Dataset Information

Mitochondrial respiration is necessary to combat oxidative stress in quiescent cells

ABSTRACT: Mitochondrial oxidative phosphorylation (OXPHOS) makes ATP and supports biosynthesis during proliferation, but its role in non-proliferating cells, beyond ATP production, is less understood. Here we show that OXPHOS protects quiescent (but not proliferating) cells from oxidative stress. Using in vivo models of OXPHOS deficiency (whole body and endothelium-specific) we show that OXPHOS mediated resistance to ROS (i) maintains selectivity of ROS-based anticancer therapy by protecting normal tissues during treatment, and in quiescent endothelium (ii) ameliorates systemic LPS-induced inflammation and (iii) attenuates symptoms of the inflammatory bowel disease. ROS-resistance provided by OXPHOS is independent of its role in biosynthesis or NADH recycling. Instead, in quiescent cells OXPHOS constitutively generates low levels of endogenous ROS that support basal autophagic flux and protect from exogenous ROS challenge. Hence, during evolution cells acquired mitochondria to profit from oxidative metabolism, but also built in an OXPHOS-dependent mechanism to guard against the resulting oxidative stress.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Karel Harant

LAB HEAD: Jakub Rohlena

PROVIDER: PXD021376 | Pride | 2022-10-13

REPOSITORIES: Pride

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Publications

Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.

Magalhaes-Novais Silvia S Blecha Jan J Naraine Ravindra R Mikesova Jana J Abaffy Pavel P Pecinova Alena A Milosevic Mirko M Bohuslavova Romana R Prochazka Jan J Khan Shawez S Novotna Eliska E Sindelka Radek R Machan Radek R Dewerchin Mieke M Vlcak Erik E Kalucka Joanna J Stemberkova Hubackova Sona S Benda Ales A Goveia Jermaine J Mracek Tomas T Barinka Cyril C Carmeliet Peter P Neuzil Jiri J Rohlenova Katerina K Rohlena Jakub J

Autophagy 20220308 10

Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/auto ...[more]

PMID: 35258392

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Project description:Cancer-associated fibroblasts (CAFs) are acknowledged key determinants in the progression of cancer and thereby represent important targets for cancer therapies. Given the increase attention that ablative radiotherapy is gaining in the clinics, in this study we have aimed at identifying the transcriptional responses occurring in primary CAFs exposed to high-dose irradiation. Established primary cancer-associated fibroblasts (CAFs) obtained from non-small-cell lung cancer (NSCLC) patient material were irradiated with a single dose of 18 Gy and total RNA was isolated 24 hrs after treatment. Radiation-induced transcriptional alterations were investigated by gene expression analysis using genome-wide microarrays. Obtained results were verified by qRT-PCR of relevant genes. To confirm the data achieved by microarrays, diverse functional assays were performed including DNA damage response foci assay, measurements of reactive oxygen species (ROS) by flow cytometry and senescence-associated beta-galactosidase assays were applied. Irradiation resulted in differential expression of 680 genes of which 553 were up- and 127 down-regulated. 153 genes were differentially expressed with a fold-change greater than 1 and an adjusted p-value less than 0.05 across different comparisons (non-irradiated vs. irradiated). Expression patterns revealed profound changes in biological functions and processes involved in DNA repair, apoptosis, p53 pathway, autophagy, senescence, ROS production and immune response. Conclusions: CAFs display pro- and anti-tumorigenic effects after having received a single high-dose radiation. The effects might have an impact on the tumor microenvironment in respect to tumor growth and metastasis. The complexity of the observed differential gene expression patterns and implicative biological effects are interesting future objectives for further elucidation. Established primary cancer-associated fibroblasts (CAFs) obtained from non-small-cell lung cancer (NSCLC) patient material were irradiated with a single dose of 18 Gy and total RNA was isolated 24 hrs after treatment.

Dataset Information

Mitochondrial respiration is necessary to combat oxidative stress in quiescent cells

Publications

Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.

Similar Datasets

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