Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research

Moullan, Norman; Mouchiroud, Laurent; Wang, Xu; Ryu, Dongryeol; Williams, Evan G.; Mottis, Adrienne; Jovaisaite, Virginija; Frochaux, Michael; Quirós, Pedro M.; Deplancke, Bart; Houtkooper, Riekelt H.; Auwerx, Johan

doi:10.1016/j.celrep.2015.02.034

Cited by 404 publications

(397 citation statements)

References 42 publications

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“…A recent publication highlighted the possible impact of doxycycline on mitochondrial gene expression (40). In our experiments, we included doxycycline-treated controls for both the in vivo ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

et al. 2016

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Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1a and HIF2a activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

et al. 2016

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“…Given the tight link between the UPR mt and AD observed above, we investigated the effects of two established strategies to induce the UPR mt in C. elegans ; genetically, by silencing the expression of the mitochondrial ribosomal protein mrps-5 23 , and pharmacologically, by using the mitochondrial translation inhibitor doxycycline (dox) 23,24 . Both interventions, which favor worm health and lifespan 23 , markedly induced transcripts of UPR mt , mitophagy and respiration genes in GMC101 (Fig.…”

Section: Reducing Mitochondrial Translation Lowers Aβ Proteotoxicitymentioning

confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

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Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

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“…Auwerx and colleagues (Chatzispyrou et al 2015;Moullan et al 2015) demonstrated that doxycycline negatively impacts mitochrondrial function. Doxycycline can also impact the gut microbiota in humans; the direct impact of this on adipose biology is unclear but potentially significant (Angelakis et al 2014).…”

Section: Perspectives Limitations and Future Directionsmentioning

confidence: 99%

Sorting out adipocyte precursors and their role in physiology and disease

2017

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The ability to maintain and expand the pool of adipocytes in adults is integral to the regulation of energy balance, tissue/stem cell homeostasis, and disease pathogenesis. For decades, our knowledge of adipocyte precursors has relied on cellular models. The identity of native adipocyte precursors has remained unclear. Recent studies have identified distinct adipocyte precursor populations that are physiologically regulated and contribute to the development, maintenance, and expansion of adipocyte pools in mice. With new tools available, the properties of adipocyte precursors can now be defined, and the regulation and function of adipose plasticity in development and physiology can be explored.Adipocytes ("fat cells") are critical regulators of several aspects of normal physiology, including energy balance, nutrient homeostasis, and tissue homeostasis (Rosen and Spiegelman 2014). White adipocytes represent the principle site for energy storage in mammals. These cells accumulate excess energy in the form of intracellular triglycerides packaged into large single lipid droplets. White adipocytes are also endocrine cells; adipocytes secrete numerous hormones and cytokines that impact several aspects of physiology, including nutrient homeostasis, inflammation, and reproductive biology (Ouchi et al.

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Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research

Cited by 404 publications

References 42 publications

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorting out adipocyte precursors and their role in physiology and disease

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