bims-mitinf 2018-12-30 papers

J Leukoc Biol. 2018 Dec 27.

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation.

Monica Yabal, Dale J Calleja, Daniel S Simpson, Kate E Lawlor.

Inflammasomes are multimeric protein complexes that induce the cleavage and release of bioactive IL-1β and cause a lytic form of cell death, termed pyroptosis. Due to its diverse triggers, ranging from infectious pathogens and host danger molecules to environmental irritants, the NOD-like receptor protein 3 (NLRP3) inflammasome remains the most widely studied inflammasome to date. Despite intense scrutiny, a universal mechanism for its activation remains elusive, although, recent research has focused on mitochondrial dysfunction or potassium (K+ ) efflux as key events. In this review, we give a general overview of NLRP3 inflammasome activation and explore the recently emerging noncanonical and alternative pathways to NLRP3 activation. We highlight the role of the NLRP3 inflammasome in the pathogenesis of metabolic disease that is associated with mitochondrial and oxidative stress. Finally, we interrogate the mechanisms proposed to trigger NLRP3 inflammasome assembly and activation. A greater understanding of how NLRP3 inflammasome activation is triggered may reveal new therapeutic targets for the treatment of inflammatory disease.

Keywords: caspases; inflammasome; metabolism; mitochondria; reactive oxygen species

DOI: https://doi.org/10.1002/JLB.MR0318-124R

Mol Cell. 2018 Dec 13. pii: S1097-2765(18)30936-5. [Epub ahead of print]

Role of Mitochondria in Ferroptosis.

Minghui Gao, Junmei Yi, Jiajun Zhu, Alexander M Minikes, Prashant Monian, Craig B Thompson, Xuejun Jiang.

Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with one another, whether mitochondria are involved in ferroptosis is under debate. Here, we demonstrate that mitochondria play a crucial role in cysteine-deprivation-induced ferroptosis but not in that induced by inhibiting glutathione peroxidase-4 (GPX4), the most downstream component of the ferroptosis pathway. Mechanistically, cysteine deprivation leads to mitochondrial membrane potential hyperpolarization and lipid peroxide accumulation. Inhibition of mitochondrial TCA cycle or electron transfer chain (ETC) mitigated mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation, and ferroptosis. Blockage of glutaminolysis had the same inhibitory effect, which was counteracted by supplying downstream TCA cycle intermediates. Importantly, loss of function of fumarate hydratase, a tumor suppressor and TCA cycle component, confers resistance to cysteine-deprivation-induced ferroptosis. Collectively, this work demonstrates the crucial role of mitochondria in cysteine-deprivation-induced ferroptosis and implicates ferroptosis in tumor suppression.

DOI: https://doi.org/10.1016/j.molcel.2018.10.042

Biochem Biophys Res Commun. 2018 Dec 24. pii: S0006-291X(18)32786-4. [Epub ahead of print]

Inhibition of mitochondrial translation as a therapeutic strategy for human ovarian cancer to overcome chemoresistance.

Bo Hu, Yue Guo.

Aberrant increase in mitochondrial biogenesis is common in human ovarian cancer and has great therapeutic value. In this work, we demonstrate that tigecycline, a FDA-approved broad spectrum antibiotic, selectively targets ovarian cancer cells through inhibition of mitochondrial translation. Tigecycline dose-dependently inhibits proliferation of ovarian cancer cells via arresting them at G2/M phase and induces apoptosis through caspase pathway. At the same concentration, tigecycline either does not or inhibits normal cells in a less extent than ovarian cancer cells. Mechanistically, tigecycline specifically inhibits translation by mitochondrial ribosome but not nuclear or cytosolic ribosome, leading to mitochondrial dysfunction, oxidative stress and damage, AMPK activation and inhibition of mTOR signaling in ovarian cancer cells. We further show that the inhibitory effects on ovarian cancer cell by tigecycline is mediated by its suppression of mitochondrial respiration. Importantly, the combination of tigecycline and cisplatin at sublethal concentration results in much greater efficacy than cisplatin alone in vitro and in vivo. Additionally, the effective dose of tigecycline in ovarian cancer is clinically achievable. Our study suggests that tigecycline is a useful addition to the treatment of ovarian cancer. Our work also highlights the targeted therapeutic potential of mitochondrial respiration in ovarian cancer.

Keywords: AMPK; Chemoresistance; Mitochondrial dysfunction; Tigecycline; mTOR

DOI: https://doi.org/10.1016/j.bbrc.2018.12.127