PMID- 30802640 OWN - NLM STAT- MEDLINE DCOM- 20200203 LR - 20200203 IS - 1879-260X (Electronic) IS - 0925-4439 (Linking) VI - 1865 IP - 6 DP - 2019 Jun 1 TI - NLRX1 regulates TNF-alpha-induced mitochondria-lysosomal crosstalk to maintain the invasive and metastatic potential of breast cancer cells. PG - 1460-1476 LID - S0925-4439(19)30070-5 [pii] LID - 10.1016/j.bbadis.2019.02.018 [doi] AB - An increased level of proinflammatory cytokines, including TNF-alpha in tumor microenvironment regulates the bioenergetic capacity, immune evasion and survival of cancer cells. Emerging evidences suggest that mitochondrial immune signaling proteins modulates mitochondrial bioenergetic capacity, in addition to the regulation of innate immune response. The optimal oxidative phosphorylation (OxPhos) capacity is required for the maintenance of functional lysosomes and autophagy flux. NLRX1, a mitochondrial NOD family receptor protein, regulates mitochondrial function during apoptosis and tissue injury. However, its role in regulation of mitochondrial and lysosomal function to modulate autophagy flux during inflammatory conditions is not understood. In the current study, we investigated the role of NLRX1 in modulating TNF-alpha induced autophagy flux and mitochondrial turnover and its implication in regulating the invasive and metastatic capability of breast cancer cells. Expression analyses of clinical breast cancer samples and meta-analysis of multiple public databases revealed that NLRX1 expression is significantly increased in basal-like and metastatic breast carcinoma as compared to non-basal-like and primary breast cancer. Depletion of NLRX1 expression in triple-negative breast cancer cells, altered the organization and activity of OxPhos complexes in presence of TNF-alpha. NLRX1 depletion further impaired lysosomal function and hence the turnover of damaged mitochondria through mitophagy in presence of TNF-alpha. Importantly, loss of NLRX1 decreased OxPhos-dependent cell proliferation and migration ability of triple-negative breast cancer cells in presence of TNF-alpha. These evidences suggest an essential role of NLRX1 in maintaining the crosstalk of mitochondrial metabolism and lysosomal function to regulate invasion and metastasis capability of breast cancer cells. CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Singh, Kritarth AU - Singh K AD - Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. FAU - Roy, Milton AU - Roy M AD - Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. FAU - Prajapati, Paresh AU - Prajapati P AD - SCoBIRC Department of Neuroscience, University of Kentucky, 741S.Limestone, BBSRB, Lexington, KY 40536, USA. FAU - Lipatova, Anastasia AU - Lipatova A AD - Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia. FAU - Sripada, Lakshmi AU - Sripada L AD - Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. FAU - Gohel, Dhruv AU - Gohel D AD - Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. FAU - Singh, Aru AU - Singh A AD - Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India. FAU - Mane, Meenal AU - Mane M AD - Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. FAU - Godbole, Madan M AU - Godbole MM AD - Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India. FAU - Chumakov, Peter M AU - Chumakov PM AD - Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia; Chumakov Institute of Poliomyelitis and Viral Encephalitis, Federal Scientific Center on Research and Development of Immunobiology Products, Russian Academy of Sciences, 142782 Moscow, Russia. FAU - Singh, Rajesh AU - Singh R AD - Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. Electronic address: rajesh.singh-biochem@msubaroda.ac. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190223 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 RN - 0 (Mitochondrial Proteins) RN - 0 (NLRX1 protein, human) RN - 0 (RNA, Small Interfering) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Autophagy/drug effects/genetics MH - Breast Neoplasms/*genetics/metabolism/pathology MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Female MH - *Gene Expression Regulation, Neoplastic MH - HEK293 Cells MH - Humans MH - Lymphatic Metastasis MH - Lysosomes/drug effects/*metabolism MH - MCF-7 Cells MH - Mitochondria/drug effects/*metabolism/pathology MH - Mitochondrial Proteins/antagonists & inhibitors/*genetics/metabolism MH - Mitophagy/drug effects/genetics MH - Neoplasm Invasiveness MH - Oxidative Phosphorylation/drug effects MH - RNA, Small Interfering/genetics/metabolism MH - Signal Transduction MH - Tumor Microenvironment/genetics MH - Tumor Necrosis Factor-alpha/*genetics/metabolism/pharmacology OTO - NOTNLM OT - Autophagy OT - Breast cancer OT - Inflammation OT - Lysosomes OT - Mitochondrial function OT - NLRX1 EDAT- 2019/02/26 06:00 MHDA- 2020/02/06 06:00 CRDT- 2019/02/26 06:00 PHST- 2018/08/02 00:00 [received] PHST- 2019/02/20 00:00 [revised] PHST- 2019/02/21 00:00 [accepted] PHST- 2019/02/26 06:00 [pubmed] PHST- 2020/02/06 06:00 [medline] PHST- 2019/02/26 06:00 [entrez] AID - S0925-4439(19)30070-5 [pii] AID - 10.1016/j.bbadis.2019.02.018 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1460-1476. doi: 10.1016/j.bbadis.2019.02.018. Epub 2019 Feb 23.