Suppression of autophagic flux contributes to cardiomyocyte death by activation of necroptotic pathways

Ogasawara, M.; Yano, Toshiyuki; Tanno, Masaya; Abe, Koki; Ishikawa, Satoko; Miki, Takayuki; Kuno, Atsushi; Tobisawa, Toshiyuki; Muratsubaki, Shingo; Ohno, Kouhei; Tatekoshi, Yuki; Nakata, Kei; Ohwada, Wataru; Miura, Tetsuji

doi:10.1016/j.yjmcc.2017.06.008

Cited by 39 publications

(48 citation statements)

References 50 publications

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“…The molecular mechanism connecting autophagy decline with cardiac necroptosis in aging hearts is currently unknown. A recent study from Ogasawara et al () has shown that necroptosis activation suppresses autophagic flux and restoring autophagic flux protects cardiomyocytes from necroptosis in H9c2 cells (a permanent cell line derived from rat cardiac tissue; these cells do not possess heart‐specific morphological structures). However, the relationship between autophagy and necroptosis signaling pathways as well as the role of this intermodulation mechanism in preventing I/R injury in aged myocardium have not been systematically examined.…”

Section: Discussionmentioning

confidence: 99%

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Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

et al. 2020

Aging Cell

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Necroptosis is crucially involved in severe cardiac pathological conditions. However, whether necroptosis contributes to age-related intolerance to ischemia/reperfusion (I/R) injury remains elusive. In addition, metformin as a potential anti-aging related injury drug, how it interacts with myocardial necroptosis is not yet clear. Male C57BL/6 mice at 3-4-(young) and 22-24 months of age (aged) and RIPK3-deficient (Ripk3 −/− ) mice were used to investigate aging-related I/R injury in vivo. Metformin (125 μg/ kg, i.p.), necrostatin-1 (3.5 mg/kg), and adenovirus vector encoding p62-shRNAs (Adsh-p62) were used to treat aging mice. I/R-induced myocardial necroptosis was exaggerated in aged mice, which correlated with autophagy defects characterized by p62 accumulation in aged hearts or aged human myocardium. Functionally, blocking autophagic flux promoted H/R-evoked cardiomyocyte necroptosis in vitro. We further revealed that p62 forms a complex with RIP1-RIP3 (necrosome) and promotes the binding of RIP1 and RIP3. In mice, necrostatin-1 treatment (a RIP1 inhibitor), RIP3 deficiency, and cardiac p62 knockdown in vivo demonstrated that p62-RIP1-RIP3-dependent myocardial necroptosis contributes to aging-related myocardial vulnerability to I/R injury. Notably, metformin treatment disrupted p62-RIP1-RIP3 complexes and effectively repressed I/R-induced necroptosis in aged hearts, ultimately reducing mortality in this model. These findings highlight previously unknown mechanisms of aging-related myocardial ischemic vulnerability: p62-necrosome-dependent necroptosis. Metformin acts as a cardioprotective agent that inhibits this unfavorable chain mechanism of aging-related I/R susceptibility. K E Y W O R D Saging, autophagy defect, cardioprotection, ischemia/reperfusion injury, metformin, myocardial necroptosis

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Section: Discussionmentioning

confidence: 99%

“…The molecular mechanism connecting autophagy decline with cardiac necroptosis in aging hearts is currently unknown. A recent study from Ogasawara et al (2017) Figure S7. Scale bar = 20 μm.…”

Section: Discussionmentioning

confidence: 99%

Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

et al. 2020

Aging Cell

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“…[12][13][14][15][16][17] This may be due to the fact that different cell types were used in different studies, and not all cells can undergo necroptosis, because parenchymal cells differ in gene expression and cellular signaling cascades. [12][13][14][15][16][17] This may be due to the fact that different cell types were used in different studies, and not all cells can undergo necroptosis, because parenchymal cells differ in gene expression and cellular signaling cascades.…”

Section: Plantation However It Can Inhibit Calcineurin and Cyp-d Fumentioning

confidence: 99%

“…11 The involvement of mitochondria and mPTPs as downstream necroptotic mediators is still a point of contention. [12][13][14][15][16][17] In our previous studies, we demonstrated that RIPK3mediated necroptosis in donor heart and kidney grafts can promote inflammatory injury and transplant rejection. [12][13][14][15][16][17] In our previous studies, we demonstrated that RIPK3mediated necroptosis in donor heart and kidney grafts can promote inflammatory injury and transplant rejection.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] While it is well established that mitochondria are platforms for apoptosis execution, the prospect of direct mitochondrial involvement in programmed necrosis remains controversial, and contradictory experiments point toward either mitochondria-dependent or -independent forms of necrosis or necroptosis. [12][13][14][15][16][17] In our previous studies, we demonstrated that RIPK3mediated necroptosis in donor heart and kidney grafts can promote inflammatory injury and transplant rejection. [18][19][20] Thus, eliminating RIPK3 expression in mouse heart and kidney cells or cardiac and renal allografts attenuated cell and tissue necrosis, diminished release of cell damage-associated molecular patterns (CDAMP), and reduced early graft injury and rejection.…”

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Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection

Gan

Jiang

Lian

et al. 2019

American Journal of Transplantation

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Transplantation is invariably associated with programmed cell death including apoptosis and necrosis, resulting in delayed graft function and organ rejection. We have demonstrated the contribution of necroptosis to mouse microvascular endothelial cell (MVEC) death and transplant rejection. Organ injury results in the opening of mitochondrial permeability transition pores (mPTPs), which can trigger apoptotic molecules release that ultimately results in cell death. The effect of mPTPs in the necroptotic pathway remains controversial; importantly, their role in transplant rejection is not clear. In this study, tumor necrosis factor-α triggered MVECs to undergo receptor-interacting protein kinase family (RIPK1/3)-dependent necroptosis. Interestingly, inhibition of mPTP opening could also inhibit necroptotic cell death. Cyclophilin-D (Cyp-D) is a key regulator of the mPTPs. Both inhibition and deficiency of Cyp-D protected MVECs from necroptosis (n = 3, P < .00001). Additionally, inhibition of Cyp-D attenuated RIPK3-downstream mixed-lineage kinase domain-like protein phosphorylation. In vivo, Cyp-D-deficient cardiac grafts showed prolonged survival in allogeneic BALB/c mice posttransplant compared with wild-type grafts (n = 7, P < .0001). Our study results suggest that the mPTPs may be important mechanistic mediators of necroptosis in cardiac grafts. There is therapeutic potential in targeting cell death via inhibition of the mPTP-regulating molecule Cyp-D to prevent cardiac graft rejection.

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Receptor‐Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells

et al. 2020

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Autophagy is an intracellular process that regulates the degradation of cytosolic proteins and organelles. Dying cells often accumulate autophagosomes. However, the mechanisms by which necroptotic stimulation induces autophagosomes are not defined. Here, we demonstrate that the activation of necroptosis with TNF-a plus the cell-permeable pan-caspase inhibitor Z-VAD induces LC3-II and LC3 puncta, markers of autophagosomes, via the receptor-interacting protein kinase 3 (RIPK3) in intestinal epithelial cells. Surprisingly, necroptotic stimulation reduces autophagic activity, as evidenced by enlarged puncta of the autophagic substrate SQSTM1/p62 and its increased colocalization with LC3. However, necroptotic stimulation does not induce the lysosomal-associated membrane protein 1 (LAMP1) nor syntaxin 17, which mediates autophagosome-lysosome fusion, to colocalize with LC3. These data indicate that necroptosis attenuates autophagic flux before the lysosome fusion step. Our findings may provide insights into human diseases involving necroptosis.

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Suppression of autophagic flux contributes to cardiomyocyte death by activation of necroptotic pathways

Cited by 39 publications

References 50 publications

Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

Metformin mediates cardioprotection against aging‐induced ischemic necroptosis

Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection

Receptor‐Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells

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