Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

Dodson, Matthew; Liang, Qiwei; Johnson, Michelle S.; Redmann, Matthew; Fineberg, Naomi S.; Darley‐Usmar, Victor; Zhang, Jianhua

doi:10.4161/auto.26094

Cited by 49 publications

(41 citation statements)

References 57 publications

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“…Data from previous studies also showed that 4-HNE induced human aortic smooth muscle cell proliferation and differentiation, and rat aortic smooth muscle cell proliferation, in a dose-dependent manner [42]. However, high concentrations of HNE initiated apoptosis by inducing endoplasmic reticulum stress and mitochondrial dysfunction in human colon carcinoma cells and neuroblastoma cells [43], [44]. These findings indicated that the function of HNE is complex; whether it promotes proliferation, differentiation or cell apoptosis depends upon its concentration and the cell type involved.…”

Section: Discussionmentioning

confidence: 91%

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Liu

et al. 2017

Redox Biology

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The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1 μM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-κB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline-induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-κB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH.

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Section: Discussionmentioning

confidence: 91%

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Liu

et al. 2017

Redox Biology

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“…Attenuated autophagy has been reported to accompany cellular bioenergetic dysfunction in various genetic and oxidative stress models [48], [49], [50], [51]. Previous studies suggested that bafilomycin has a direct effect on mitochondrial function [20], [21].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons

et al. 2017

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Autophagy is an important cell recycling program responsible for the clearance of damaged or long-lived proteins and organelles. Pharmacological modulators of this pathway have been extensively utilized in a wide range of basic research and pre-clinical studies. Bafilomycin A1 and chloroquine are commonly used compounds that inhibit autophagy by targeting the lysosomes but through distinct mechanisms. Since it is now clear that mitochondrial quality control, particularly in neurons, is dependent on autophagy, it is important to determine whether these compounds modify cellular bioenergetics. To address this, we cultured primary rat cortical neurons from E18 embryos and used the Seahorse XF96 analyzer and a targeted metabolomics approach to measure the effects of bafilomycin A1 and chloroquine on bioenergetics and metabolism. We found that both bafilomycin and chloroquine could significantly increase the autophagosome marker LC3-II and inhibit key parameters of mitochondrial function, and increase mtDNA damage. Furthermore, we observed significant alterations in TCA cycle intermediates, particularly those downstream of citrate synthase and those linked to glutaminolysis. Taken together, these data demonstrate a significant impact of bafilomycin and chloroquine on cellular bioenergetics and metabolism consistent with decreased mitochondrial quality associated with inhibition of autophagy.

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“…It was reported that increased apoptosis or excessive autophagy in the intervertebral disc cells was also involved in the pathogenesis of IVDD [11,[15][16][17]. Meanwhile, apoptosis and autophagy were closely linked and autophagy could either inhibit or delay the occurrence of apoptosis [18][19][20][21][22][23], or promote apoptosis [24,25]. However, the crosstalk between autophagy and apoptosis in the intervertebral disc cells and its implication in the pathogenesis of IVDD has not been clarified.…”

Section: Introductionmentioning

confidence: 94%

The effect of transforming growth factor β1 on the crosstalk between autophagy and apoptosis in the annulus fibrosus cells under serum deprivation

Yang

et al. 2014

Cytokine

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Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

Abstract: (2013) Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma

Cited by 49 publications

References 57 publications

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons

The effect of transforming growth factor β1 on the crosstalk between autophagy and apoptosis in the annulus fibrosus cells under serum deprivation

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