Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARα Agonists Modulate Mitochondrial Fusion-Fission Dynamics: Relevance to Reactive Oxygen Species (ROS)-Related Neurodegenerative Disorders?

Zolezzi, Juan M.; Silva-Álvarez, Carmen; Ordenes, Daniela; Godoy, Juan A.; Carvajal, Francisco J.; Santos, Manuel J.; Inestrosa, Nibaldo C.

doi:10.1371/journal.pone.0064019

Cited by 89 publications

(69 citation statements)

References 55 publications

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“…36,37 As compared with vehicle, Mdivi-1 (5 and 50 mM) increased SE-induced mitochondrial elongation and neuronal death. The lowest dose of Mdivi-1 (0.5 mM) did not affect them (Figures 7c and d).…”

Section: Resultsmentioning

confidence: 98%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...

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Section: Resultsmentioning

confidence: 98%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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“…This mitochondrial protective signaling mechanism also involves nuclear gene expression. Sulindac protection involves PPAR-α, which has been reported to increase mitochondrial biogenesis through elevated PGC-1-α levels (38) and regulate peroxisome proliferation (39) as well as increase iNOS transcription (17). Induced iNOS is believed to be a mediator in late-phase ischemic preconditioning (20), and its downstream effects may include modulation of the respiratory chain by inhibiting complex I, which in turn has the potential to elicit decreased mitochondrial ROS generation and enhanced cellular protection (40).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

Sur

Kesaraju

Prentice

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration (AMD), the major cause of blinding in the elderly. In the present study, sulindac, a nonsteroidal antiinflammatory drug (NSAID), was tested for protection against oxidative stressinduced damage in an established RPE cell line . Besides its established antiinflammatory activity, sulindac has previously been shown to protect cardiac tissue against ischemia/reperfusion damage, although the exact mechanism was not elucidated. As shown here, sulindac can also protect RPE cells from chemical oxidative damage or UV light by initiating a protective mechanism similar to what is observed in ischemic preconditioning (IPC) response. The mechanism of protection appears to be triggered by reactive oxygen species (ROS) and involves known IPC signaling components such as PKG and PKC epsilon in addition to the mitochondrial ATP-sensitive K + channel. Sulindac induced iNOS and Hsp70, late-phase IPC markers in the RPE cells. A unique feature of the sulindac protective response is that it involves activation of the peroxisome proliferator-activated receptor alpha (PPAR-α). We have also used low-passage human fetal RPE and polarized primary fetal RPE cells to validate the basic observation that sulindac can protect retinal cells against oxidative stress. These findings indicate a mechanism for preventing oxidative stress in RPE cells and suggest that sulindac could be used therapeutically for slowing the progression of AMD.preconditioning | oxidative stress | sulindac | retinal pigmented epithelial cells | age-related macular degeneration O xidative damage, resulting from excess production of reactive oxygen species (ROS), has been implicated in the progression of key ocular disorders such as cataracts, glaucoma, and age-related macular degeneration (AMD). Death of retinal pigmented epithelial (RPE) cells has been shown to be an important contributor to AMD pathophysiology. RPE cells are known to be highly metabolically active, and there is strong evidence that the RPE cells are sensitive to oxidative stress (1). It has been reported that the pathophysiology of AMD is due to cumulative oxidative damage to RPE cells resulting from an imbalance between the generation of ROS and the ability of these cells to destroy and/or protect against ROS damage to macromolecules (2, 3). Hence, strategies for protecting RPE cells against oxidative damage may be particularly important in maintaining retinal function and preventing the development or progression of AMD.Sulindac was one of the first nonsteroidal antiinflammatory drugs (NSAIDs) used to treat inflammation. It is a prodrug, composed of R and S epimers, whose NSAID activity is dependent on the reduction of the epimers to sulindac sulfide, the active cyclooxygenase (COX) inhibitor (4). This reduction is catalyzed by two members of the methionine sulfoxide reductase (Msr) family, MsrA and MsrB,...

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“…Peroxisome proliferator activated receptor γ (PPAR-γ) agonists increase mitochondrial biogenesis and normalize the fission fusion ratio in this organelle that be altered with inflammation and high levels of TNF-α 76 . Agonistic effects of PA on PPAR-γ, lowering oxidative stress and serum TNF-α levels and positive effects of PA on mitochondrial functions are the main anti-diabetic mechanisms of PSO 75 .…”

Section: Effects On Insulin Resistancementioning

confidence: 99%

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IJPSR

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Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARα Agonists Modulate Mitochondrial Fusion-Fission Dynamics: Relevance to Reactive Oxygen Species (ROS)-Related Neurodegenerative Disorders?

Cited by 89 publications

References 55 publications

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

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