NLRX1 regulates TNF-α-induced mitochondria-lysosomal crosstalk to maintain the invasive and metastatic potential of breast cancer cells

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Singh, Kritarth¹  Roy, Milton¹  Prajapati, Paresh²  Lipatova, Anastasia³  Sripada, Lakshrni¹  Gohel, Dhruv¹  Singh, Aru⁴  Mane, Meenal¹  Godbole, Madan M.⁴  Churnakov, Peter M.^3,5  Singh, Rajesh¹ 

[1] Maharaja Sayajirao Univ Baroda, Fac Sci, Dept Biochem, Vadodara 390002, Gujarat, India

[2] Univ Kentucky, SCoBIRC Dept Neurosci, BBSRB, 741S Limestone, Lexington, KY 40536 USA

[3] Russian Acad Sci, Engelhardt Inst Mol Biol, Vavilov St 32, Moscow 119991, Russia

[4] Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India

[5] Russian Acad Sci, Chumakov Inst Poliomyelitis & Viral Encephalitis, Fed Sci Ctr Res & Dev Immunobiol Prod, Moscow 142782, Russia

关键词: NLRX1;    Autophagy;    Mitochondrial function;    Lysosomes;    Inflammation;    Breast cancer;   

DOI  :  10.1016/j.bbadis.2019.02.018

来源: Elsevier

【 摘 要 】

An increased level of proinflammatory cytokines, including TNF-a 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-a 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-a. NLRX1 depletion further impaired lysosomal function and hence the turnover of damaged mitochondria through mitophagy in presence of TNF-a. Importantly, loss of NLRX1 decreased OxPhos-dependent cell proliferation and migration ability of triple-negative breast cancer cells in presence of TNF-a. 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.

【 授权许可】

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