bims-mecmid 2022-01-16 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2022–01–16
eight papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Mitochondria shed their outer membrane in response to infection-induced stress.
Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells.
The Role of Mitochondrial Dynamic Dysfunction in Age-Associated Type 2 Diabetes.
Absence of Cardiolipin From the Outer Leaflet of a Mitochondrial Inner Membrane Mimic Restricts Opa1-Mediated Fusion.
Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics.
DRP1 interacts directly with BAX to induce its activation and apoptosis.
Sheng Mai San ameliorated heat stress-induced liver injury via regulating energy metabolism and AMPK/Drp1-dependent autophagy process.
Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.

Science. 2022 Jan 14. 375(6577): eabi4343

Mitochondria shed their outer membrane in response to infection-induced stress.

Xianhe Li, Julian Straub, Tânia Catarina Medeiros, Chahat Mehra, Fabian den Brave, Esra Peker, Ilian Atanassov, Katharina Stillger, Jonas Benjamin Michaelis, Emma Burbridge, Colin Adrain, Christian Münch, Jan Riemer, Thomas Becker, Lena F Pernas.

[Figure: see text].

DOI: https://doi.org/10.1126/science.abi4343
J Cancer. 2021 ;12(24): 7358-7373

Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells.

Guang-Ping Zou, Chun-Xia Yu, Sheng-Lan Shi, Qiu-Gen Li, Xiao-Hua Wang, Xin-Hui Qu, Zhang-Jian Yang, Wei-Rong Yao, Dan-Dan Yan, Li-Ping Jiang, Yu-Ying Wan, Xiao-Jian Han.

  Cisplatin (DDP) is the first-line chemotherapeutic agent for ovarian cancer. However, the development of DDP resistance seriously influences the chemotherapeutic effect and prognosis of ovarian cancer. It was reported that DDP can directly impinge on the mitochondria and activate the intrinsic apoptotic pathway. Herein, the role of mitochondrial dynamics in DDP chemoresistance in human ovarian cancer SKOV3 cells was investigated. In DDP-resistant SKOV3/DDP cells, mitochondrial fission protein DRP1 was down-regulated, while mitochondrial fusion protein MFN2 was up-regulated. In accordance with the expression of DRP1 and MFN2, the average mitochondrial length was significantly increased in SKOV3/DDP cells. In DDP-sensitive parental SKOV3 cells, downregulation of DRP1 and upregulation of mitochondrial fusion proteins including MFN1,2 and OPA1 occurred at day 2~6 under cisplatin stress. Knockdown of DRP1 or overexpression of MFN2 promoted the resistance of SKOV3 cells to cisplatin. Intriguingly, weaker migration capability and lower ATP level were detected in SKOV3/DDP cells. Respective knockdown of DRP1 in parental SKOV3 cells or MFN2 in SKOV3/DDP cells using siRNA efficiently reversed mitochondrial dynamics, migration capability and ATP level. Moreover, MFN2 siRNA significantly aggravated the DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3/DDP cells. In contrast, DRP1 siRNA alleviated DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3 cells. Thus, these results indicate that mitochondrial dynamics mediated by DRP1 and MFN2 contributes to the development of DDP resistance in ovarian cancer cells, and will also provide a new strategy to prevent chemoresistance in ovarian cancer by targeting mitochondrial dynamics.

Keywords:  apoptosis; chemoresistance; cisplatin; mitochondrial dynamics; ovarian cancer

DOI:  https://doi.org/10.7150/jca.61379
World J Mens Health. 2022 Jan 01.

The Role of Mitochondrial Dynamic Dysfunction in Age-Associated Type 2 Diabetes.

Teresa Vezza, Pedro Díaz-Pozo, Francisco Canet, Aranzazu M de Marañón, Zaida Abad-Jiménez, Celia García-Gargallo, Ildefonso Roldan, Eva Solá, Celia Bañuls, Sandra López-Domènech, Milagros Rocha, Víctor M Víctor.

  Mitochondrial dynamics, such as fusion and fission, play a critical role in maintaining cellular metabolic homeostasis. The molecular mechanisms underlying these processes include fusion proteins (Mitofusin 1 [MFN1], Mitofusin 2 [MFN2], and optic atrophy 1 [OPA1]) and fission mediators (mitochondrial fission 1 [FIS1] and dynamin-related protein 1 [DRP1]), which interact with each other to ensure mitochondrial quality control. Interestingly, defects in these proteins can lead to the loss of mitochondrial DNA (mtDNA) integrity, impairment of mitochondrial function, a severe alteration of mitochondrial morphology, and eventually cell death. Emerging evidence has revealed a causal relationship between dysregulation of mitochondria dynamics and age-associated type 2 diabetes, a metabolic disease whose rates have reached an alarming epidemic-like level with the majority of cases (59%) recorded in men aged 65 and over. In this sense, fragmentation of mitochondrial networks is often associated with defects in cellular energy production and increased apoptosis, leading, in turn, to excessive reactive oxygen species release, mitochondrial dysfunction, and metabolic alterations, which can ultimately contribute to β-cell dysfunction and insulin resistance. The present review discusses the processes of mitochondrial fusion and fission and their dysfunction in type 2 diabetes, with special attention given to the therapeutic potential of targeting mitochondrial dynamics in this complex metabolic disorder.

Keywords:  Aging; Men; Mitochondria; Type 2 diabetes

DOI:  https://doi.org/10.5534/wjmh.210146
Front Mol Biosci. 2021 ;8 769135

Absence of Cardiolipin From the Outer Leaflet of a Mitochondrial Inner Membrane Mimic Restricts Opa1-Mediated Fusion.

Yifan Ge, Sivakumar Boopathy, Tran H Nguyen, Camila Makhlouta Lugo, Luke H Chao.

  Cardiolipin is a tetra-acylated di-phosphatidylglycerol lipid enriched in the matrix-facing (inner) leaflet of the mitochondrial inner membrane. Cardiolipin plays an important role in regulating mitochondria function and dynamics. Yet, the mechanisms connecting cardiolipin distribution and mitochondrial protein function remain indirect. In our previous work, we established an in vitro system reconstituting mitochondrial inner membrane fusion mediated by Opa1. We found that the long form of Opa1 (l-Opa1) works together with the proteolytically processed short form (s-Opa1) to mediate fast and efficient membrane fusion. Here, we extend our reconstitution system to generate supported lipid bilayers with asymmetric cardiolipin distribution. Using this system, we find the presence of cardiolipin on the inter-membrane space-facing (outer) leaflet is important for membrane tethering and fusion. We discuss how the presence of cardiolipin in this leaflet may influence protein and membrane properties, and future applications for this approach.

Keywords:  OPA1; cardiolipin; membrane asymmetry; membrane heterogeneity; mitochondrial fusion

DOI:  https://doi.org/10.3389/fmolb.2021.769135
J Clin Med. 2021 Dec 27. pii: 135. [Epub ahead of print]11(1):

Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics.

Kuan-Chou Chen, Chang-Rong Chen, Chang-Yu Chen, Chiung-Chi Peng, Robert Y Peng.

  Bicalutamide (Bic) is an androgen deprivation therapy (ADT) for treating prostate cancer, while ADT is potentially associated with acute kidney injury. Previously, we recognized Bic induced renal mitochondria dysfunction in vitro and in vivo via the ROS -HIF1α pathway. Whether OXPHOS complex, as well as mitochondrial dynamics, can be influenced by Bic via modulation of peroxisome proliferator-activated receptor coactivator 1α (PGC1α), NADPH oxidase 4 (Nox4), mitofusins 1/2 (MFN 1/2), optic atrophy 1 (OPA1), and sirtuins (SIRTs) has not been documented. Renal mesangial cell line was treated with Bic (30~60 μM) for the indicated time. SIRTs, complex I, mitochondrial dynamics- and oxidative stress-related proteins were analyzed. Bic dose-dependently reduced mitochondrial potential, but dose- and time-dependently suppressed translocase of the outer mitochondrial membrane member 20 (Tomm 20), complex I activity. Nox4 and glutathione lead to decreased NAD+/NADH ratio, with upregulated superoxide dismutase 2. SIRT1 was initially stimulated and then suppressed, while SIRT3 was time- and dose-dependently downregulated. PGC1α, MFN2, and OPA1 were all upregulated, with MFN1 and pro-fission dynamin-related protein I downregulated. Bic exhibits potential to damage mitochondria via destroying complex I, complex I activity, and mitochondrial dynamics. Long-term treatment with Bic should be carefully followed up.

Keywords:  NADPH oxidase 4 (Nox4); PGC1α; bicalutamide; complex I NDUFB8; glutathione (GSH); mitofusins 1/2 (MFN 1/2); optic atrophy 1 (OPA1); sirtuins (SIRTs)1/3; superoxide dismutase 2 (SOD2)

DOI:  https://doi.org/10.3390/jcm11010135
EMBO J. 2022 Jan 13. e108587

DRP1 interacts directly with BAX to induce its activation and apoptosis.

Andreas Jenner, Aida Peña-Blanco, Raquel Salvador-Gallego, Begoña Ugarte-Uribe, Cristiana Zollo, Tariq Ganief, Jan Bierlmeier, Marcus Mund, Jason E Lee, Jonas Ries, Dirk Schwarzer, Boris Macek, Ana J Garcia-Saez.

  The apoptotic executioner protein BAX and the dynamin-like protein DRP1 co-localize at mitochondria during apoptosis to mediate mitochondrial permeabilization and fragmentation. However, the molecular basis and functional consequences of this interplay remain unknown. Here, we show that BAX and DRP1 physically interact, and that this interaction is enhanced during apoptosis. Complex formation between BAX and DRP1 occurs exclusively in the membrane environment and requires the BAX N-terminal region, but also involves several other BAX surfaces. Furthermore, the association between BAX and DRP1 enhances the membrane activity of both proteins. Forced dimerization of BAX and DRP1 triggers their activation and translocation to mitochondria, where they induce mitochondrial remodeling and permeabilization to cause apoptosis even in the absence of apoptotic triggers. Based on this, we propose that DRP1 can promote apoptosis by acting as noncanonical direct activator of BAX through physical contacts with its N-terminal region.

Keywords:  BCL-2 proteins; fluorescence correlation spectroscopy; membrane protein complex; mitochondrial division; super-resolution microscopy

DOI:  https://doi.org/10.15252/embj.2021108587
Phytomedicine. 2021 Dec 31. pii: S0944-7113(21)00460-8. [Epub ahead of print]97 153920

Sheng Mai San ameliorated heat stress-induced liver injury via regulating energy metabolism and AMPK/Drp1-dependent autophagy process.

Xiaosong Zhang, Yaqian Jia, Ziwen Yuan, Yanqiao Wen, Yahui Zhang, Jianmin Ren, Peng Ji, Wanling Yao, Yongli Hua, Yanming Wei.

   BACKGROUND: Liver damage is one of the most common complications in humans and animals after heat stress (HS). Sheng Mai San (SMS), a traditional Chinese medicine prescription that originated in the Jin Dynasty, exert a therapeutic effect on HS. However, how SMS prevents liver injury after heat exposure remains unknown.
PURPOSE: This study aimed to investigate the pharmacological effect and molecular mechanisms of SMS on HS-induced liver injury.
STUDY DESIGN: A comprehensive strategy via incorporating pharmacodynamics, targeted metabolomics, and molecular biology technology was adopted to investigate energy metabolism changes and the therapeutic mechanisms of SMS in HS-induced rat liver injury.
METHODS: First, Sprague-Dawley rats were subjected to HS (38 °C/ 75% RH/ 2 h/ day) for 7 consecutive days to establish the HS model, and SMS was given orally for treatment 2 h before heat exposure. Thereafter, liver function and pathological changes in liver tissue were evaluated. Finally, the underlying mechanisms of SMS were determined using targeted energy metabolomics to comprehensively analyze the metabolic pathways and were further verified through Western-blot and qRT-PCR assays.
RESULTS: Our results showed that SMS alleviated HS-induced liver dysfunction by reducing the alanine aminotransferase (ALT), aspartate aminotransferase (AST), and AST/ALT ratios in serum and improving hepatic pathological damage. Meanwhile, SMS suppressed inflammatory response, oxidative injury, and overexpression of heat shock proteins in liver tissue after heat exposure. With the help of targeted energy metabolomics, we found that SMS could effectively regulate glycolysis and tricarboxylic acid (TCA) cycle to relieve energy metabolism disorder. Furthermore, we confirmed that SMS can facilitate the phosphorylation of AMP-activated protein kinase (AMPK) to maintain mitochondrial homeostasis through a dynamin protein 1 (Drp1)-dependent mitophagy process.
CONCLUSION: On the basis of energy metabolomics, the present study for the first time systematically illustrated the protective effect of SMS on HS-induced liver injury, and preliminarily confirmed that an AMPK-mediated Drp1-dependent mitophagy and mitochondria rebuilding process plays an important role in SMS intervention on HS-induced rat liver. Together, our study lends further support to the use of SMS in treating HS condition.

Keywords:  Autophagy; Energy metabolism; Heat stress; Liver injury; Oxidative stress; Sheng Mai San

DOI:  https://doi.org/10.1016/j.phymed.2021.153920
JCI Insight. 2022 Jan 11. pii: e150041. [Epub ahead of print]

Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.

Yae-Huei Liou, Jean Personnaz, David Jacobi, Nelson H Knudsen, Mayer M Chalom, Kyle A Starost, Israel C Nnah, Chih-Hao Lee.

  Mitophagy and mitochondrial integrated stress response (ISR) are two primary protective mechanisms to maintain functional mitochondria. Whether these two processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 over-expression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD fed mice. RNA-seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I stimulated genes through Atf5, which inhibits the transactivation activity of Irf3 known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 over-expression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.

Keywords:  Glucose metabolism; Metabolism; Mitochondria; Obesity

DOI:  https://doi.org/10.1172/jci.insight.150041