Acetylated tau exacerbates learning and memory impairment by disturbing with mitochondrial homeostasis

Liu, Qian; Wang, Xin; Hu, Yu; Zhao, Junning; Huang, Chunhui; Li, Ting; Zhang, Bing-Ge; Yang, He; Wu, Yanqing; Zhang, Zaijun; Wang, Guoping; Liu, Gongping

doi:10.1016/j.redox.2023.102697

Cited by 14 publications

(9 citation statements)

References 87 publications

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“…In our laboratory, reverse transcription and real-time quantitative PCR were carried out following the established protocols. 3 Total RNA was extracted using RNAisO PIus (Cat#: 9109, Takara), and then a reverse transcription reagent kit (Cat#: RR037A, Takara; Cat#: BL699A, Biosharp) was utilized to obtain cDNA. RT-PCR was carried out using a StepOnePlus Real-Time PCR Detection System (AB Applied Biosystems, Singapore).…”

Section: Methodsmentioning

confidence: 99%

A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

Wang,

Liu,

et al. 2024

Sig Transduct Target Ther

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Impaired brain glucose metabolism is an early indicator of Alzheimer’s disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3β (IDH3β) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice’s brains. Further investigations demonstrated that the knockdown of IDH3β induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3β, the elevated PAX6 in turn inhibited the expression of IDH3β, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3β and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β. Breaking this loop by upregulating IDH3β or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.

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Section: Methodsmentioning

confidence: 99%

A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

Wang,

Liu,

et al. 2024

Sig Transduct Target Ther

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“…Targeting mitochondrial dynamics can affect mitochondrial structure, modify mitochondrial distribution, enhance mitochondrial function, and influence the regulation of apoptosis (Su et al., 2010). In recent years, BGP‐15 has been used in treating specific disorders associated with mitochondrial dysfunction, involving the regulation of mitochondrial dynamic homeostasis, but up to now there is no information about its affecting a known receptor or specific binding protein (Al‐Zubaidi et al., 2021; Gyongyosi et al., 2023; Liu et al., 2023). In this study, we observed that BGP‐15 improved TauKQ‐induced mitochondrial dysfunction and cell apoptosis by enhancing mitochondrial dynamics, suggesting its potential as a therapeutic agent for AD.…”

Section: Discussionmentioning

confidence: 99%

Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells

Zhang,

Fang,

Zhao

et al. 2024

Journal of Neurochemistry

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An increase in tau acetylation at K274 and K281 and abnormal mitochondrial dynamics have been observed in the brains of Alzheimer's disease (AD) patients. Here, we constructed three types of tau plasmids, TauKQ (acetylated tau mutant, by mutating its K274/K281 into glutamine to mimic disease‐associated lysine acetylation), TauKR (non‐acetylated tau mutant, by mutating its K274/K281 into arginine), and TauWT (wild‐type human full‐length tau). By transfecting these tau plasmids in HEK293 cells, we found that TauWT and TauKR induced mitochondrial fusion by increasing the level of mitochondrial fusion proteins. Conversely, TauKQ induced mitochondrial fission by reducing mitochondrial fusion proteins, exacerbating mitochondrial dysfunction and apoptosis. BGP‐15 ameliorated TauKQ‐induced mitochondrial dysfunction and apoptosis by improving mitochondrial dynamics. Our findings suggest that acetylation of K274/281 represents an important post‐translational modification site regulating mitochondrial dynamics, and that BGP‐15 holds potential as a therapeutic agent for mitochondria‐associated diseases such as AD.

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“…TGF-β1 exerted harmful effects on mitochondrial function by decreasing mitochondrial mass and mitochondrial DNA in human renal proximal tubular epithelial cells associated with renal fibrosis [ 58 ]. We also found decreased MMP, ATP production, and OCR of mitochondria, along with increased mitochondrial ROS levels in TGF-β1-activated ESCs, indicating excessive oxidative stress and mitochondrial dysfunction [ 59 ]. Additionally, we observed increased protein expressions of mitochondrial fusion, fission, and mitophagy in activated ESCs, concurrent with mitochondrial elongation, suggesting that mitochondrial elongation was the outcome of an imbalance in mitochondrial dynamics.…”

Section: Discussionmentioning

confidence: 99%

Glutaminolysis regulates endometrial fibrosis in intrauterine adhesion via modulating mitochondrial function

Chen,

Ye,

Huang

et al. 2024

Biol Res

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Background Endometrial fibrosis, a significant characteristic of intrauterine adhesion (IUA), is caused by the excessive differentiation and activation of endometrial stromal cells (ESCs). Glutaminolysis is the metabolic process of glutamine (Gln), which has been implicated in multiple types of organ fibrosis. So far, little is known about whether glutaminolysis plays a role in endometrial fibrosis. Methods The activation model of ESCs was constructed by TGF-β1, followed by RNA-sequencing analysis. Changes in glutaminase1 (GLS1) expression at RNA and protein levels in activated ESCs were verified experimentally. Human IUA samples were collected to verify GLS1 expression in endometrial fibrosis. GLS1 inhibitor and glutamine deprivation were applied to ESCs models to investigate the biological functions and mechanisms of glutaminolysis in ESCs activation. The IUA mice model was established to explore the effect of glutaminolysis inhibition on endometrial fibrosis. Results We found that GLS1 expression was significantly increased in activated ESCs models and fibrotic endometrium. Glutaminolysis inhibition by GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES or glutamine deprivation treatment suppressed the expression of two fibrotic markers, α-SMA and collagen I, as well as the mitochondrial function and mTORC1 signaling in ESCs. Furthermore, inhibition of the mTORC1 signaling pathway by rapamycin suppressed ESCs activation. In IUA mice models, BPTES treatment significantly ameliorated endometrial fibrosis and improved pregnancy outcomes. Conclusion Glutaminolysis and glutaminolysis-associated mTOR signaling play a role in the activation of ESCs and the pathogenesis of endometrial fibrosis through regulating mitochondrial function. Glutaminolysis inhibition suppresses the activation of ESCs, which might be a novel therapeutic strategy for IUA.

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Acetylated tau exacerbates learning and memory impairment by disturbing with mitochondrial homeostasis

Cited by 14 publications

References 87 publications

A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells

Glutaminolysis regulates endometrial fibrosis in intrauterine adhesion via modulating mitochondrial function

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