ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

Nakano, Masaki; Imamura, Hiromi; Sasaoka, Norio; Yamamoto, Masamichi; Uemura, Norihito; Shudo, Toshiyuki; Fuchigami, Tomohiro; Takahashi, Ryōsuke; Kakizuka, Akira

doi:10.1016/j.ebiom.2017.07.024

Cited by 60 publications

(48 citation statements)

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“…Because Glut3 is known to have a higher affinity for glucose than Glut1 (Simpson et al., ), we hypothesized that the extent of increase in ATP levels differs between the NNE and the NE when exposed to the extrauterine environment. To test this, we monitored the steady‐state level of ATP in embryos at the tissue level in real time using GO‐ATeam2, a genetically encoded cytosolic ATP sensor (M. Yamamoto et al., manuscript in preparation) (De Bock et al., ; Nakano, Imamura, Nagai, & Noji, ; Nakano et al., ). GO‐ATeam2 is a Förster resonance energy transfer (FRET)‐based ATP sensor that enables real‐time measurement of the steady‐state ATP level at single‐cell resolution (Figure e).…”

Section: Resultsmentioning

confidence: 99%

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Mammalian embryos show metabolic plasticity toward the surrounding environment during neural tube closure

et al. 2018

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Developing embryos rewire energy metabolism for developmental processes. However, little is known about how metabolic rewiring is coupled with development in a spatiotemporal manner. Here, we show that mammalian embryos display plasticity of glucose metabolism in response to the extracellular environment at the neural tube closure (NTC) stage, when the intrauterine environment changes upon placentation. To study how embryos modulate their metabolic state upon environmental change, we analyzed the steady-state level of ATP upon exposure to extrauterine environments using both an enzymatic assay and a genetically encoded ATP sensor. Upon environmental changes, NTC-stage embryos exhibited increased ATP content, whereas embryos before and after NTC did not. The increased ATP in the NTC-stage embryos seemed to depend on glycolysis. Intriguingly, an increase in mitochondrial membrane potential (ΔΨm) was also observed in the neural ectoderm (NE) and the neural plate border of the non-neural ectoderm (NNE) region. This implies that glycolysis can be coupled with the TCA cycle in the NE and the neural plate border depending on environmental context. Disrupting ΔΨm inhibited folding of the cranial neural plate. Thus, we propose that embryos tune metabolic plasticity to enable coupling of glucose metabolism with the extracellular environment at the NTC stage.

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Section: Resultsmentioning

confidence: 99%

“…GO-ATeam2 transgenic mice were generated by M. Yamamoto (manuscript in preparation) (Nakano et al, 2017). For live-imaging analysis of NTC, we used SCAT3 transgenic mice generated in our laboratory (Yamaguchi et al, 2011).…”

Section: Live-imaging Analysismentioning

confidence: 99%

Mammalian embryos show metabolic plasticity toward the surrounding environment during neural tube closure

et al. 2018

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“…The ATP level is important, especially because of its function to carry the chemical energy required for intracellular biochemical reactions and apoptotic cell death . Previous studies have shown that esculetin increases ATP levels in mouse lung tissue and mouse models of Parkinson's disease . However, according to the best of our knowledge, there is no study on the effects of esculetin on ATP levels in tumour tissue.…”

Section: Discussionmentioning

confidence: 99%

“…[34,35] Previous studies have shown that esculetin increases ATP levels in mouse lung tissue and mouse models of Parkinson's disease. [36,37] However, according to the best of our knowledge, there is no study on the effects of esculetin on ATP levels in tumour tissue.…”

Section: Discussionmentioning

confidence: 99%

Investigation of cell death mechanism and activity of esculetin-loaded PLGA nanoparticles on insulinoma cellsin vitro

Kaçar

Bahadorı

Tekkeli

et al. 2020

Journal of Pharmacy and Pharmacology

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Aim The purpose of this study was to prepare targeted cancer therapy formulation against insulinoma INS‐1 cells and to study its effect on cell death with related mechanisms in vitro. Methods Polylactide‐co‐glycolide (PLGA) nano‐micelles were used for preparation of esculetin nano‐formulation (nano‐esculetin). The cells were treated with nano‐esculetin and free esculetin. Apoptotic and necrotic cell death percentages, cell proliferation, ATP and GTP reductions and insulin levels were investigated on insulinoma INS‐1 cells for both free and nano‐esculetin formulations. Results About 50 mg of PLGA was able to carry 20 mg esculetin in 20 ml of formulation. The obtained optimized formulation was 150 nm, with 92% encapsulation efficiency and a slow‐release behaviour was observed during release studies. Nano‐esculetin bearing 25, 50 and 100 μg esculetin and free esculetin in equivalent doses successfully decreased cell viability. The prevailing cell death mechanism was necrosis. Along with cell proliferation, intracellular insulin and the ratio of ATP and GTP were decreased even with 12.5, 25 and 50 μg esculetin bearing nano‐formulation and its equivalent free esculetin. Conclusions The results revealed that esculetin is able to show its anti‐tumor afficacy after loading to PLGA nano‐micelles and nano‐encapsulation intensifies its cytotoxic activity in vitro. Current study shows that esculetin and its nano formulations are promising agents in treatment of insulinoma.

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“…A recent study reported that the activation of AMPK by metformin ameliorated the progression of Huntington’s disease in a mouse model (Arnoux, Willam et al, 2018), and the potential therapeutic use of metformin for neurodegenerative diseases is being discussed (Rotermund, Machetanz et al, 2018). Furthermore, the involvement of ATP and ADKs in preventing the manifestation of Parkinson’s disease in mouse models and patients has been proposed (Garcia-Esparcia, Hernandez-Ortega et al, 2015, Nakano, Imamura et al, 2017). Protein aggregation induced by the ATP catastrophe may be a general mechanism for the development of proteinopathies.…”

Section: Discussionmentioning

confidence: 99%

High and stable ATP levels prevent aberrant intracellular protein aggregation

Takaine

Imamura

Yoshida

2019

Preprint

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23ATP is the main source of chemical energy in all life and is maintained at several millimolar 24 in eukaryotic cells. However, the mechanisms responsible for and physiological relevance of 25 this high and stable concentration of ATP remain unclear. We herein demonstrate that 26 AMP-activated protein kinase (AMPK) and adenylate kinase (ADK) cooperate to maintain 27 cellular ATP levels regardless of glucose concentrations. Single cell imaging of ATP-reduced 28 yeast mutants revealed that ATP concentrations in these mutants underwent stochastic and 29 transient depletion of ATP repeatedly, which induced the cytotoxic aggregation of 30 endogenous proteins and pathogenic proteins, such as huntingtin and α-synuclein. Moreover, 31 pharmacological elevations in ATP levels in an ATP-reduced mutant prevented the 32 accumulation of α-synuclein aggregates and its cytotoxicity. The removal of cytotoxic 33 aggregates depended on proteasomes, and proteasomal activity cooperated with AMPK or 34 ADK to resist proteotoxic stresses. The present results provide the first evidence to show that 35 cellular ATP homeostasis ensures proteostasis and revealed that stochastic fluctuations in 36 cellular ATP concentrations contribute to cytotoxic protein aggregation, implying that AMPK 37 and ADK are important factors that prevent proteinopathies, such as neurodegenerative 38 diseases. 39 40 2019); however, it currently remains unclear whether ATP-dependent protein 51 solubilization/desolubilization play any significant roles in cell physiology. 52 53 We recently established a reliable imaging technique to quantify intracellular ATP 54 concentrations in single living yeast cells using the genetically encoded fluorescent ATP 55 biosensor QUEEN (Yaginuma, Kawai et al., 2014), which enables long-term evaluations of 56 ATP homeostasis in individual cells (Takaine et al., 2019). Our findings demonstrated that 57 intracellular ATP concentrations did not vary within a yeast population grown in the same 58 culture (Takaine et al., 2019), which was in contrast to the large variations observed in 59 intracellular ATP concentrations within a bacterial cell population (Yaginuma et al., 2014). 60 Moreover, intracellular ATP concentrations in individual living yeast cells were stably and 61 robustly maintained at approximately 4 mM, irrespective of carbon sources and cell cycle 62 stages, and temporal fluctuations in intracellular ATP concentrations were small ( Takaine et 63 al., 2019). Based on these findings, we hypothesized that an exceptionally robust mechanism 64 may exist to precisely regulate ATP concentrations in eukaryotes. It also remains unclear why 65 ATP is stably maintained at a markedly higher concentration than the K m (Michaelis constant) 66 required for the enzymatic activity of almost all ATPases (Edelman, Blumenthal et al., 1987), 67 and the consequences associated with failed ATP homeostasis in living organisms have not 68 yet been elucidated. 69 70The most promising candidate regulator of ATP homeostasis is AMP-activated prote...

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ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

Cited by 60 publications

References 70 publications

Mammalian embryos show metabolic plasticity toward the surrounding environment during neural tube closure

Mammalian embryos show metabolic plasticity toward the surrounding environment during neural tube closure

Investigation of cell death mechanism and activity of esculetin-loaded PLGA nanoparticles on insulinoma cellsin vitro

High and stable ATP levels prevent aberrant intracellular protein aggregation

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