Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming

Ying, Zhongfu; Ge, Xiang; Zheng, Lingjun; Tang, Huazhong; Duan, Lifan; Lin, Xiubin; Zhao, Qiuge; Chen, Keshi; Wu, Yi; Xing, Guangsuo; Lv, Yiwang; Li, Linpeng; Yang, Lijian; Bao, Feixiang; Long, Qi; Zhou, Yanshuang; He, Xiaodong; Wang, Yaofeng; Gao, Minghui; Pei, Duanqing; Chan, Wai‐Yee

doi:10.1016/j.cmet.2018.12.017

Cited by 18 publications

(20 citation statements)

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“…CaRe status may be directly linked to the epigenetic processes discussed above. ROS release from mitochondria (Ying et al ., ) and hydrogen peroxide exposure (Niu et al ., ) can alter histone methylation, and the oxidative status of a JMJD3 ‐regulating transcription factor (STAT6) directly alters JMJD3 (He et al ., ). JARID2 and the associated epigenetic remodeling complex PRC2, and JMJD3, exhibit a wide range of responses to oxidative and other cellular stressors, triggered by environmental signals such as heat shock (Marasca, Bodega & Orlando, ).…”

Section: Connections Between Care Status and Sex Determinationmentioning

confidence: 99%

Cellular calcium and redox regulation: the mediator of vertebrate environmental sex determination?

et al. 2020

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Many reptiles and some fish determine offspring sex by environmental cues such as incubation temperature. The mechanism by which environmental signals are captured and transduced into specific sexual phenotypes has remained unexplained for over 50 years. Indeed, environmental sex determination (ESD) has been viewed as an intractable problem because sex determination is influenced by a myriad of genes that may be subject to environmental influence. Recent demonstrations of ancient, conserved epigenetic processes in the regulatory response to environmental cues suggest that the mechanisms of ESD have a previously unsuspected level of commonality, but the proximal sensor of temperature that ultimately gives rise to one sexual phenotype or the other remains unidentified. Here, we propose that in ESD species, environmental cues are sensed by the cell through highly conserved ancestral elements of calcium and redox (CaRe) status, then transduced to activate ubiquitous signal transduction pathways, or influence epigenetic processes, ultimately to drive the differential expression of sex genes. The early evolutionary origins of CaRe regulation, and its essential role in eukaryotic cell function, gives CaRe a propensity to be independently recruited for diverse roles as a 'cellular sensor' of environmental conditions. Our synthesis provides the first cohesive mechanistic model connecting environmental signals and sex determination pathways in vertebrates, providing direction and a framework for developing targeted experimentation.

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Section: Connections Between Care Status and Sex Determinationmentioning

confidence: 99%

Cellular calcium and redox regulation: the mediator of vertebrate environmental sex determination?

et al. 2020

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“…For example, during the Fenton reaction, hydrogen peroxide (H 2 O 2 ) reacts with ferrous iron (Fe 2+ ) to generate ferric iron (Fe 3+ ), a hydroxyl radical (•OH), and a hydroxyl ion (OH − ) 58 . Transient ROS-induced mPTP openings are associated with early phase somatic cell reprogramming and their metabolic switch 35,59 . Studies in human and mouse fibroblast cells have shown that mPTP openings promote demethylation of pluripotency promoters, an integral event in the acquisition of pluripotency during the later stages of reprogramming 35,59 .…”

Section: Discussionmentioning

confidence: 99%

“…Transient ROS-induced mPTP openings are associated with early phase somatic cell reprogramming and their metabolic switch 35,59 . Studies in human and mouse fibroblast cells have shown that mPTP openings promote demethylation of pluripotency promoters, an integral event in the acquisition of pluripotency during the later stages of reprogramming 35,59 . Indeed, increasing mPTP opening frequency with ROS-inducing agents prior to the metabolic switch was shown to increase reprogramming efficiency 35 .…”

Section: Discussionmentioning

confidence: 99%

Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

Kozlov

Lone

Betts

et al. 2020

Sci Rep

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Recent evidence has emerged that cancer cells can use various metabolites as fuel sources. Restricting cultured cancer cells to sole metabolite fuel sources can promote metabolic changes leading to enhanced glycolysis or mitochondrial OXPHOS. However, the effect of metabolite-restriction on non-transformed cells remains largely unexplored. Here we examined the effect of restricting media fuel sources, including glucose, pyruvate or lactate, on the metabolic state of cultured human dermal fibroblasts. Fibroblasts cultured in lactate-only medium exhibited reduced PDH phosphorylation, indicative of OXPHOS, and a concurrent elevation of ROS. Lactate exposure primed fibroblasts to switch to glycolysis by increasing transcript abundance of genes encoding glycolytic enzymes and, upon exposure to glucose, increasing glycolytic enzyme levels. furthermore, lactate treatment stabilized HIF-1α, a master regulator of glycolysis, in a manner attenuated by antioxidant exposure. our findings indicate that lactate preconditioning primes fibroblasts to switch from OXPHOS to glycolysis metabolism, in part, through ROS-mediated HIF-1α stabilization. interestingly, we found that lactate preconditioning results in increased transcript abundance of MYC and SNAI1, key facilitators of early somatic cell reprogramming. Defined metabolite treatment may represent a novel approach to increasing somatic cell reprogramming efficiency by amplifying a critical metabolic switch that occurs during ipSc generation. The preferential use of glycolysis even in the presence of oxygen is known as aerobic glycolysis or the Warburg effect, a unique form of metabolism originally identified in cancer cells, but also found in many non-transformed cells 1,2. By shuttling glucose primarily through glycolysis, cancer cells fuel their proliferation by accumulating glycolytic intermediates required for fatty acid and nucleic acid synthesis. As lactate is a by-product of glycolysis, cancer cells exist in an acidic microenvironment which serves to facilitate angiogenesis and tumour invasion 3. Research examining the relationship between cancer cells and their microenvironment has revealed a novel phenomenon known as the reverse Warburg effect 4. The reverse Warburg effect is based on the theory that cells within a tumour can switch between glycolysis and oxidative phosphorylation (OXPHOS) 5-7. The reverse Warburg effect postulates that oxidative cancer cells secrete reactive oxygen species (ROS) which induce oxidative stress in surrounding stromal cells such as cancer-associated fibroblast (CAF) cells 8,9. To respond to this stress, CAFs adopt aerobic glycolysis as their primary form of metabolism 8,9. Glycolytic CAFs secrete lactate and precursors for nucleic acid and fatty acid synthesis, which are then taken up by adjacent cancer cells to fuel OXPHOS and support proliferation, thereby continuing the cycle 8,9. Long considered merely a by-product of glycolysis, lactate is emerging as an important signalling molecule and energy source 10-15. In addition to promoti...

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“…Previous research has implicated action potential‐derived calcium release through ryanodine receptors in axon – oligodendrocyte communication, stimulating glutamate release from the axo‐myelinic synapse (Micu et al, ). The involvement of MPTP in calcium release following the action potential is less expected, however previous studies have shown that pore opening is not always associated with degenerative pathways and transient opening of the pore has been implicated in somatic reprogramming (Ying et al, ) and in acute ischemic preconditioning of cardiomyocytes, which can protect against subsequent sustained ischemia (Hausenloy et al, ). The axonal ER and mitochondria are closely coupled (Wu et al, ) and previous studies demonstrate the role of ER calcium release in mediating MPTP opening following a variety of insults (Villegas et al, ).…”

Section: Discussionmentioning

confidence: 99%

Microtubule‐dependent processes precede pathological calcium influx in excitotoxin‐induced axon degeneration

Tian

Hanson

Canty

et al. 2019

Journal of Neurochemistry

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Axon degeneration and axonal loss is a feature of neurodegenerative disease and injury and occurs via programmed pathways that are distinct from cell death pathways. While the pathways of axonal loss following axon severing are well described, less is known about axonal loss following other neurodegenerative insults. Here we use primary mouse cortical neuron cultures grown in compartmentalized chambers to investigate the role of calcium in the degeneration of axons that occurs following a somal insult by the excitotoxin kainic acid. Calcium influx has been implicated in both excitotoxicity and axon degeneration mechanisms, however the link between a somal insult and axonal calcium increase is unclear. Live imaging of axons demonstrated that pharmacologically preventing intracellular calcium increases through the endoplasmic reticulum or mitochondria significantly (p < 0.05) reduced axon degeneration. Live calcium‐imaging with the Ca2+ indicator Fluo‐4 demonstrated that kainic acid exposure to the soma resulted in a rapid, and transient, increase in calcium in the axon, which occured even at low kainic acid concentrations that do not cause axon degeneration within 24 h. However, this calcium transient was followed by a gradual increase in axonal calcium, which was associated with axonal loss. Furthermore, treatment with a range of doses of the microtubule stabilizing drug taxol, which protects against axon fragmentation in this model, prevented this gradual calcium increase, suggesting that the intra‐axonal calcium changes are downstream of microtubule associated events. Biochemical analysis of taxol treated neurons demonstrated a shift in microtubule post‐translational modifications, with a significant (p < 0.05) increase in acetylated tubulin and a significant (p < 0.05) decrease in tyrosinated tubulin, suggestive of a more stable microtubule pool. Together our results suggest that axonal degeneration following excitotoxicity is dependent on an increase in axonal calcium, which is downstream of a microtubule‐dependent event.

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Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming

Cited by 18 publications

References 0 publications

Cellular calcium and redox regulation: the mediator of vertebrate environmental sex determination?

Cellular calcium and redox regulation: the mediator of vertebrate environmental sex determination?

Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

Microtubule‐dependent processes precede pathological calcium influx in excitotoxin‐induced axon degeneration

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