: 99%

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Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Quintanilla

Jin

Fuenzalida

et al. 2008

Journal of Biological Chemistry

Self Cite

116

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Peroxisome proliferator-activated receptor-␥ (PPAR␥) is a member of the PPAR family of transcription factors. Synthetic PPAR␥ agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR␥ activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR␥ activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh Q7/Q7 ) or mutant (STHdh Q111/Q111 ) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPAR␥ activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPAR␥, as all protective effects were prevented by the PPAR␥ antagonist GW9662. Additionally, the PPAR␥ signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR␥ expression and reduced PPAR␥ transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR␥ pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR␥ activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.

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Peroxisome Proliferator-activated Receptor γ Up-regulates the Bcl-2 Anti-apoptotic Protein in Neurons and Induces Mitochondrial Stabilization and Protection against Oxidative Stress and Apoptosis

Cited by 224 publications

References 74 publications

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

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