Expression of the Alternative Oxidase Influences Jun N-Terminal Kinase Signaling and Cell Migration

Andjelković, Ana; Mordas, Amelia; Bruinsma, Lyon; Ketola, Annika; Cannino, Giuseppe; Giordano, Luca; Dhandapani, Praveen K.; Szibor, Marten; Dufour, Éric; Jacobs, Howard T.

doi:10.1128/mcb.00110-18

Cited by 16 publications

(14 citation statements)

References 120 publications

(136 reference statements)

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“…And the tumorigenesis potential of GBM CSCs was related to NDRG4 [24]. Moreover, the regulation of mitochondrial alternative oxidase expression could affect cell migration by changing of mitochondrial heat production [25]. The results of those researches were consistent with our primary hypothesis.…”

Section: Discussionsupporting

confidence: 83%

NDRG1 regulates osteosarcoma cells via mediating the mitochondrial function and CSCs differentiation

2021

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Background Cancer stem cells (CSCs) are mainly contributed to malignancy metastatic potential and resistant therapy of osteosarcoma (OS). The mitochondria-related apoptosis was generally accepted as the target of tumor therapy. However, the effect of N-myc downstream-regulated gene 1 (NDRG1) on CSCs and mitochondrial health in OS is still unknown. Methods In OS cells, MG63 and U2OS, the siRNA of NDRG1 were conducted. Transwell, western blot, RT-qPCR, and mitochondria isolation were used to identify the effect of NDRG on OS cells and mitochondria. Moreover, the differentiation-related factors of CSCs were determined. Results After downregulation of NDRG1, the cell viability, invasion ability decreased whereas cell apoptosis increased. The expressions profiles of fibronectin, vimentin, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP) 2, MMP9, and MMP13 were downregulated, but E-cadherin expression level was upregulated by NDRG1 siRNA. At the same time, cytochrome (Cyt) C levels were increased in cytosol with the decreasing in mitochondria after siRNA treatment. The mitochondrial membrane potential (MMPs) was declined, and the function of mitochondria was impeded. The expressions of uncoupling proteins (UCP) 2, voltage dependent anion channel (VDAC), peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α, and cyclooxygenase (COX) 2 were downregulated by NDRG1 silencing. Moreover, NDRG performed its function primarily through the Wnt pathway and could regulate the differentiation of osteosarcoma stem cells. Conclusion Silencing of NDRG1 could damage the function of mitochondria, promote the CSCs differentiation, alleviating OS progression.

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Section: Discussionsupporting

confidence: 83%

NDRG1 regulates osteosarcoma cells via mediating the mitochondrial function and CSCs differentiation

2021

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“…Similarly, two different lines of mice ubiquitously expressing AOX (El‐Khoury et al ; Szibor et al ) showed no significant deviations from controls, even when over 350 physiological, behavioral and metabolic parameters were measured. Nevertheless, AOX was able to confer protection against various kinds of physiological stress, ranging from exposure to respiratory poisons such as cyanide or antimycin A (Fernandez‐Ayala et al ; El‐Khoury et al ; Szibor et al ), genetically engineered OXPHOS deficiency (Kemppainen et al 2014; Rajendran et al ) pathological models related to oxidative, proteotoxic, nutritional, and proinflammatory stress (Fernandez‐Ayala et al ; Humphrey et al ; El‐Khoury et al ; Mills et al ; Giordano et al ), or disturbed nuclear‐receptor and Jun‐kinase signaling (Andjelković et al, ; Andjelković et al, ).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic effects of dietary stress in combination with a respiratory chain bypass in mice

et al. 2019

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The alternative oxidase (AOX) from Ciona intestinalis was previously shown to be expressible in mice and to cause no physiological disturbance under unstressed conditions. Because AOX is known to become activated under some metabolic stress conditions, resulting in altered energy balance, we studied its effects in mice subjected to dietary stress. Wild‐type mice ( Mus musculus , strain C57BL/6JOlaHsd) fed a high‐fat or ketogenic (high‐fat, low‐carbohydrate) diet show weight gain with increased fat mass, as well as loss of performance, compared with chow‐fed animals. Unexpectedly, AOX‐expressing mice fed on these metabolically stressful, fat‐rich diets showed almost indistinguishable patterns of weight gain and altered body composition as control animals. Cardiac performance was impaired to a similar extent by ketogenic diet in AOX mice as in nontransgenic littermates. AOX and control animals fed on ketogenic diet both showed wide variance in weight gain. Analysis of the gut microbiome in stool revealed a strong correlation with diet, rather than with genotype. The microbiome of the most and least obese outliers reared on the ketogenic diet showed no consistent trends compared with animals of normal body weight. We conclude that AOX expression in mice does not modify physiological responses to extreme diets.

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“…Notably, AOX by-passes two proton pumps of the ETC, namely cIII and cIV [6,7], and represents a metabolic rescue mechanism that is absent in vertebrates [3]. Notwithstanding its natural absence, AOX can be xenotopically expressed in a catalytically active form in human cells with primary respiratory chain dysfunction [8] or mouse mtDNA-depleted cells [9], in drosophila disease models [10][11][12][13][14][15], and in the mouse [7,16] by using an AOX cDNA transiently expressed or integrated into specific sites in the genome. Remarkably, in most cases this has been achieved without producing adverse phenotypic effects, at least under standard physiological conditions, i.e., in the absence of metabolic stress signaling related to respiratory disruption [7].…”

Section: Introductionmentioning

confidence: 99%

Alternative oxidase encoded by sequence-optimized and chemically-modified RNA transfected into mammalian cells is catalytically active

et al. 2021

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Plants and other organisms, but not insects or vertebrates, express the auxiliary respiratory enzyme alternative oxidase (AOX) that bypasses mitochondrial respiratory complexes III and/or IV when impaired. Persistent expression of AOX from Ciona intestinalis in mammalian models has previously been shown to be effective in alleviating some metabolic stresses produced by respiratory chain inhibition while exacerbating others. This implies that chronic AOX expression may modify or disrupt metabolic signaling processes necessary to orchestrate adaptive remodeling, suggesting that its potential therapeutic use may be confined to acute pathologies, where a single course of treatment would suffice. One possible route for administering AOX transiently is AOX-encoding nucleic acid constructs. Here we demonstrate that AOX-encoding chemically-modified RNA (cmRNA), sequence-optimized for expression in mammalian cells, was able to support AOX expression in immortalized mouse embryonic fibroblasts (iMEFs), human lung carcinoma cells (A549) and primary mouse pulmonary arterial smooth muscle cells (PASMCs). AOX protein was detectable as early as 3 h after transfection, had a half-life of ~4 days and was catalytically active, thus supporting respiration and protecting against respiratory inhibition. Our data demonstrate that AOX-encoding cmRNA optimized for use in mammalian cells represents a viable route to investigate and possibly treat mitochondrial respiratory disorders.

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Expression of the Alternative Oxidase Influences Jun N-Terminal Kinase Signaling and Cell Migration

Abstract: Downregulation of Jun N-terminal kinase (JNK) signaling inhibits cell migration in diverse model systems. In Drosophila pupal development, attenuated JNK signaling in the thoracic dorsal epithelium leads to defective midline closure, resulting in cleft thorax.

Cited by 16 publications

References 120 publications

NDRG1 regulates osteosarcoma cells via mediating the mitochondrial function and CSCs differentiation

NDRG1 regulates osteosarcoma cells via mediating the mitochondrial function and CSCs differentiation

Phenotypic effects of dietary stress in combination with a respiratory chain bypass in mice

Alternative oxidase encoded by sequence-optimized and chemically-modified RNA transfected into mammalian cells is catalytically active

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