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

Giordano, Luca; Aneja, Manish Kumar; Sommer, Natascha; Alebrahimdehkordi, Nasim; Seraji, Alireza; Weißmann, Norbert; Rudolph, Carsten; Plank, Christian; Jacobs, Howard T.; Szibor, Marten

doi:10.1038/s41434-021-00235-z

Cited by 6 publications

(3 citation statements)

References 45 publications

(73 reference statements)

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“…For instance, the use of DNases as therapeutics could alleviate the immunogenic role of cf-DNA [62]. Furthermore, cf-mtDNA levels in the plasma of COPD patients could be used to monitor systemic mitochondrial dysfunction, disease progression, and treatment efficacy (especially with treatments involving mitochondrial transfer, ROS scavengers, mitochondrial biogenesis stimulators, iron chelators, and mitophagy inhibitors) [8][9][10]59,[63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD

Giordano

Gregory

Verdaguer

et al. 2022

Cells

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Cigarette smoke (CS) is the most common risk factor for chronic obstructive pulmonary disease (COPD). The present study aimed to elucidate whether mtDNA is released upon CS exposure and is detected in the plasma of former smokers affected by COPD as a possible consequence of airway damage. We measured cell-free mtDNA (cf-mtDNA) and nuclear DNA (cf-nDNA) in COPD patient plasma and mouse serum with CS-induced emphysema. The plasma of patients with COPD plasma and serum of mice with CS-induced emphysema showed increased cf-mtDNA levels. In cell culture, exposure to a sublethal dose of CSE decreased mitochondrial membrane potential, increased oxidative stress, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles (EVs). Mitochondrial DNA release into EVs occurred concomitantly with increased expression of markers that associate with DNA damage responses, including DNase III, DNA-sensing receptors (cGAS and NLRP3), proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-18, and CXCL2), and markers of senescence (p16 and p21); the majority of the responses are also triggered by cytosolic DNA delivery in vitro. Exposure to a lethal CSE dose preferentially induced mtDNA and nDNA release in the cell debris. Collectively, the results of this study associate markers of mitochondrial stress, inflammation, and senescence with mtDNA release induced by CSE exposure. Because high cf-mtDNA is detected in the plasma of COPD patients and serum of mice with emphysema, our findings support the future study of cf-mtDNA as a marker of mitochondrial stress in response to CS exposure and COPD pathology.

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Section: Discussionmentioning

confidence: 99%

Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD

Giordano

Gregory

Verdaguer

et al. 2022

Cells

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“…AOX also inhibits the mitochondrial membrane hyperpolarization, and the superoxide overproduction induced by acute hypoxia in pulmonary artery smooth muscle cells, avoiding the subsequent pulmonary vasoconstriction in mice (366). In this regard, a chemically modified RNA encoding a humanized AOX has been recently generated as a therapeutic route (115). Lastly, inflammatory mediators such as nitric oxide and oxygen radicals have been suggested to play a role in the impairment of ATP production, resulting in a form of histotoxic hypoxia (1,224).…”

Section: Oxygen Deliverymentioning

confidence: 99%

Oxygen in Metabolic Dysfunction and Its Therapeutic Relevance

Lopez‐Pascual

Trayhurn

Martínéz

et al. 2021

Antioxidants & Redox Signaling

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Significance: In recent years, a number of studies have shown altered oxygen partial pressure at a tissue level in metabolic disorders, and some researchers have considered oxygen to be a (macro) nutrient. Oxygen availability may be compromised in obesity and several other metabolism-related pathological conditions, including sleep apnea-hypopnea syndrome, the metabolic syndrome (which is a set of conditions), type 2 diabetes, cardiovascular disease and cancer.Recent Advances: Strategies designed to reduce adiposity and its accompanying disorders have been mainly centered on nutritional interventions and physical activity programs. However, novel therapies are needed since these approaches have not been sufficient to counteract the worldwide increasing rates of metabolic disorders. In this regard, intermittent hypoxia training and hyperoxia could be potential treatments through oxygen-related adaptations. Moreover, living at high altitude may have a protective effect against the development of abnormal metabolic conditions. In addition, oxygen delivery systems may be of therapeutic value for supplying the tissue-specific oxygen requirements.Critical Issues: Precise in vivo methods to measure oxygenation are vital to disentangle some of the controversies related to this research area. Furthermore, it is evident that there is a growing need for novel in vitro models to study the potential pathways involved in metabolic dysfunction in order to find appropriate therapeutic targets.Future directions: Based on the existing evidence, it is suggested that oxygen availability has a key role in obesity and related comorbidities. Oxygen should be considered in relation to potential therapeutic strategies in the treatment and prevention of metabolic disorders.

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“…The premise that the transgenic expression of AOX would be beneficial for higher animals under OXPHOS dysfunction has been successfully tested in diverse models [9][10][11][12][13][14] . In addition to providing respiration resistant to inhibitors of CIII and CIV, AOX enabled complete or partial recovery of deleterious phenotypes caused by mutations in subunits of the OXPHOS complexes 3,10,[15][16][17] and has been considered as a therapy enzyme in putative future treatments 18,19 .…”

Section: Introductionmentioning

confidence: 99%

Systemic impact of the expression of the mitochondrial alternative oxidase onDrosophiladevelopment

Camargo

Saari

Garcia

et al. 2021

Preprint

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Despite the beneficial effects shown when the mitochondrial alternative oxidase AOX from Ciona intestinalis (Tunicata: Ascidiacea) is xenotopically expressed in mammalian and insect models, important detrimental outcomes have also been reported, raising concerns regarding its envisioned deployment as a therapy enzyme for human mitochondrial and related diseases. Because of its non-proton pumping terminal oxidase activity, AOX can bypass the cytochrome c segment of the respiratory chain and alleviate the possible overload of electrons that occurs upon oxidative phosphorylation (OXPHOS) dysfunction, not contributing though to the proton-motive force needed for mitochondrial ATP synthesis. We have shown previously that AOX-expressing flies present a dramatic drop in pupal viability when the larvae are cultured on a low nutrient diet, indicating that AOX interferes with normal developmental metabolism. Here, we applied combined omics analyses to show that the interaction between low nutrient diet and AOX expression causes a general alteration of larval amino acid metabolism and lipid accumulation, which are associated with functional and morphological alterations of the larval digestive tract and with a drastic decrease in larval biomass accumulation. Pupae at the pre-lethality stage present a general downregulation of mitochondrial metabolism and a signature for starvation and deregulated signaling processes. This AOX-induced lethality is partially rescued when the low nutrient diet is supplemented with tryptophan and/or methionine. The developmental dependence on these amino acids, associated with elevated levels of lactate dehydrogenase, lactate, 2-hydroxyglutarate, choline-containing metabolites and breakdown products of membrane phospholipids, indicates that AOX expression promotes tissue proliferation and growth of the Drosophila larvae, but this is ultimately limited by energy dissipation via mitochondrial uncoupling. We speculate that the combination of diet and AOX expression may be used for the metabolic regulation of proliferative tissues, such as tumors.

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

Cited by 6 publications

References 45 publications

Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD

Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD

Oxygen in Metabolic Dysfunction and Its Therapeutic Relevance

Systemic impact of the expression of the mitochondrial alternative oxidase onDrosophiladevelopment

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