Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation

Xue, Yanan; Liu, Yanan; Su, Jing; Li, Jiu-Ling; Wu, Yao; Guo, Rui; Yu, Bingbing; Yan, Xiaoyu; Zhang, Lichao; Sun, Liankun; Yang, Li

doi:10.1002/cam4.2130

Cited by 17 publications

(19 citation statements)

References 38 publications

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“…In fact, prostate tissue physiologically accumulates high amount of citrate, thanks to a zinc-mediated inhibition of ACO2. 37 , 38 Even though it is well known that ACO2 is not a rate-limiting enzyme of the TCA cycle, our data pointed out the importance of its reaction in promoting cancer metabolic rewiring. In fact, we demonstrated that increased levels of ACO2 in MCF-7 cells are able to affect aerobic glycolytic rate as demonstrated by the reduction of extracellular lactate efflux.…”

Section: Discussionmentioning

confidence: 63%

Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response

et al. 2019

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Background Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement in cancer metabolism have been provided so far. Methods Biochemical assays coupled with molecular biology, in silico, and cellular tools were applied to circumstantiate the impact of ACO2 in the breast cancer cell line MCF-7 metabolism. Fluorescence lifetime imaging microscopy (FLIM) of NADH was used to corroborate the changes in bioenergetics. Results We showed that ACO2 levels are decreased in breast cancer cell lines and human tumour biopsies. We generated ACO2- overexpressing MCF-7 cells and employed comparative analyses to identify metabolic adaptations. We found that increased ACO2 expression impairs cell proliferation and commits cells to redirect pyruvate to mitochondria, which weakens Warburg-like bioenergetic features. We also demonstrated that the enhancement of oxidative metabolism was supported by mitochondrial biogenesis and FoxO1-mediated autophagy/mitophagy that sustains the increased ROS burst. Conclusions This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies.

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Section: Discussionmentioning

confidence: 63%

Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response

et al. 2019

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“…In contrast, PCa cells no longer present zinc-accumulation and citrate-secretion, but activated TCA cycle/OXPHOS, thereby generating additional ATP (78, 80) ( Figure 2B). Latonen et al and Xue et al show an increase in aconitase expression in PCa cells compared to non-cancerous tissue, which indicates their citrate oxidizing ability (81,82). Acetyl-CoA provided by the TCA cycle serves as substrate for lipogenesis, which is known to be hyper-activated in PCa and associated with androgen resistance and tumor aggressiveness (17,(83)(84)(85).…”

Section: The Peculiar Energy Metabolism Of Pca and Its Implications Omentioning

confidence: 99%

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

2020

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A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis—known as the Warburg effect—is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1–4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1–3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high de novo fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed.

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“…Because zinc inhibition of other mitochondrial components causes MMP loss and ROS generation [77], we suggest that decreased mACN activity due to zinc may also be the result of these injurious processes. Indeed, mACN inactivation has been linked to MMP loss [122] and ROS accumulation [123]. However, it is worth noting that MMP loss in [122] was induced by excess calcium, not zinc, and [123] the study was conducted using a human prostate cancer cell line, which, as noted earlier, may have a significantly different biology than neurons [122,123].…”

Section: Tca Cyclementioning

confidence: 97%

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

Liu

Gale

Reynolds³

et al. 2021

Preprint

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Zinc is a highly abundant cation in the brain, where it is essential for cellular function, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc, can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential, leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

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Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation

Cited by 17 publications

References 38 publications

Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response

Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

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