bims-meprid 2020-11-15 papers

Issue of 2020‒11‒15
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

IUBMB Life. 2020 Nov 12.

Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer.

Anna Shteinfer-Kuzmine, Ankit Verma, Tasleem Arif, Or Aizenberg, Avijit Paul, Varda Shoshan-Barmaz.

The cross-talk between the mitochondrion and the nucleus regulates cellular functions, including differentiation and adaptation to stress. Mitochondria supply metabolites for epigenetic modifications and other nuclear-associated activities and certain mitochondrial proteins were found in the nucleus. The voltage-dependent anion channel 1 (VDAC1), localized at the outer mitochondrial membrane (OMM) is a central protein in controlling energy production, cell growth, Ca2+ homeostasis, and apoptosis. To alter the cross-talk between the mitochondria and the nucleus, we used specific siRNA to silence the expression of VDAC1 in glioblastoma (GBM) U87-MG and U118-MG cell-derived tumors, and then monitored the nuclear localization of mitochondrial proteins and the methylation and acetylation of histones. Depletion of VDAC1 from tumor cells reduced metabolism, leading to inhibition of tumor growth, and several tumor-associated processes and signaling pathways linked to cancer development. In addition, we demonstrate that certain mitochondrial pro-apoptotic proteins such as caspases 3, 8, and 9, and p53 were unexpectedly overexpressed in tumors, suggesting that they possess additional non-apoptotic functions. VDAC1 depletion and metabolic reprograming altered their expression levels and subcellular localization, specifically their translocation to the nucleus. In addition, VDAC1 depletion also leads to epigenetic modifications of histone acetylation and methylation, suggesting that the interchange between metabolism and cancer signaling pathways involves mitochondria-nucleus cross-talk. The mechanisms regulating mitochondrial protein trafficking into and out of the nucleus and the role these proteins play in the nucleus remain to be elucidated.

Keywords: VDAC1; apoptosis; cancer; epigenetics; metabolism; mitochondria; nuclear

DOI: https://doi.org/10.1002/iub.2407

Sci Adv. 2020 Nov;pii: eabc8492. [Epub ahead of print]6(46):

Persistent epigenetic reprogramming of sweet taste by diet.

Anoumid Vaziri, Morteza Khabiri, Brendan T Genaw, Christina E May, Peter L Freddolino, Monica Dus.

Diets rich in sugar, salt, and fat alter taste perception and food preference, contributing to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here, we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of Drosophila melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

DOI: https://doi.org/10.1126/sciadv.abc8492

Int J Mol Sci. 2020 Nov 06. pii: E8320. [Epub ahead of print]21(21):

Hypoxic Regulation of Gene Transcription and Chromatin: Cause and Effect.

Jessica D Kindrick, David R Mole.

Cellular responses to low oxygen (hypoxia) are fundamental to normal physiology and to the pathology of many common diseases. Hypoxia-inducible factor (HIF) is central to this by enhancing the transcriptional activity of many hundreds of genes. The cellular response to HIF is cell-type-specific and is largely governed by the pre-existing epigenetic landscape. Prior to activation, HIF-binding sites and the promoters of HIF-target genes are already accessible, in contact with each other through chromatin looping and display markers of activity. However, hypoxia also modulates the epigenetic environment, both in parallel to and as a consequence of HIF activation. This occurs through a combination of oxygen-sensitive changes in enzyme activity, transcriptional activation of epigenetic modifiers, and localized recruitment to chromatin by HIF and activated RNApol2. These hypoxic changes in the chromatin environment may both contribute to and occur as a consequence of transcriptional regulation. Nevertheless, they have the capacity to both modulate and extend the transcriptional response to hypoxia.

Keywords: 2-oxoglutarate-dependent dioxygenase; acetylation; chromatin; epigenetics; histone; hypoxia; hypoxia-inducible factor; methylation; transcription

DOI: https://doi.org/10.3390/ijms21218320

Mol Cell. 2020 Oct 29. pii: S1097-2765(20)30725-5. [Epub ahead of print]

TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology.

Shasha Chen, Shengduo Liu, Junxian Wang, Qirou Wu, Ailian Wang, Hongxin Guan, Qian Zhang, Dan Zhang, Xiaojian Wang, Hai Song, Jun Qin, Jian Zou, Zhengfan Jiang, Songying Ouyang, Xin-Hua Feng, Tingbo Liang, Pinglong Xu.

Mitochondrial morphology shifts rapidly to manage cellular metabolism, organelle integrity, and cell fate. It remains unknown whether innate nucleic acid sensing, the central and general mechanisms of monitoring both microbial invasion and cellular damage, can reprogram and govern mitochondrial dynamics and function. Here, we unexpectedly observed that upon activation of RIG-I-like receptor (RLR)-MAVS signaling, TBK1 directly phosphorylated DRP1/DNM1L, which disabled DRP1, preventing its high-order oligomerization and mitochondrial fragmentation function. The TBK1-DRP1 axis was essential for assembly of large MAVS aggregates and healthy antiviral immunity and underlay nutrient-triggered mitochondrial dynamics and cell fate determination. Knockin (KI) strategies mimicking TBK1-DRP1 signaling produced dominant-negative phenotypes reminiscent of human DRP1 inborn mutations, while interrupting the TBK1-DRP1 connection compromised antiviral responses. Thus, our findings establish an unrecognized function of innate immunity governing both morphology and physiology of a major organelle, identify a lacking loop during innate RNA sensing, and report an elegant mechanism of shaping mitochondrial dynamics.

Keywords: DRP1; RLR-MAVS; TBK1; antiviral immunity; cell fate determination; innate immunity; mitochondrial dynamics; mitochondrion; nucleic acid sensing; phosphorylation

DOI: https://doi.org/10.1016/j.molcel.2020.10.018

Oxid Med Cell Longev. 2020 ;2020 4971525

Lactate Induces Cisplatin Resistance in S. cerevisiae through a Rad4p-Dependent Process.

Leslie Amaral, Filipa Mendes, Manuela Côrte-Real, Maria João Sousa, Susana Rodrigues Chaves.

Cisplatin is a widely used antineoplastic agent that has DNA as the main target, though cellular resistance hampers its therapeutic efficacy. An emerging hallmark of cancer cells is their altered metabolism, characterized by increased glycolysis even under aerobic conditions, with increased lactate production (known as the Warburg effect). Although this altered metabolism often results in increased resistance to chemotherapy, it also provides an opportunity for targeted therapeutic intervention. It has been suggested that cisplatin cytotoxicity can be affected by tumor metabolism, though with varying effects. We therefore sought to better characterize how lactate affects cisplatin sensitivity in the simplified Saccharomyces cerevisiae model. We show that lactate renders yeast cells resistant to cisplatin, independently of growth rate or respiration ability. We further show that histone acetylation is not affected, but histone phosphorylation is decreased in lactate-containing media. Finally, we show that Rad4p, essential for nucleotide excision repair, is required for the observed phenotype and thus likely underlies the mechanism responsible for lactate-mediated resistance to cisplatin. Overall, understanding how lactate modulates cisplatin sensitivity will aid in the development of new strategies to overcome drug resistance.

DOI: https://doi.org/10.1155/2020/4971525