Calcium/calmodulin‐dependent protein kinase regulates the PINK1/Parkin and DJ‐1 pathways of mitophagy during sepsis

Zhang, Xianghong; Yuan, Du; Sun, Qian; Xu, Li; Lee, Emma; Lewis, Anthony; Zuckerbraun, Brian S.; Rosengart, Matthew R.

doi:10.1096/fj.201601096rrr

Cited by 28 publications

(9 citation statements)

References 81 publications

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“…An alternative mechanism of activation of AMPK during sepsis is through calcium‐dependent activation of calcium/calmodulin‐dependent protein kinases (CaMK). CaMK has been shown to be activated during sepsis 49,50 and have been implicated in direct activation of AMPK through Thr 172 phosphorylation 51 . Although this could be a potential mechanism of AMPK activation in our models, we did not measure the activity of CaMK in our studies.…”

Section: Discussionmentioning

confidence: 98%

Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness

Jin

Manrique‐Caballero

et al. 2020

FASEB j.

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The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis-induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10-to 12-week-old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O 2 consumption rates (OCR) and the membrane potential (Δψ m ). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6-24 hours after CLP/IM. Pharmacologic activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK-driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects | 7037 JIN et al.

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Section: Discussionmentioning

confidence: 98%

Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness

Jin

Manrique‐Caballero

et al. 2020

FASEB j.

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“…Furthermore, mitochondrial calcium overload after a massive calcium flux causes opening of the mitochondrial permeability transition pores resulting in the mitochondrial membrane depolarization, mitochondrial dysfunctions, damages, and ultimately cell death [49,50,51]. Autophagy is induced by mitochondrial depolarization to eliminate the damaged or dysfunctional mitochondria, a specific process called mitophagy that attenuates apoptosis or necrosis [52,53]. Indeed, our results also observed an induction of mitophagy in MELAS iPS cells in the presence of CCCP, whereas mitophagy was scarce at the basal condition, even during a state of enhanced general autophagy.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease

Lin

Huang

et al. 2019

Cells

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Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade damaged cytoplasmic components as well as dysfunctional mitochondria is essential for ensuring cell survival. We analyzed the role of autophagy inpatient-specific induced pluripotent stem (iPS) cells generated from fibroblasts of patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. MELAS iPS cells recapitulated the pathogenesis of MELAS syndrome, and showed an increase of autophagy in comparison with its isogenic normal counterpart, whereas mitophagy is very scarce at the basal condition. Our results indicated that the existence of pathogenic mtDNA alone in mitochondrial disease was not sufficient to elicit the degradation of dysfunctional mitochondria. Nonetheless, oxidative insults induced bulk macroautophagy with the accumulation of autophagosomes and autolysosomes upon marked elevation of ROS, overload of intracellular calcium, and robust depolarization of mitochondrial membrane potential, while mitochondria respiratory function was impaired and widespread mitophagy compromised cell viability. Collectively, our studies provide insights into the dysfunction of autophagy and activation of mitophagy contributing to the pathological mechanism of mitochondrial disease.

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“…Recent studies showed that mitochondrial dysfunction occurs during sepsis, and PINK1-Parkin mitophagy can protect cardiomyocytes and macrophages in response to septic insults. [22–25] We therefore hypothesized that PINK1-Parkin mitophagy might exert a protective function against sepsis-induced renal injury.…”

Section: Introductionmentioning

confidence: 99%

Involvement of phosphatase and tensin homolog-induced putative kinase 1–Parkin-mediated mitophagy in septic acute kidney injury

Dai

et al. 2019

Chinese Medical Journal

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Background:Studies have reported mitophagy activation in renal tubular epithelial cells (RTECs) in acute kidney injury (AKI). Phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and E3 ubiquitin-protein ligase Parkin are involved in mitophagy regulation; however, little is known about the role of PINK1-Parkin mitophagy in septic AKI. Here we investigated whether the PINK1-Parkin mitophagy pathway is involved in septic AKI and its effects on cell apoptosis in vitro and on renal functions in vivo.Methods:Mitophagy-related gene expression was determined using Western blot assay in human RTEC cell line HK-2 stimulated with bacterial lipopolysaccharide (LPS) and in RTECs from septic AKI rats induced by cecal ligation and perforation (CLP). Autophagy-related ultrastructural features in rat RTECs were observed using electron microscopy. Gain- and loss-of-function approaches were performed to investigate the role of the PINK1-Parkin pathway in HK-2 cell mitophagy. Autophagy activators and inhibitors were used to assess the effects of mitophagy modulation on cell apoptosis in vitro and on renal functions in vivo.Results:LPS stimulation could significantly induce LC3-II and BECN-1 protein expression (LC3-II: 1.72 ± 0.05 vs. 1.00 ± 0.05, P < 0.05; BECN-1: 5.33 ± 0.57 vs. 1.00 ± 0.14, P < 0.05) at 4 h in vitro. Similarly, LC3-II, and BECN-1 protein levels were significantly increased and peaked at 2 h after CLP (LC3-II: 3.33 ± 0.12 vs. 1.03 ± 0.15, P < 0.05; BECN-1: 1.57 ± 0.26 vs. 1.02 ± 0.11, P < 0.05) in vivo compared with those after sham operation. Mitochondrial deformation and mitolysosome-mediated mitochondria clearance were observed in RTECs from septic rats. PINK1 knockdown significantly attenuated LC3-II protein expression (1.35 ± 0.21 vs. 2.38 ± 0.22, P < 0.05), whereas PINK1 overexpression markedly enhanced LC3-II protein expression (2.07 ± 0.21 vs. 1.29 ± 0.19, P < 0.05) compared with LPS-stimulated HK-2 cells. LPS-induced proapoptotic protein expression remained unchanged in autophagy activator-treated HK-2 cells and was significantly attenuated in PINK1-overexpressing cells, but was remarkably upregulated in autophagy inhibitor-treated and in PINK1-depleted cells. Consistent results were observed in flow cytometric apoptosis assay and in renal function indicators in rats.Conclusion:PINK1-Parkin-mediated mitophagy might play a protective role in septic AKI, serving as a potential therapeutic target for septic AKI.

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Calcium/calmodulin‐dependent protein kinase regulates the PINK1/Parkin and DJ‐1 pathways of mitophagy during sepsis

Cited by 28 publications

References 81 publications

Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness

Activation of AMP‐activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness

Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease

Involvement of phosphatase and tensin homolog-induced putative kinase 1–Parkin-mediated mitophagy in septic acute kidney injury

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