Mitochondrial Translocation of p53 Modulates Neuronal Fate by Preventing Differentiation-Induced Mitochondrial Stress

Xavier, Joana M.; Morgado, Ana L.; Solá, Susana; Rodrigues, Cecília M. P.

doi:10.1089/ars.2013.5417

Cited by 42 publications

(50 citation statements)

References 68 publications

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“…Interestingly, they reported that after growth factor depletion mROS reached a maximum increase of ~200% at 1 h and this increase was significantly but not completely restored at 3 h (no further time points were tested) [24]. Results from Xavier and colleagues are in agreement with our findings, also reporting a transient increase in superoxide mROS 1 h after the induction of NSC differentiation [27]. These results are in line with ours when using 60 sec of laser, indicating that 405 nm laser exposure is capable of triggering processes similar to those occurring at early stages of NSC differentiation.…”

Section: Discussionsupporting

confidence: 92%

“…We demonstrated the mechanisms by which blue light has neurogenic properties in vitro. One single laser pulse of 60 sec (300 mW/cm 2 , 18 J/cm 2 fluence) transiently induces the generation of mitochondrial Nox-derived ROS to levels similar to those found during earlier stages of neuronal differentiation [24,27]. Hence, when finely tuned, light is capable of triggering ROS-involved physiological processes such as neuronal differentiation.…”

Section: Discussionmentioning

confidence: 83%

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Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles

et al. 2017

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles

et al. 2017

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“…15 TUDCA prevented mitochondrial membrane depolarization occurring at early stages of neural differentiation, such as at 6 h, as assessed by a significant increase in DiOC 6 (3) mitochondrial incorporation (P < 0.01) (Fig. 1A).…”

Section: Tudca Prevents Differentiation-induced Mitochondrial Stressmentioning

confidence: 85%

“…15 In addition, we have previously demonstrated that TUDCA is a strong inhibitor of apoptosis by preventing mitochondrial apoptotic signaling, including mitochondrial membrane perturbations and cytochrome c release. 4,25 Therefore, we investigated the potential effect of TUDCA during differentiation-induced mitochondrial stress, as well as its efficacy in regulating NSC differentiation.…”

Section: Tudca Prevents Differentiation-induced Mitochondrial Stressmentioning

confidence: 99%

“…The protective effect of mitochondrial p53 appeared to be partially dependent on manganese superoxide dismutase (MnSOD). 15 Moreover, a tight control of mitochondrial damage during differentiation was also shown to be important for cell fate determination. Indeed, mtDNA damage might be the primary signal for NSC commitment to the astroglial lineage, and lack of neurogenesis seen during repair of neuronal injury.…”

Section: Introductionmentioning

confidence: 99%

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Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversion by regulating mitochondria-cell cycle retrograde signaling

et al. 2014

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, sex determining region Y-box 2; GFAP, glial fibrillary acidic protein; DiOC 6 (3), 3, 3 0 -dihexyloxacarbocyanine iodide.The low survival and differentiation rates of stem cells after either transplantation or neural injury have been a major concern of stem cell-based therapy. Thus, further understanding long-term survival and differentiation of stem cells may uncover new targets for discovery and development of novel therapeutic approaches. We have previously described the impact of mitochondrial apoptosis-related events in modulating neural stem cell (NSC) fate. In addition, the endogenous bile acid, tauroursodeoxycholic acid (TUDCA) was shown to be neuroprotective in several animal models of neurodegenerative disorders by acting as an anti-apoptotic and anti-oxidant molecule at the mitochondrial level. Here, we hypothesize that TUDCA might also play a role on NSC fate decision. We found that TUDCA prevents mitochondrial apoptotic events typical of early-stage mouse NSC differentiation, preserves mitochondrial integrity and function, while enhancing self-renewal potential and accelerating cell cycle exit of NSCs. Interestingly, TUDCA prevention of mitochondrial alterations interfered with NSC differentiation potential by favoring neuronal rather than astroglial conversion. Finally, inhibition of mitochondrial reactive oxygen species (mtROS) scavenger and adenosine triphosphate (ATP) synthase revealed that the effect of TUDCA is dependent on mtROS and ATP regulation levels. Collectively, these data underline the importance of mitochondrial stress control of NSC fate decision and support a new role for TUDCA in this process.

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Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer

et al. 2020

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The cross‐talk between the mitochondrion and the nucleus regulates cellular functions, including differentiation and adaptation to stress. Mitochondria supply metabolites for epigenetic modifications and other nuclear‐associated activities and certain mitochondrial proteins were found in the nucleus. The voltage‐dependent anion channel 1 (VDAC1), localized at the outer mitochondrial membrane (OMM) is a central protein in controlling energy production, cell growth, Ca2+ homeostasis, and apoptosis. To alter the cross‐talk between the mitochondria and the nucleus, we used specific siRNA to silence the expression of VDAC1 in glioblastoma (GBM) U87‐MG and U118‐MG cell‐derived tumors, and then monitored the nuclear localization of mitochondrial proteins and the methylation and acetylation of histones. Depletion of VDAC1 from tumor cells reduced metabolism, leading to inhibition of tumor growth, and several tumor‐associated processes and signaling pathways linked to cancer development. In addition, we demonstrate that certain mitochondrial pro‐apoptotic proteins such as caspases 3, 8, and 9, and p53 were unexpectedly overexpressed in tumors, suggesting that they possess additional non‐apoptotic functions. VDAC1 depletion and metabolic reprograming altered their expression levels and subcellular localization, specifically their translocation to the nucleus. In addition, VDAC1 depletion also leads to epigenetic modifications of histone acetylation and methylation, suggesting that the interchange between metabolism and cancer signaling pathways involves mitochondria‐nucleus cross‐talk. The mechanisms regulating mitochondrial protein trafficking into and out of the nucleus and the role these proteins play in the nucleus remain to be elucidated.

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Mitochondrial Translocation of p53 Modulates Neuronal Fate by Preventing Differentiation-Induced Mitochondrial Stress

Abstract: In conclusion, our results reveal a novel role for mitochondrial p53, which modulates mitochondrial damage and apoptosis-related events in the context of neural differentiation, thus enhancing neuronal fate.

Cited by 42 publications

References 68 publications

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles

Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversion by regulating mitochondria-cell cycle retrograde signaling

Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer

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