bims-mecmid 2021-11-14 papers

Issue of 2021‒11‒14
six papers selected by
Mauricio Cardenas Rodriguez
University of Padova

Chemosphere. 2020 Oct 09. pii: S0045-6535(20)32762-4. [Epub ahead of print] 128567

Development of classification models for predicting inhibition of mitochondrial fusion and fission using machine learning methods.

Weihao Tang, Jingwen Chen, Huixiao Hong.

Mitochondrial fusion and fission are processes to maintain mitochondrial function when cells respond to environment stresses. Disruption of mitochondrial fusion and fission influences cell health and can cause adverse events such as neurodegenerative disorders. It is critical to identify environmental chemicals that can disrupt mitochondrial fusion and fission. However, experimentally testing all the chemicals is not practical because experimental methods are time-consuming and costly. Quantitative structure-activity relationship (QSAR) modeling is an attractive approach for evaluation of chemicals disrupting potential on mitochondrial fusion and fission. In this study, QSAR models were developed for differentiating chemicals capable of inhibition of mitochondrial fusion and fission using machine learning algorithms (i.e. random forest, logistic regression, Bernoulli naive Bayes, and deep neural network). One hundred iterations of five-fold cross validations and external validations showed that the best model on mitochondrial fusion had area under the receiver operating characteristic curve (AUC) of 82.8% and 78.1%, respectively; and the best model for mitochondrial fission yielded AUC of 84.3% and 97.5%, respectively. Furthermore, 45 and 56 structural alerts were identified for inhibition of mitochondrial fusion and fission, respectively. The results demonstrated that the models and the structural alerts could be useful for screening chemicals that inhibit mitochondrial fusion and fission.

Keywords: Machine learning; Mitochondrial fusion and fission; QSAR; Structural alerts

DOI: https://doi.org/10.1016/j.chemosphere.2020.128567

Osteoarthritis Cartilage. 2021 Nov 09. pii: S1063-4584(21)00962-6. [Epub ahead of print]

ERK1/2-Mediated Activation of DRP1 Regulates Mitochondrial Dynamics and Apoptosis in Chondrocytes.

Mohammad Y Ansari, Kimberly Novak, Tariq M Haqqi.

OBJECTIVE: To determine the Dynamin-related protein 1 (DRP1) regulation of mitochondrial fission in chondrocytes under pathological conditions, an area which is underexplored in osteoarthritis pathogenesis.DESIGN: DRP1 protein expression was determined by IHC or IF staining of cartilage sections. IL-1β-induced DRP1 mRNA expression in chondrocytes was quantified by qPCR and protein expression by immunoblotting. Mitochondrial fragmentation in chondrocytes was visualized by MitoTracker staining or IF staining of mitochondrial marker proteins or by transient expression of mitoDsRed. Mitochondrial ROS levels were determined by MitoSOX staining. Apoptosis was determined by LDH release assay, Caspase 3/7 activity assay, propidium iodide, and TUNEL staining and IF staining of cleaved caspase 3. Cytochrome c release was determined by confocal microscopy. Surgical destabilization of the medial meniscus (DMM) was used to induce OA in mice.
RESULTS: Expression of DRP1 and mitochondrial damage was high in human OA cartilage and in the joints of mice subjected to DMM surgery which also showed increased chondrocytes apoptosis. IL-1β-induced mitochondrial network fragmentation and chondrocyte apoptosis via modulation of DRP1 expression and activity and induce apoptosis via Bax-mediated release of Cytochrome c. Pharmacological inhibition of DRP1 activity by Mdivi-1 blocked IL-1β-induced mitochondrial damage and apoptosis in chondrocytes. Additionally, IL-1β-induced activation of ERK1/2 is crucial for DRP1 activation and induction of mitochondrial network fragmentation in chondrocytes as these were blocked by inhibiting ERK1/2 activation.
CONCLUSIONS: These findings demonstrate that ERK1/2 is a critical player in DRP1-mediated induction of mitochondrial fission and apoptosis in IL-1β-stimulated chondrocytes.

Keywords: Apoptosis; Cytochrome c; DNM1L; Mitochondrial fission; Mitochondrial network fragmentation; Osteoarthritis

DOI: https://doi.org/10.1016/j.joca.2021.11.003

Front Immunol. 2021 ;12 670338

Mitochondrial Fission Factor Is a Novel Interacting Protein of the Critical B Cell Survival Regulator TRAF3 in B Lymphocytes.

Yingying Liu, Samantha Gokhale, Jaeyong Jung, Sining Zhu, Chang Luo, Debanjan Saha, Jessie Yanxiang Guo, Huaye Zhang, Saw Kyin, Wei-Xing Zong, Eileen White, Ping Xie.

Proteins controlling mitochondrial fission have been recognized as essential regulators of mitochondrial functions, mitochondrial quality control and cell apoptosis. In the present study, we identified the critical B cell survival regulator TRAF3 as a novel binding partner of the key mitochondrial fission factor, MFF, in B lymphocytes. Elicited by our unexpected finding that the majority of cytoplasmic TRAF3 proteins were localized at the mitochondria in resting splenic B cells after ex vivo culture for 2 days, we found that TRAF3 specifically interacted with MFF as demonstrated by co-immunoprecipitation and GST pull-down assays. We further found that in the absence of stimulation, increased protein levels of mitochondrial TRAF3 were associated with altered mitochondrial morphology, decreased mitochondrial respiration, increased mitochondrial ROS production and membrane permeabilization, which eventually culminated in mitochondria-dependent apoptosis in resting B cells. Loss of TRAF3 had the opposite effects on the morphology and function of mitochondria as well as mitochondria-dependent apoptosis in resting B cells. Interestingly, co-expression of TRAF3 and MFF resulted in decreased phosphorylation and ubiquitination of MFF as well as decreased ubiquitination of TRAF3. Moreover, lentivirus-mediated overexpression of MFF restored mitochondria-dependent apoptosis in TRAF3-deficient malignant B cells. Taken together, our findings provide novel insights into the apoptosis-inducing mechanisms of TRAF3 in B cells: as a result of survival factor deprivation or under other types of stress, TRAF3 is mobilized to the mitochondria through its interaction with MFF, where it triggers mitochondria-dependent apoptosis. This new role of TRAF3 in controlling mitochondrial homeostasis might have key implications in TRAF3-mediated regulation of B cell transformation in different cellular contexts. Our findings also suggest that mitochondrial fission is an actionable therapeutic target in human B cell malignancies, including those with TRAF3 deletion or relevant mutations.

Keywords: B cell malignancies; B lymphocytes; MFF; TRAF3; apoptosis; mitochondria

DOI: https://doi.org/10.3389/fimmu.2021.670338

J Cell Mol Med. 2021 Nov 10.

HAX1 maintains the glioma progression in hypoxia through promoting mitochondrial fission.

Jinghui Lin, Yang Wang, Zhiqing Lin.

HCLS1-associated protein X-1 (HAX1), an anti-apoptotic molecular, overexpresses in glioma. However, the role of HAX1 in glioma cell surviving in hypoxic environment remains unclear. Western blotting, qRT-PCR, Transwell assay, TUNEL assay, wounding healing assay, clone formation, tumour xenograft model and immunohistochemical staining were used to investigate the role of HAX1 in glioma. HAX1 regulated by HIF-1α was increased in glioma cells cultured in hypoxia. Silencing of HAX1 could cause an increased apoptosis of glioma cells cultured in hypoxia. Silencing of HAX1 also decreased the proliferation, migration and invasion of glioma cells cultured in hypoxia. Increased mitochondrial fission could prevent glioma cells from the damage induced by HAX1 knockdown in hypoxia. Furthermore, HAX1 was found to regulate glioma cells through phosphorylated AKT/Drp signal pathway. In conclusion, our study suggested that HAX1 promoted survival of glioma cells in hypoxic environment via AKT/Drp signal pathway. Our study also provided a potential therapeutic target for glioma.

Keywords: HCLS1-associated protein X-1; glioma; hypoxia; mitochondrial fission

DOI: https://doi.org/10.1111/jcmm.17038

Front Pharmacol. 2021 ;12 754005

Cordycepin Decreases Ischemia/Reperfusion Injury in Diabetic Hearts via Upregulating AMPK/Mfn2-dependent Mitochondrial Fusion.

Houyou Yu, Xin Hong, Lihua Liu, Yangpeng Wu, Xuemei Xie, Guoxiang Fang, Shaomin Zhi.

Diabetes mellitus is considered to be a major risk factor for cardiovascular disease, the most common cause of death in diabetes. However, therapeutic strategies for myocardial protection in patients with diabetes are still limited. Cordycepin is a traditional Tibetan medicine with a long history of widespread use, and exerts a wide range of anti-tumor, anti-inflammatory, and anti-oxidative effects. In recent years, although the therapeutic potential of cordycepin has attracted the attention of researchers, it remains unknown whether cordycepin plays a protective role in myocardial ischemia/reperfusion (MI/R) injury in diabetic patients. Here, using a diabetic mouse model, we found that cordycepin protected diabetic hearts from MI/R injury by promoting mitochondrial fusion and Mfn2 expression. Our in vitro results showed that cordycepin enhanced Mfn2-medicated mitochondrial fusion, improved mitochondrial function, and reduced cardiomyocyte apoptosis in high-glucose/high-fat cultured simulated ischemia/reperfusion cardiomyocytes. Furthermore, we found that knockout of Mfn2 significantly blocked the cardioprotective effects of cordycepin in diabetic mice. Finally, an AMPK-dependent pathway was found to upregulate Mfn2 expression upon cordycepin treatment, indicating that cordycepin protected diabetic hearts via AMPK/Mfn2-dependent mitochondrial fusion. Collectively, our study firstly demonstrated that cordycepin could be a potential cardioprotective agent for MI/R injury, and we established a novel mechanism by which upregulated AMPK/Mfn2-dependent mitochondrial fusion contributes to the cardioprotective role of cordycepin.

Keywords: cardioprotection; cordycepin; diabetes; mitochondrial fusion; myocardial ischemia/reperfusion

DOI: https://doi.org/10.3389/fphar.2021.754005

J Biophotonics. 2021 Nov 12. e202100305

Mitochondrial dynamics and quantification of MDVs in cardiomyoblasts using structured illumination microscopy.

Ida S Opstad, Gustav Godtliebsen, Balpreet Singh Ahluwalia, Truls Myrmel, Krishna Agarwal, Åsa Birna Birgisdottir.

Keywords: 3DSIM; MDVs; Mitochondria-derived vesicles; Trainable Weka Segmentation; cardiomyoblasts; mitochondria; mitochondria tubules; three-dimensional structured illumination microscopy

DOI: https://doi.org/10.1002/jbio.202100305