Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy

Mukherjee, Riddhita; Tetri, Laura H; Li, Sin‐Jin; Fajardo, Giovanni; Ostberg, Nicolai P; Tsegay, Kaleb B.; Gera, Kanika; Cornell, Timothy T.; Bernstein, Daniel; Mochly‐Rosen, Daria; Haileselassie, Bereketeab

doi:10.1016/j.yjmcc.2023.01.008

Cited by 7 publications

(4 citation statements)

References 47 publications

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“…Studies have demonstrated that TP53 activation and associated signaling are involved in the development of sepsis-induced multiple organ dysfunction syndrome (MODS) [42] . TP53 appears to mediate sepsis-induced end-organ failure [43] , and interrupting the association of TP53 with mitochondria reduces mortality in sepsis models [44] .SMAD3 is a receptor regulatory protein that is activated by serine kinase phosphorylation and subsequently signals to downstream targets [45] . Previous studies have reported increased mortality in SMAD3-de cient mice in the context of lipopolysaccharide (LPS)-stimulated sepsis, suggesting that SMAD3 reduces the sensitivity of vital organs to LPS [46] .…”

Section: Discussionmentioning

confidence: 99%

Exploring the interactions between mitochondria-related genes and the immune microenvironment in sepsis: a bioinformatics study

Li,

Ma,

Liu

et al. 2024

Preprint

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In this study, we utilized bioinformatics to investigate the intricate interplay between mitochondria-related genes and the immune microenvironment in sepsis, a life-threatening condition with complex pathophysiology. Through analysis of mRNA expression profiles from NCBI GEO, we identified 49 differentially expressed genes (DEGs) associated with mitochondria (MitoDEGs) by intersecting them with mitochondrial lineage genes. Gene ontology (GO) enrichment and Kyoto Gene and Genome Encyclopedia (KEGG) pathway analyses were conducted to elucidate the functional roles of MitoDEGs in sepsis. A protein‒protein interaction (PPI) network highlighted 10 central MitoDEGs as hub genes crucial in sepsis. Furthermore, utilizing NetworkAnalyst, we predicted transcription factors and constructed a competitive endogenous RNA (ceRNA) regulatory network to unveil potential interactions of MitoDEGs with miRNAs and lncRNAs. Notably, our study revealed alterations in immune cell infiltration within the sepsis microenvironment, with Spearman analysis demonstrating significant correlations between hub MitoDEGs and specific immune cell subsets. These comprehensive findings shed light on the crosstalk between mitochondrial function and immune responses in sepsis, offering novel insights for the identification of therapeutic targets in the management of this critical condition.

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Section: Discussionmentioning

confidence: 99%

Exploring the interactions between mitochondria-related genes and the immune microenvironment in sepsis: a bioinformatics study

Li,

Ma,

Liu

et al. 2024

Preprint

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“…Furthermore, DRP1 is necessary for p53 translocation to mitochondria to trigger neuron necrosis under oxidative stress [ 23 ]. Mukherjee et al used immunoprecipitation and proximity ligation assays to demonstrate that DRP1 and p53 interaction through direct protein–protein binding mediated p53 mitochondrial localization and dysfunction in LPS-induced septic cardiomyopathy [ 24 ]. Our previous study has demonstrated that the protein expression of DRP1 and p53 is significantly increased in NRCMs exposed to ISO, while Flt3 activation reverses their alterations [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Flt3 Activation Mitigates Mitochondrial Fragmentation and Heart Dysfunction through Rebalanced L-OPA1 Processing by Hindering the Interaction between Acetylated p53 and PHB2 in Cardiac Remodeling

Zhang,

Zheng,

Bao

et al. 2023

Antioxidants

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Recent studies have shown that FMS-like receptor tyrosine kinase 3 (Flt3) has a beneficial effect on cardiac maladaptive remodeling. However, the role and mechanism of Flt3 in mitochondrial dynamic imbalance under cardiac stress remains poorly understood. This study aims to investigate how Flt3 regulates p53-mediated optic atrophy 1 (OPA1) processing and mitochondrial fragmentation to improve cardiac remodeling. Mitochondrial fragmentation in cardiomyocytes was induced by isoprenaline (ISO) and H2O2 challenge, respectively, in vitro. Cardiac remodeling in mice was established by ligating the left anterior descending coronary artery or by chronic ISO challenge, respectively, in vivo. Our results demonstrated that the protein expression of acetylated-p53 (ac-p53) in mitochondria was significantly increased under cell stress conditions, facilitating the dissociation of PHB2-OPA1 complex by binding to prohibitin 2 (PHB2), a molecular chaperone that stabilizes OPA1 in mitochondria. This led to the degradation of the long isoform of OPA1 (L-OPA1) that facilitates mitochondrial fusion and resultant mitochondrial network fragmentation. This effect was abolished by a p53 K371R mutant that failed to bind to PHB2 and impeded the formation of the ac-p53-PHB2 complex. The activation of Flt3 significantly reduced ac-p53 expression in mitochondria via SIRT1, thereby hindering the formation of the ac-p53-PHB2 complex and potentiating the stability of the PHB2-OPA1 complex. This ultimately inhibits L-OPA1 processing and leads to the balancing of mitochondrial dynamics. These findings highlight a novel mechanism by which Flt3 activation mitigates mitochondrial fragmentation and dysfunction through the reduction of L-OPA1 processing by dampening the interaction between ac-p53 and PHB2 in cardiac maladaptive remodeling.

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“…H9C2 cells were selected for use to study the lesions of septic cardiomyopathy [ 17 ]. H9C2 cells were obtained from Procell Life Science & Technology Co.Ltd.…”

Section: Methodsmentioning

confidence: 99%

MiR-31-5p alleviates septic cardiomyopathy by targeting BAP1 to inhibit SLC7A11 deubiquitination and ferroptosis

Liu,

Hu,

et al. 2024

BMC Cardiovasc Disord

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Septic cardiomyopathy is one of the most severe and common complications in patients with sepsis and poses a great threat to their prognosis. However, the potential mechanisms and effective therapeutic drugs need to be explored. The control of cardiac cell death by miRNAs has emerged as a prominent area of scientific interest in the diagnosis and treatment of heart disorders in recent times. In the present investigation, we discovered that overexpression of miR-31-5p prevented LPS-induced damage to H9C2 cells and that miR-31-5p could inhibit BAP1 production by binding to its 3’-UTR. BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase. BAP1 upregulation blocked effect of miR-31-5p on H9C2 cell injury. Moreover, BAP1 inhibited the expression of solute carrier family 7 member 11 (SLC7A11) by deubiquitinating histone 2 A (H2Aub) on the promoter of SLC7A11. Furthermore, overexpression of miR-31-5p and downregulation of BAP1 inhibited SLC7A11 mediated ferroptosis. In addition, the downregulation of SLC7A11 reversed the inhibitory effect of miR-31-5p on the expression of myocardial injury and inflammatory factors, and cell apoptosis was reversed. In conclusion, these results indicate that miR-31-5p alleviates malignant development of LPS-induced H9C2 cell injury by targeting BAP1 and regulating SLC7A11 deubiquitination-mediated ferroptosis, which confirmed the protective effect of miR-31-5p on H9C2 cell injury and revealed potential mechanisms that may provide new targets for treatment of septic cardiomyopathy.

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Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy

Cited by 7 publications

References 47 publications

Exploring the interactions between mitochondria-related genes and the immune microenvironment in sepsis: a bioinformatics study

Exploring the interactions between mitochondria-related genes and the immune microenvironment in sepsis: a bioinformatics study

Flt3 Activation Mitigates Mitochondrial Fragmentation and Heart Dysfunction through Rebalanced L-OPA1 Processing by Hindering the Interaction between Acetylated p53 and PHB2 in Cardiac Remodeling

MiR-31-5p alleviates septic cardiomyopathy by targeting BAP1 to inhibit SLC7A11 deubiquitination and ferroptosis

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