bims-mecmid 2021-10-24 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2021–10–24
nine papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Role of GTPase-Dependent Mitochondrial Dynamins in Heart Diseases.
MIEF1/2 orchestrate mitochondrial dynamics through direct engagement with both the fission and fusion machineries.
Mitochondrial dynamics regulators: implications for therapeutic intervention in cancer.
DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen.
Shen Qi Li Xin formula improves chronic heart failure through balancing mitochondrial fission and fusion via upregulation of PGC-1α.
Mitochondrial dynamics and its impact on human health and diseases: inside the DRP1 blackbox.
Adiponectin Ameliorated Pancreatic Islet Injury Induced by Chronic Intermittent Hypoxia through Inhibiting the Imbalance in Mitochondrial Fusion and Division.
Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane.
Bone marrow mesenchymal stem cell-derived exosomes inhibit chondrocyte apoptosis and the expression of MMPs by regulating Drp1-mediated mitophagy.

Front Cardiovasc Med. 2021 ;8 720085

Role of GTPase-Dependent Mitochondrial Dynamins in Heart Diseases.

Jiangen Liu, Xianjing Song, Youyou Yan, Bin Liu.

  Heart function maintenance requires a large amount of energy, which is supplied by the mitochondria. In addition to providing energy to cardiomyocytes, mitochondria also play an important role in maintaining cell function and homeostasis. Although adult cardiomyocyte mitochondria appear as independent, low-static organelles, morphological changes have been observed in cardiomyocyte mitochondria under stress or pathological conditions. Indeed, cardiac mitochondrial fission and fusion are involved in the occurrence and development of heart diseases. As mitochondrial fission and fusion are primarily regulated by mitochondrial dynamins in a GTPase-dependent manner, GTPase-dependent mitochondrial fusion (MFN1, MFN2, and OPA1) and fission (DRP1) proteins, which are abundant in the adult heart, can also be regulated in heart diseases. In fact, these dynamic proteins have been shown to play important roles in specific diseases, including ischemia-reperfusion injury, heart failure, and metabolic cardiomyopathy. This article reviews the role of GTPase-dependent mitochondrial fusion and fission protein-mediated mitochondrial dynamics in the occurrence and development of heart diseases.

Keywords:  DRP1; MFN2; OPA1; heart disease; mfn1

DOI:  https://doi.org/10.3389/fcvm.2021.720085
BMC Biol. 2021 Oct 21. 19(1): 229

MIEF1/2 orchestrate mitochondrial dynamics through direct engagement with both the fission and fusion machineries.

Rong Yu, Tong Liu, Shao-Bo Jin, Maria Ankarcrona, Urban Lendahl, Monica Nistér, Jian Zhao.

   BACKGROUND: Mitochondrial dynamics is the result of a dynamic balance between fusion and fission events, which are driven via a set of mitochondria-shaping proteins. These proteins are generally considered to be binary components of either the fission or fusion machinery, but potential crosstalk between the fission and fusion machineries remains less explored. In the present work, we analyzed the roles of mitochondrial elongation factors 1 and 2 (MIEF1/2), core components of the fission machinery in mammals.
RESULTS: We show that MIEFs (MIEF1/2), besides their action in the fission machinery, regulate mitochondrial fusion through direct interaction with the fusion proteins Mfn1 and Mfn2, suggesting that MIEFs participate in not only fission but also fusion. Elevated levels of MIEFs enhance mitochondrial fusion in an Mfn1/2- and OPA1-dependent but Drp1-independent manner. Moreover, mitochondrial localization and self-association of MIEFs are crucial for their fusion-promoting ability. In addition, we show that MIEF1/2 can competitively decrease the interaction of hFis1 with Mfn1 and Mfn2, alleviating hFis1-induced mitochondrial fragmentation and contributing to mitochondrial fusion.
CONCLUSIONS: Our study suggests that MIEFs serve as a central hub that interacts with and regulates both the fission and fusion machineries, which uncovers a novel mechanism for balancing these opposing forces of mitochondrial dynamics in mammals.

Keywords:  Drp1; MIEF1/2; Mfn1/2; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; hFis1

DOI:  https://doi.org/10.1186/s12915-021-01161-7
Cell Biol Toxicol. 2021 Oct 18.

Mitochondrial dynamics regulators: implications for therapeutic intervention in cancer.

Sanjay Kumar, Rahail Ashraf, Aparna C K.

  Regardless of the recent advances in therapeutic developments, cancer is still among the primary causes of death globally, indicating the need for alternative therapeutic strategies. Mitochondria, a dynamic organelle, continuously undergo the fusion and fission processes to meet cell requirements. The balanced fission and fusion processes, referred to as mitochondrial dynamics, coordinate mitochondrial shape, size, number, energy metabolism, cell cycle, mitophagy, and apoptosis. An imbalance between these opposing events alters mitochondWangrial dynamics, affects the overall mitochondrial shape, and deregulates mitochondrial function. Emerging evidence indicates that alteration of mitochondrial dynamics contributes to various aspects of tumorigenesis and cancer progression. Therefore, targeting the mitochondrial dynamics regulator could be a potential therapeutic approach for cancer treatment. This review will address the role of imbalanced mitochondrial dynamics in mitochondrial dysfunction during cancer progression. We will outline the clinical significance of mitochondrial dynamics regulators in various cancer types with recent updates in cancer stemness and chemoresistance and its therapeutic potential and clinical utility as a predictive biomarker.

Keywords:  Cancer; Cancer stem cells; Chemoresistance; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1007/s10565-021-09662-5
Int J Mol Sci. 2021 Oct 15. pii: 11125. [Epub ahead of print]22(20):

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen.

Sierra R Bruno, Amit Kumar, Zoe F Mark, Ravishankar Chandrasekaran, Emily Nakada, Nicolas Chamberlain, Bethany Mihavics, Joseph Walzer, Jonathon Cahoon, Anne E Dixon, Brian Cunniff, Vikas Anathy.

  Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.

Keywords:  DRP1; HDM; allergic airway disease; epithelial cell; mitochondrial fission

DOI:  https://doi.org/10.3390/ijms222011125
J Physiol Sci. 2021 Oct 18. 71(1): 32

Shen Qi Li Xin formula improves chronic heart failure through balancing mitochondrial fission and fusion via upregulation of PGC-1α.

Yan-Bo Sui, Jian Xiu, Jin-Xuan Wei, Pei-Pei Pan, Bi-Hong Sun, Li Liu.

   BACKGROUND: Our previous study proved that Shen Qi Li Xin formula (SQLXF) improved the heart function of chronic heart failure (CHF) patients, while the action mechanism remains unclear.
METHODS: H&E staining and TUNEL staining were performed to measure myocardial damages. Western blot was used to examine the expression of proteins. Moreover, CCK-8 assay and flow cytometry were used to measure cell viability and cell apoptosis, respectively. Concentrations of ATP and ROS in cells, and mitochondrial membrane potential (MMP) were detected to estimate oxidative stress.
RESULTS: In vivo, we found that SQLXF improved cardiac hemodynamic parameters, reduced LDH, CK-MB and BNP production, and attenuated myocardial damages in CHF rats. Besides, SQLXF promoted mitochondrial fusion-related proteins expression and inhibited fission-related proteins expression in CHF rats and oxygen glucose deprivation/reoxygenation (OGD/R)-induced cardiac myocytes (CMs). In vitro, our data show that certain dose of SQLXF inhibited OGD/R-induced CMs apoptosis, cell viability decreasing and oxidative stress.
CONCLUSION: Overall, certain dose of SQLXF could effectively improve the cardiac function of CHF rats through inhibition of CMs apoptosis via balancing mitochondrial fission and fusion. Our data proved a novel action mechanism of SQLXF in CHF improvement, and provided a reference for clinical.

Keywords:  Cardiac function; Chronic heart failure; Mitochondrial fission; Mitochondrial fusion; Shen Qi Li Xin formula

DOI:  https://doi.org/10.1186/s12576-021-00816-y
J Mol Med (Berl). 2021 Oct 16.

Mitochondrial dynamics and its impact on human health and diseases: inside the DRP1 blackbox.

Riddhi Banerjee, Agradeep Mukherjee, Shirisha Nagotu.

  Mitochondria are essential organelles that play a significant role in various cellular processes apart from providing energy in eukaryotic cells. An intricate link between mitochondrial structure and function is now unequivocally accepted. Several molecular players have been identified, which are important in maintaining the structure of the organelle. Dynamin-related protein 1 (DRP1) is one such conserved protein that is a vital regulator of mitochondrial dynamics. Multidisciplinary studies have helped elucidate the structure of the protein and its mechanism of action in great detail. Mutations in various domains of the protein have been identified that are associated with debilitating conditions in patients. The involvement of the protein in disease conditions such as neurodegeneration, cancer, and cardiovascular disorders is also gaining attention. The purpose of this review is to highlight recent findings on the role of DRP1 in human disease conditions and address its importance as a therapeutic target.

Keywords:  Cancer; Cardiovascular disease; DRP1; Mitochondria; Mutations; Neurodegeneration

DOI:  https://doi.org/10.1007/s00109-021-02150-7
Chin Med Sci J. 2021 Sep 30. 36(3): 225-233

Adiponectin Ameliorated Pancreatic Islet Injury Induced by Chronic Intermittent Hypoxia through Inhibiting the Imbalance in Mitochondrial Fusion and Division.

Can He, Xi-Long Zhang, Qiang Zhang, Lu-Yao Ge, Wen-Xiao Ding.

  Objective This study aimed to assess the protective value of adiponectin (APN) in pancreatic islet injury induced by chronic intermittent hypoxia (CIH). Methods Sixty rats were randomly divided into three groups: normal control (NC) group, CIH group, and CIH with APN supplement (CIH+APN) group. After 5 weeks of CIH exposure, we conducted oral glucose tolerance tests (OGTT) and insulin released test (IRT), examined and compared the adenosine triphosphate (ATP) levels, mitochondrial membrane potential (MMP) levels, reactive oxygen species (ROS) levels, enzymes gene expression levels of Ant1, Cs, Hmox1, and Cox4i1 which represented mitochondrial tricarboxylic acid cycle function, the protein and gene expression levels of DRP1, FIS1, MFN1, and OPA1 which represented mitochondrial fusion and division, and the protein expression levels of BAX, BCL-2, cleaved Caspase-3, and cleaved PARP which represented mitochondrial associated apoptosis pathway of pancreatic islet. Results OGTT and IRT showed blood glucose and insulin levels had no differences among the NC, CIH and CIH+APN groups (both P>0.05) at 0 min, 20 min, 30 min, 60 min, 120 min. However, we found that compared to NC group, CIH increased the ROS level, reduced ATP level and MMP level. The islets of CIH exposed rats showed reduced gene expression levels of Ant1, Cs, Hmox1, and Cox4i1, decreased protein and gene expression levels of MFN1 and OPA1, increased protein and gene expression levels of DRP1 and FIS1, increased protein expression levels of cleaved Caspase-3 and cleaved PARP, with lower ratio of BCL-2/BAX at protein expression level. All the differences among three groups were statistically significant. APN treated CIH rats showed mitigated changes in the above measurements associated with islet injuries. Conclusion APN may ameliorate the pancreatic islet injury induced by CIH via inhibiting the imbalance in mitochondrial fusion and division.

Keywords:  adiponectin; chronic intermittent hypoxia; mitochondrial fusion and division; obstructive sleep apnea hypopnea syndrome; pancreatic islet

DOI:  https://doi.org/10.24920/003834
EMBO J. 2021 Oct 18. e108428

Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane.

Yang Xu, Hediye Erdjument-Bromage, Colin K L Phoon, Thomas A Neubert, Mindong Ren, Michael Schlame.

  Mitochondrial cristae are extraordinarily crowded with proteins, which puts stress on the bilayer organization of lipids. We tested the hypothesis that the high concentration of proteins drives the tafazzin-catalyzed remodeling of fatty acids in cardiolipin, thereby reducing bilayer stress in the membrane. Specifically, we tested whether protein crowding induces cardiolipin remodeling and whether the lack of cardiolipin remodeling prevents the membrane from accumulating proteins. In vitro, the incorporation of large amounts of proteins into liposomes altered the outcome of the remodeling reaction. In yeast, the concentration of proteins involved in oxidative phosphorylation (OXPHOS) correlated with the cardiolipin composition. Genetic ablation of either remodeling or biosynthesis of cardiolipin caused a substantial drop in the surface density of OXPHOS proteins in the inner membrane of the mouse heart and Drosophila flight muscle mitochondria. Our data suggest that OXPHOS protein crowding induces cardiolipin remodelling and that remodeled cardiolipin supports the high concentration of these proteins in the inner mitochondrial membrane.

Keywords:  Barth syndrome; lipid-protein interaction; macromolecular crowding; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.15252/embj.2021108428
Acta Histochem. 2021 Oct 14. pii: S0065-1281(21)00118-5. [Epub ahead of print]123(8): 151796

Bone marrow mesenchymal stem cell-derived exosomes inhibit chondrocyte apoptosis and the expression of MMPs by regulating Drp1-mediated mitophagy.

Sen Tang, Tao Tang, Guicheng Gao, Qiangqiang Wei, Kuo Sun, Wenzhou Huang.

  Osteoarthritis (OA) is a joint degenerative disease commonly seen in the elderly. Bone marrow mesenchymal stem cell-exosomes (BMSC-exosomes) are closely associated with the progression of OA. Here, we investigated whether BMSC-exosomes can affect OA development by regulating mitophagy. Primary rat chondrocytes were treated with advanced glycation end products (AGEs) to induce cell damage. The results of flow cytometry showed that AGEs treatment significantly promoted apoptosis of chondrocytes. AGEs treatment also enhanced the expression of matrix metalloproteinases (MMPs), MMP-3 and MMP-13, and dynamin-related protein 1 (Drp1) in chondrocytes. To investigate the impact of BMSC-exosomes on chondrocytes, chondrocytes were treated with BMSC-exosomes. AGEs-mediated increase of apoptosis and up-regulation of MMP-3, MMP-13, and Drp1 in chondrocytes were abrogated by BMSC-exosomes. Western blot analysis of autophagy-related proteins and Mito-Keima assay revealed that BMSC-exosome treatment elevated the expression of autophagy-related proteins, LC3-II/LC3-I and Beclin-1, and promoted mitophagy in the AGEs-treated chondrocytes. Moreover, Drp1 overexpression repressed the expression of LC3-II/LC3-I and Beclin-1, and enhanced apoptosis and the expression of MMP-3 and MMP-13 in AGEs-treated chondrocytes. BMSC-exosomes reversed the impact of Drp1 overexpression on AGEs-treated chondrocytes. In conclusion, this work demonstrates that BMSC-exosomes inhibit chondrocyte apoptosis and the expression of MMPs, which attributes to regulate Drp1-mediated mitophagy. Thus, BMSC-exosomes may be a potential treatment for OA.

Keywords:  Drp1; MMPs; apoptosis; bone marrow mesenchymal stem cells; exosomes; mitophagy

DOI:  https://doi.org/10.1016/j.acthis.2021.151796