Mitochondria in Sepsis-Induced AKI

Sun, Jian; Zhang, Jingxiao; Tian, Jiakun; Virzì, Grazia Maria; Kumar, Dharmendra; Cueto, Laura; Yin, Yongjie; Rosner, Mitchell H.; Ronco, Claudio

doi:10.1681/asn.2018111126

Cited by 160 publications

(123 citation statements)

References 111 publications

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“…However, the balance was skewed to favor fission in the endotoxin-induced AKI [ 33 – 35 ]. Changes in mitochondrial morphology, characterized by initial fragmentation of the organelles followed by ultrastructural alterations resulting in mitochondrial swelling and cristae deformation, are observed in renal tubular cells during septic AKI [ 8 ]. Our results show the mitochondrial swelling and cristae deformation in renal tubular cells, the expression of fusion includes Mfn1, Mfn2, and OPA1 proteins and mRNA upregulation, and the fission includes Drp1 and Fis1 proteins and mRNA downregulation in LPS-induced AKI.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that persistent inflammation and oxidative stress results in changes in the mitochondrial dynamics and the degradation process of injured mitochondrial in LPS-induced AKI [ 8 , 9 ]. The correct morphology and effective function of the mitochondria are maintained through the dynamic balance of fusion/fission events, so that cells can actively and effectively adapt to environmental changes [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…The correct morphology and effective function of the mitochondria are maintained through the dynamic balance of fusion/fission events, so that cells can actively and effectively adapt to environmental changes [ 10 ]. Early body subjected to stress, mitochondrial fission/fusion adaptive change, when excessive mitochondrial damage, mitochondrial fission than fusion, cause the cells death [ 8 , 11 , 12 ]. In cell death, mitochondrial fission precedes caspase activation and chromosome condensation.…”

Section: Introductionmentioning

confidence: 99%

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HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury

Zhang

Sun

et al. 2020

BioMed Research International

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Background. Endotoxin-associated acute kidney injury (AKI), a disease characterized by marked oxidative stress and inflammation disease, is a major cause of mortality in critically ill patients. Mitochondrial fission and pyroptosis often occur in AKI. However, the underlying biological pathways involved in endotoxin AKI remain poorly understood, especially those related to mitochondrial dynamics equilibrium disregulation and pyroptosis. Previous studies suggest that heme oxygenase- (HO-) 1 confers cytoprotection against AKI during endotoxic shock, and PTEN-induced putative kinase 1 (PINK1) takes part in mitochondrial dysfunction. Thus, in this study, we examine the roles of HO-1/PINK1 in maintaining the dynamic process of mitochondrial fusion/fission to inhibit pyroptosis and mitigate acute kidney injury in rats exposed to endotoxin. Methods. An endotoxin-associated AKI model induced by lipopolysaccharide (LPS) was used in our study. Wild-type (WT) rats and PINK1 knockout (PINK1KO) rats, respectively, were divided into four groups: the control, LPS, Znpp+LPS, and Hemin+LPS groups. Rats were sacrificed 6 h after intraperitoneal injecting LPS to assess renal function, oxidative stress, and inflammation by plasma. Mitochondrial dynamics, morphology, and pyroptosis were evaluated by histological examinations. Results. In the rats with LPS-induced endotoxemia, the expression of HO-1 and PINK1 were upregulated at both mRNA and protein levels. These rats also exhibited inflammatory response, oxidative stress, mitochondrial fission, pyroptosis, and decreased renal function. After upregulating HO-1 in normal rats, pyroptosis was inhibited; mitochondrial fission and inflammatory response to oxidative stress were decreased; and the renal function was improved. The effects were reversed by adding Znpp (a type of HO-1 inhibitor). Finally, after PINK1 knockout, there is no statistical difference in the LPS-treated group and Hemin or Znpp pretreated group. Conclusions. HO-1 inhibits inflammation response and oxidative stress and regulates mitochondria fusion/fission to inhibit pyroptosis, which can alleviate endotoxin-induced AKI by PINK1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury

Zhang

Sun

et al. 2020

BioMed Research International

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“…Thus, swollen mitochondria were observed in human and experimental s-AKI tubules [94,161,162]. During sepsis, kidney oxygen consumption is reduced leading to decreased intracellular ATP levels, but this is not due to a reduced tissue oxygenation [94,163]. Rather, in murine LPS-induced AKI, kidney mitochondrial dysfunction, and reduced expression of PGC-1α and its mitochondrial target genes correlated with AKI severity [94,162].…”

Section: Pgc-1α In Akimentioning

confidence: 96%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

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“…Recent studies have shown that mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis [11]. Moreover, mitochondrial dysfunction is also associated with kidney and liver injuries in patients with sepsis [12][13][14]. Besides, animal studies have shown that the reduction of mitochondrial calcium uptake was associated with the survival rate of rats [15].…”

Section: Introductionmentioning

confidence: 99%

Association of Mitochondrial Respiratory Chain Enzymes with the Risk and Mortality of Sepsis Among Chinese Children

et al. 2020

Preprint

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Background: Sepsis is a leading cause of pediatric morbidity and mortality worldwide. The aim of this study was to explore the association of mitochondrial respiratory chain enzyme activities with the risk for pediatric sepsis, and interrogate their association with hospitalized mortality among affected children.Methods: A total of 50 incident cases with sepsis and 49 healthy controls participated in this study. Logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI).Results: The levels of CoQ10, complex II, complex I+III and FoF1-ATPase were significantly higher in controls than in cases. In children with sepsis, levels of CoQ10 and complex I+III were significantly higher in survived cases than in deceased cases. Per 0.05 μmol/L, 50 nmol/min.mg and 100 nmol/min.mg increment in CoQ10, complex I+III and FoF1-ATPase were associated with significantly lowered risk of having sepsis, even after adjusting for confounding factors (OR=0.85, 0.68 and 0.04, P: 0.001, <0.001 and <0.001, respectively). Per 0.05 μmol/L and 50 nmol/min.mg increment in CoQ10 and complex I+III was associated with significantly lowered risk of dying from sepsis during hospitalization, and significance retained after adjustment (OR=0.73 and 0.76, 95% CI: 0.59 to 0.90 and 0.64 to 0.89, P=0.004 and 0.001, respectively) in sepsis children.Conclusion: Our findings indicate the promising predictive contribution of serum CoQ10 and complex I+III to the risk of pediatric sepsis and its associated mortality during hospitalization among Chinese children.

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Mitochondria in Sepsis-Induced AKI

Cited by 160 publications

References 111 publications

HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury

HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

Association of Mitochondrial Respiratory Chain Enzymes with the Risk and Mortality of Sepsis Among Chinese Children

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