Palmitate induces RIP1/RIP3-dependent necrosis via MLKL-mediated pore formation in the plasma membrane of RAW 264.7 cells

Kim, Seong Keun; Yun, Mihee; Seo, Gimoon; Lee, Ji-Young; Lee, Seong Beom

doi:10.1016/j.bbrc.2016.11.068

Cited by 10 publications

(5 citation statements)

References 32 publications

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“…The activation of the NLRP3 inflammasome then triggers the activation of downstream inflammatory cascades. In addition, palmitate was reported to induce receptor-interacting protein (RIP)1/RIP3 activation, which mediates the form of programmed lytic cell death called “necroptosis.” RIP1/RIP3 activation also leads to the activation of Drp1, resulting in ROS production and subsequent activation of NLRP3 inflammasome ( 60 ). Evidence shows that the NLRP3 inflammasome plays a pivotal role in the ischemia/reperfusion (I/R) injury, to which diabetic subjects are more sensitive ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes

et al. 2020

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Background: Plenty of evidence suggested that chronic low-grade inflammation triggered by innate immunity activation contributes to the pathogenesis of type 2 diabetes (T2D). Using the trans-mitochondrial cybrid cell model, we have demonstrated that mitochondria independently take part in the pathological process of insulin resistance (IR) and pro-inflammatory phenotype in cybrid cells harboring mitochondrial haplogroup B4, which are more likely to develop T2D. The mitochondrial network is more fragmented, and the expression of fusion-related proteins is low in Cybrid B4. We also discovered the causal role of mitochondrial dynamics (mtDYN) proteins in regulating IR in this cybrid model, and the bidirectional interaction between mtDYN and mitochondrial oxidative stress is considered etiologically important. In this study, we further investigated whether mtDYN bridges the gap between nutrient excess and chronic inflammation in T2D. Methods: Trans-mitochondrial cybrid cells derived from the 143B human osteosarcoma cell line were cultured in a medium containing glucose (25 mM) with or without saturated fatty acid (0.25 mM BSA-conjugated palmitate), and the expression of innate immunity/inflammasome molecules was compared between cybrid B4 (the major T2D-susceptible haplogroup among the Chinese population) and cybrid D4 (the major T2D-resistant haplogroup among the Chinese population). We investigated the causal relationship between mtDYN and nutrient excess-induced inflammation in cybrid B4 by genetic manipulation of mtDYN and by pharmacologically inhibiting mitochondrial fission using the Drp1 inhibitor, mdivi-1, and metformin. Results: Under nutrient excess with high fatty acid, cybrid B4 presented increased mitochondrial pro-fission profiles and enhanced chronic inflammation markers (RIG-I, MDA5, MAVS) and inflammasome (NLRP3, Caspase-1, IL-1β), whereas the levels in cybrid D4 were not or less significantly altered. In cybrid B4 under nutrient excess, overexpression of fusion proteins (Mfn1 or Mfn2) significantly repressed the expression of innate immunity/inflammasome-related molecules, while knockdown had a less significant effect. On the contrary, knockdown of fission proteins (Drp1 or Fis1) significantly repressed the expression of innate immunity/inflammasome-related molecules, while overexpression had a less significant effect. In addition, Drp1 inhibitor mdivi-1 and metformin inhibited mitochondrial fission and attenuated the pro-inflammation expression as well. Conclusion: Our results discovered the causal relationship between mtDYN and nutrient excess-induced chronic inflammation in a diabetes-susceptible cell model. Targeting mtDYN by direct interfering pro-fission can be a therapeutic intervention for chronic inflammation in T2D.

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Section: Discussionmentioning

confidence: 99%

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes

et al. 2020

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“…Several studies focus on PA-induced cell death, including apoptosis 30 and necrosis 31 . Zhen Wang et al 8 found that the exposure of cortical astrocytes to PA (0.2 mM for 24 h) caused largely apoptosis, but little necrosis.…”

Section: Discussionmentioning

confidence: 99%

The autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes

Chen

Nie

et al. 2018

Cell Death Dis

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The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.

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“…It forms a complex with RIP1 and RIP3 to induce necroptosis [ 7 ]. Kim et al suggest palmitate-induced, RIP1/RIP3/MLKL-dependent cell death might not only occur via mitochondrial ROS generation but also could be induced through other potential mechanisms such as pore forming in the plasma membrane [ 13 ]. It’s clear that RIPK3 and MLKL play critical roles in necroptosis [ 14 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury

Zhou

et al. 2017

Oncotarget

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Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. Further, we found NSA reduced MLKL levels via the ubiquitination proteasome pathway, but not by inhibiting RNA transcription. Interestingly, NSA administration increased cleaved PARP-1 levels, indicating the protective effects of MLKL inhibition is not related to apoptosis. These findings suggest MLKL is a new therapeutic target for neurological pathologies like stroke. Therefore, promoting degradation of MLKL may be a novel avenue to reduce necrotic cell death after ischemic brain injury.

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Palmitate induces RIP1/RIP3-dependent necrosis via MLKL-mediated pore formation in the plasma membrane of RAW 264.7 cells

Cited by 10 publications

References 32 publications

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes

The autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes

The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury

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