Rotenone‐induced reactive oxygen species signal the recruitment of STAT3 to mitochondria

Mohammed, Fareed; Gorla, Madhavi; Bisoyi, Vandana; Tammineni, Prasad; Sepuri, Naresh Babu V.

doi:10.1002/1873-3468.13741

Cited by 27 publications

(19 citation statements)

References 32 publications

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“…Emerging evidence suggests that the main site of superoxide generation in the mitochondria is the flavin mononucleotide group of complex I through reverse electron transfer, consistent with data that shows inhibition of succinate-related ROS generation by diphenyleneiodonium without affecting the flavin group of complex II [48][49][50]. Moreover, complex III of the mitochondrial respiratory chain generates ROS species through the ubiquinone-reactive sites, Q0 and Qi [51,52]. The redox activity of 66-kDa Src homology 2 domain-containing protein (p66Shc) within mitochondria has been shown to directly generate hydrogen peroxide through oxidation of cytochrome c without intermediate formation of superoxide anion [53,54].…”

Section: Oxidative Stresssupporting

confidence: 77%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD). The mitochondria are the major sites of β-oxidation, a catabolic process by which fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.

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Section: Oxidative Stresssupporting

confidence: 77%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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“…In its turn, mitochondrial STAT3 facilitates ATP production affecting predominantly the activity of ETC complexes I and II and decreases ROS generation. Therefore, STAT3 senses and regulates ROS levels (27,93). Mitochondrial STAT has been also shown to bind to the mPTP component cyclophilin D and prevent its opening which can be one of the crucial mechanisms of ROS generation inhibition (94).…”

Section: The Mitochondrial Stat3 and Mitfmentioning

confidence: 99%

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

et al. 2020

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Mast cells play a key role in the regulation of innate and adaptive immunity and are involved in pathogenesis of many inflammatory and allergic diseases. The most studied mechanism of mast cell activation is mediated by the interaction of antigens with immunoglobulin E (IgE) and a subsequent binding with the high-affinity receptor Fc epsilon RI (FcεRI). Increasing evidences indicated that mitochondria are actively involved in the FcεRI-dependent activation of this type of cells. Here, we discuss changes in energy metabolism and mitochondrial dynamics during IgE-antigen stimulation of mast cells. We reviewed the recent data with regards to the role played by mitochondrial membrane potential, mitochondrial calcium ions (Ca 2+) influx and reactive oxygen species (ROS) in mast cell FcεRI-dependent activation. Additionally, in the present review we have discussed the crucial role played by the pyruvate dehydrogenase (PDH) complex, transcription factors signal transducer and activator of transcription 3 (STAT3) and microphthalmia-associated transcription factor (MITF) in the development and function of mast cells. These two transcription factors besides their nuclear localization were also found to translocate in to the mitochondria and functions as direct modulators of mitochondrial activity. Studying the role played by mast cell mitochondria following their activation is essential for expanding our basic knowledge about mast cell physiological functions and would help to design mitochondria-targeted anti-allergic and anti-inflammatory drugs.

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“…By reducing the amount of pSTAT3 Y705 in the nucleus, PDIA3 may increase the available pool of cytoplasmic STAT3 capable of being phosphorylated on S727 and, after translocation to the mitochondria, promoting mitochondrial function and cell survival. Alternatively, reduced PDIA3 can function as a ROS scavenger [ 77 ], and increased ROS promotes STAT3 phosphorylation on S727 and mitochondrial recruitment [ 78 ]. Thus, the ROS increases observed in PDIA3-/- cells could be the mechanistic link between PDIA3 and pSTAT3 S727.…”

Section: Discussionmentioning

confidence: 99%

PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD

Keasey

Razskazovskiy

Jia³

et al. 2021

Cell Commun Signal

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Background Protein disulfide isomerase A3 (PDIA3, also named GRP58, ER-60, ERp57) is conserved across species and mediates protein folding in the endoplasmic reticulum. PDIA3 is, reportedly, a chaperone for STAT3. However, the role of PDIA3 in regulating mitochondrial bioenergetics and STAT3 phosphorylation at serine 727 (S727) has not been described. Methods Mitochondrial respiration was compared in immortalized human cerebral microvascular cells (CMEC) wild type or null for PDIA3 and in whole organism C. Elegans WT or null for pdi-3 (worm homologue). Mitochondrial morphology and cell signaling pathways in PDIA3-/- and WT cells were assessed. PDIA3-/- cells were subjected to oxygen–glucose deprivation (OGD) to determine the effects of PDIA3 on cell survival after injury. Results We show that PDIA3 gene deletion using CRISPR-Cas9 in cultured CMECs leads to an increase in mitochondrial bioenergetic function. In C. elegans, gene deletion or RNAi knockdown of pdi-3 also increased respiratory rates, confirming a conserved role for this gene in regulating mitochondrial bioenergetics. The PDIA3-/- bioenergetic phenotype was reversed by overexpression of WT PDIA3 in cultured PDIA3-/- CMECs. PDIA3-/- and siRNA knockdown caused an increase in phosphorylation of the S727 residue of STAT3, which is known to promote mitochondrial bioenergetic function. Increased respiration in PDIA3-/- CMECs was reversed by a STAT3 inhibitor. In PDIA3-/- CMECs, mitochondrial membrane potential and reactive oxygen species production, but not mitochondrial mass, was increased, suggesting an increased mitochondrial bioenergetic capacity. Finally, PDIA3-/- CMECs were more resistant to oxygen–glucose deprivation, while STAT3 inhibition reduced the protective effect. Conclusions We have discovered a novel role for PDIA3 in suppressing mitochondrial bioenergetic function by inhibiting STAT3 S727 phosphorylation.

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Rotenone‐induced reactive oxygen species signal the recruitment of STAT3 to mitochondria

Cited by 27 publications

References 32 publications

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD

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