bims-mecmid 2022-05-29 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2022–05–29
ten papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Role of Mitochondrial Dynamics in Cocaine's Neurotoxicity.
Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission.
Sinapic Acid Ameliorates REV-ERB α Modulated Mitochondrial Fission against MPTP-Induced Parkinson's Disease Model.
Bisphenol-A Mediated Impaired DRP1-GFER Axis and Cognition Restored by PGC-1α Upregulation Through Nicotinamide in the Rat Brain Hippocampus.
DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
Artesunate restores mitochondrial fusion-fission dynamics and alleviates neuronal injury in Alzheimer's disease models.
Panax notoginseng saponin R1 attenuates allergic rhinitis through AMPK/Drp1 mediated mitochondrial fission.
Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina.
Battery wastewater induces nephrotoxicity via disordering the mitochondrial dynamics.
Cardioprotective effects of gypenoside XVII against ischemia/reperfusion injury: Role of endoplasmic reticulum stress, autophagy, and mitochondrial fusion fission balance.

Int J Mol Sci. 2022 May 12. pii: 5418. [Epub ahead of print]23(10):

Role of Mitochondrial Dynamics in Cocaine's Neurotoxicity.

Shuheng Wen, Toshihiko Aki, Takeshi Funakoshi, Kana Unuma, Koichi Uemura.

  The dynamic balance of mitochondrial fission and fusion maintains mitochondrial homeostasis and optimal function. It is indispensable for cells such as neurons, which rely on the finely tuned mitochondria to carry out their normal physiological activities. The potent psychostimulant cocaine impairs mitochondria as one way it exerts its neurotoxicity, wherein the disturbances in mitochondrial dynamics have been suggested to play an essential role. In this review, we summarize the neurotoxicity of cocaine and the role of mitochondrial dynamics in cellular physiology. Subsequently, we introduce current findings that link disturbed neuronal mitochondrial dynamics with cocaine exposure. Finally, the possible role and potential therapeutic value of mitochondrial dynamics in cocaine neurotoxicity are discussed.

Keywords:  Drp1; cocaine; endoplasmic reticulum; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.3390/ijms23105418
Front Oncol. 2022 ;12 893396

Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission.

Dantong Zhu, Fengtong Han, Liuke Sun, Sandeep K Agnihotri, Ying Hu, Hansruedi Büeler.

  Mitochondrial metabolism and dynamics (fission and fusion) critically regulate cell survival and proliferation, and abnormalities in these pathways are implicated in both neurodegenerative disorders and cancer. Mitochondrial fission is necessary for the growth of mutant Ras-dependent tumors. Here, we investigated whether loss of PTEN-induced kinase 1 (PINK1) - a mitochondrial kinase linked to recessive familial Parkinsonism - affects the growth of oncogenic Ras-induced tumor growth in vitro and in vivo. We show that RasG12D-transformed embryonic fibroblasts (MEFs) from PINK1-deficient mice display reduced growth in soft agar and in nude mice, as well as increased necrosis and decreased cell cycle progression, compared to RasG12D-transformed MEFs derived from wildtype mice. PINK1 re-expression (overexpression) at least partially rescues these phenotypes. Neither PINK1 deletion nor PINK1 overexpression altered Ras expression levels. Intriguingly, PINK1-deficient Ras-transformed MEFs exhibited elongated mitochondria and altered DRP1 phosphorylation, a key event in regulating mitochondrial fission. Inhibition of DRP1 diminished PINK1-regulated mitochondria morphological changes and tumor growth suggesting that PINK1 deficiency primarily inhibits Ras-driven tumor growth through disturbances in mitochondrial fission and associated cell necrosis and cell cycle defects. Moreover, we substantiate the requirement of PINK1 for optimal growth of Ras-transformed cells by showing that human HCT116 colon carcinoma cells (carrying an endogenous RasG13D mutation) with CRISPR/Cas9-introduced PINK1 gene deletions also show reduced mitochondrial fission and decreased growth. Our results support the importance of mitochondrial function and dynamics in regulating the growth of Ras-dependent tumor cells and provide insight into possible mechanisms underlying the lower incidence of cancers in Parkinson's disease and other neurodegenerative disorders.

Keywords:  PTEN-induced kinase-1 (PINK1); Ras protein; Ras-induced tumors; cell cycle; dynamin-related protein 1 (DRP1); mitochondrial dynamics; mitochondrial metabolism

DOI:  https://doi.org/10.3389/fonc.2022.893396
Biomol Ther (Seoul). 2022 May 25.

Sinapic Acid Ameliorates REV-ERB α Modulated Mitochondrial Fission against MPTP-Induced Parkinson's Disease Model.

Sang-Bin Lee, Hyun Ok Yang.

  Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, and accumulating evidence indicates that mitochondrial dysfunction is associated with progressive deterioration in PD patients. Previous studies have shown that sinapic acid has a neuroprotective effect, but its mechanisms of action remain unclear. The neuroprotective effect of sinapic acid was assayed in a PD mouse model generated by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as in SH-SY5Y cells. Target protein expression was detected by western blotting. Sinapic acid treatment attenuated the behavioral defects and loss of dopaminergic neurons in the PD models. Sinapic acid also improved mitochondrial function in the PD models. MPTP treatment increased the abundance of mitochondrial fission proteins such as dynamin-related protein 1 (Drp1) and phospho-Drp1 Ser616. In addition, MPTP decreased the expression of the REV-ERB α protein. These changes were attenuated by sinapic acid treatment. We used the pharmacological REV-ERB α inhibitor SR8278 to confirmation of protective effect of sinapic acid. Treatment of SR8278 with sinapic acid reversed the protein expression of phospho-Drp1 Ser616 and REV-ERB α on MPTP-treated mice. Our findings demonstrated that sinapic acid protects against MPTP-induced PD and these effects might be related to the inhibiting abnormal mitochondrial fission through REV-ERB α.

Keywords:  ; MPTP; Mitochondrial fission; Parkinson disease; REB-ERB α; Sinapic acid

DOI:  https://doi.org/10.4062/biomolther.2022.020
Mol Neurobiol. 2022 May 25.

Bisphenol-A Mediated Impaired DRP1-GFER Axis and Cognition Restored by PGC-1α Upregulation Through Nicotinamide in the Rat Brain Hippocampus.

Shweta Goyal, Saurabh Tiwari, Brashket Seth, Phoolmala, Ankit Tandon, Rajnish Kumar Chaturvedi.

  The regulatory network of mitochondrial biogenesis and dynamics is vital for mitochondrial functions and cellular homeostasis. Any impairment in the mitochondrial network leads to neurodegenerative disorders. Our earlier studies suggest that environmental toxicant Bisphenol-A (BPA) exposure reduces neurogenesis by abnormal mitochondrial dynamics and mitochondrial biogenesis through impairment of mitochondrial fission factor dynamin-related protein (DRP1) and mitochondrial import protein GFER, which leads to demyelination, neurodegeneration, and cognitive deficits in the rats. In the present study, we found that chronic BPA exposure reduces PGC-1α levels (master regulator of mitochondrial biogenesis), alters mitochondrial localization of DRP1 and GFER, and reduces the number of PGC-1α/NeuN+ and PGC-1α/β-tubulin+ neurons in the rat hippocampus, suggesting reduced PGC-1α-mediated neurogenesis. Nicotinamide significantly increased PGC-1α protein levels, PGC-1α/NeuN+ co-labeled cells in BPA-treated rat hippocampus and PGC-1α/β-tubulin+ co-labeled cells in neuron culture derived from hippocampal neural stem cells. Interestingly, PGC-1α upregulation by nicotinamide also resulted in increased GFER levels and restored mitochondrial localization of GFER (increased GFER/TOMM20 co-labeled cells) in vitro and in vivo following BPA treatment. Nicotinamide also reduced DRP1 levels and prevented DRP1 mitochondrial localization in BPA-treated neuronal cultures and hippocampus, suggesting reduced mitochondrial fission. This resulted in reduced cytochrome c levels in neuronal culture and reduced hippocampal neurodegeneration (reduced caspase-3/NeuN+ co-labeled neurons) following nicotinamide treatment in BPA-treated group. Consequently, activation of PGC-1α by nicotinamide restored BPA-mediated cognitive deficits in rats. Results suggest that the treatment of nicotinamide has therapeutic potential and rescues BPA-mediated neuronal death and cognitive deficits by upregulating the PGC-1α and GFER-DRP1 link, thus balancing mitochondrial homeostasis.

Keywords:  Bisphenol-A; Cognition; DRP1; GFER; Hippocampus; Mitochondria; Nicotinamide; PGC-1α

DOI:  https://doi.org/10.1007/s12035-022-02862-y
Dev Cell. 2022 May 15. pii: S1534-5807(22)00306-9. [Epub ahead of print]

DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.

Barbara Pernaute, Salvador Pérez-Montero, Juan Miguel Sánchez Nieto, Aida Di Gregorio, Ana Lima, Katerina Lawlor, Sarah Bowling, Gianmaria Liccardi, Alejandra Tomás, Pascal Meier, Hiromi Sesaki, Guy A Rutter, Ivana Barbaric, Tristan A Rodríguez.

  The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response.

Keywords:  apoptosis; early development; embryonic stem cell differentiation; mitochondrial dynamics; mitophagy; pluripotency

DOI:  https://doi.org/10.1016/j.devcel.2022.04.020
J Neurochem. 2022 May 21.

Artesunate restores mitochondrial fusion-fission dynamics and alleviates neuronal injury in Alzheimer's disease models.

Yi-Ren Qin, Chi-Qian Ma, Jian-Hua Jiang, Da-Peng Wang, Quan-Quan Zhang, Mei-Rong Liu, Hong-Ru Zhao, Qi Fang, Yang Liu.

  Alzheimer's disease (AD) remains a leading cause of dementia and no therapy that reverses underlying neurodegeneration is available. Recent studies suggest the protective role of artemisinin, an antimalarial drug, in neurological disorders. In this study, we investigated the therapeutic potential of artesunate, a water-soluble derivative of artemisinin, on amyloid-beta (Aβ)-treated challenged microglial BV-2, neuronal N2a cells, and the amyloid precursor protein/presenilin (APP/PS1) mice model. We found that Aβ significantly induced multiple AD-related phenotypes, including increased expression/production of pro-inflammatory cytokines from microglial cells, enhanced cellular and mitochondrial production of reactive oxygen species, promoted mitochondrial fission, inhibited mitochondrial fusion, suppressed mitophagy or biogenesis in both cell types, stimulated apoptosis of neuronal cells, and microglia-induced killing of neurons. All these in vitro phenotypes were attenuated by artesunate. In addition, the over-expression of the mitochondrial fission protein Drp-1, or down-regulation of the mitochondrial fusion protein OPA-1 both reduced the therapeutic benefits of artesunate. Artesunate also alleviated AD phenotypes in APP/PS1 mice, reducing Aβ deposition, and reversing deficits in memory and learning. Artesunate protects neuronal and microglial cells from AD pathology, both in vitro and in vivo. Maintaining mitochondrial dynamics and simultaneously targeting multiple AD pathogenic mechanisms are associated with the protective effects of artesunate. Consequently, artesunate may become a promising therapeutic for AD.

Keywords:  Alzheimer's disease; artesunate; mitochondrial dynamics; mitophagy; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.1111/jnc.15620
Biochem Pharmacol. 2022 May 24. pii: S0006-2952(22)00200-3. [Epub ahead of print] 115106

Panax notoginseng saponin R1 attenuates allergic rhinitis through AMPK/Drp1 mediated mitochondrial fission.

Yalin Zhang, Yilan Song, Chongyang Wang, Jingzhi Jiang, Siqi Liu, Qiaoyun Bai, Liangchang Li, Hainan Jin, Yongde Jin, Guanghai Yan.

  We investigated whether panax notoginseng saponin (PNS-R1) attenuates allergic rhinitis (AR) through AMPK/Drp1-mediated mitochondrial fission. AR model was established in mice by ovalbumin (OVA). In vitro, human nasal epithelial cells (HNEpCs) were stimulated using recombinant human interleukin 13 (IL-13). PNS-R1 was administrated in vivo and in vitro. Then, HE staining of nasal tissue, ELISA detection of immunoglobulin E (IgE) and proinflammatory cytokine levels in serum and nasal lavage fluid, flow cytometry analysis of Th1/Th2 ratio and apoptosis, TUNEL staining, Western blot, detection of reactive oxygen species (ROS) and mitochondrial ROS, immunofluorescence analysis of Tom20 and mitochondrial fission protein Drp1 co-localization, and, mitochondrial membrane potential detection, were performed. PNS-R1 attenuated allergic symptoms in AR mice, decreased OVA-specific IgE, IL-4, IL-6, IL-8, IL-13, and TNF-α levels, and restored the Th1/Th2 imbalance. Meanwhile, we found that PNS-R1 treatment significantly reduced apoptosis, ROS production, and co-localization of Tom20 and Drp1 in the nasal epithelium of AR mice. In vitro, we found that PNS-R1 upregulated mitochondrial membrane potential and reduced ROS and mitochondrial ROS production as well as cleaved-caspase-3/9, Bax, Cyt-c, Apaf-1 expression and mitochondrial fission. Mechanistically, we found that PNS-R1 downregulated Drp1 phosphorylation (Ser 616) and Drp1 translocation in an AMPK-dependent manner, promoted MFN2 expression, and reduced TXNIP, NLRP3, caspase-1, and IL-1β expression. PNS-R1 may protect mitochondrial integrity by inhibiting AMPK/Drp1 and TXNIP/NLRP3 signaling pathway, thereby alleviating AR symptoms in mice. PNS-R1 may have great potential as a therapeutic agent for AR.

Keywords:  AMPK; Drp1; NLRP3; PNS-R1; TXNIP; mitochondrial fission

DOI:  https://doi.org/10.1016/j.bcp.2022.115106
J Cell Biochem. 2022 May 26.

Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina.

Verena Warnsmann, Lisa-Marie Marschall, Anja C Meeßen, Maike Wolters, Lea Schürmanns, Marion Basoglu, Stefan Eimer, Heinz D Osiewacz.

  Mitochondria are dynamic eukaryotic organelles involved in a variety of essential cellular processes including the generation of adenosine triphosphate (ATP) and reactive oxygen species as well as in the control of apoptosis and autophagy. Impairments of mitochondrial functions lead to aging and disease. Previous work with the ascomycete Podospora anserina demonstrated that mitochondrial morphotype as well as mitochondrial ultrastructure change during aging. The latter goes along with an age-dependent reorganization of the inner mitochondrial membrane leading to a change from lamellar cristae to vesicular structures. Particularly from studies with yeast, it is known that besides the F1 Fo -ATP-synthase and the phospholipid cardiolipin also the "mitochondrial contact site and cristae organizing system" (MICOS) complex, existing of the Mic60- and Mic10-subcomplex, is essential for proper cristae formation. In the present study, we aimed to understand the mechanistic basis of age-related changes in the mitochondrial ultrastructure. We observed that MICOS subunits are coregulated at the posttranscriptional level. This regulation partially depends on the mitochondrial iAAA-protease PaIAP. Most surprisingly, we made the counterintuitive observation that, despite the loss of lamellar cristae and of mitochondrial impairments, the ablation of MICOS subunits (except for PaMIC12) leads to a pronounced lifespan extension. Moreover, simultaneous ablation of subunits of both MICOS subcomplexes synergistically increases lifespan, providing formal genetic evidence that both subcomplexes affect lifespan by different and at least partially independent pathways. At the molecular level, we found that ablation of Mic10-subcomplex components leads to a mitohormesis-induced lifespan extension, while lifespan extension of Mic60-subcomplex mutants seems to be controlled by pathways involved in the control of phospholipid homeostasis. Overall, our data demonstrate that both MICOS subcomplexes have different functions and play distinct roles in the aging process of P. anserina.

Keywords:  MICOS; Podospora anserina; aging; cristae; mitochondria; mitohormesis

DOI:  https://doi.org/10.1002/jcb.30278
Chemosphere. 2022 May 20. pii: S0045-6535(22)01511-9. [Epub ahead of print]303(Pt 1): 135018

Battery wastewater induces nephrotoxicity via disordering the mitochondrial dynamics.

Jiangnan Yi, Jianzhao Liao, Tian Bai, Bole Wang, Chamba Yangzom, Zulfiqar Ahmed, Khalid Mehmood, Rao Zahid Abbas, Ying Li, Zhaoxin Tang, Hui Zhang.

  The rapid development of new energy battery enterprises manifolds the obsolete and scrapped batteries which are considered serious concern for the environment and ecology. Increasing trend of recycling batteries waste is public hazard throughout the world. The batteries wastes affect the various body systems but exact toxicological mechanism of battery wastewater is still unexplored. The present study was designed to observe the toxicological effects of batteries wastes on kidney functional dynamics. In this experiment, a total of 20 male mice were randomly divided into two groups including control and treatment (battery wastewater) group. The control group was provided the normal saline while the battery wastewater group were provided battery waste-water for a period of 21 days. The isolated kidneys were processed for histopathological analysis, biochemical assays, mRNA and protein estimation. The results showed that battery wastewater provision increased the mitochondrial division-related genes and proteins (Drp1, MFF, Fis1) and decreased the expression level of fusion-related nuclear proteins (MFN1, MFN2, OPA1) in kidneys. Moreover, the battery wastewater exposure significantly up-regulated the autophagy (PINK, Parkin, mTOR, ATG5, LC3-b, p62) and apoptosis (Bax, Cytc, APAF1, P53, Caspase3, Caspase8) related mRNA and proteins levels in kidneys. However, down-regulation of mRNA and proteins levels of Bcl2 and Beclin1 were also observed in kidneys after batteries wastes exposure. In conclusion, it is evident that the battery wastewater leads to renal apoptosis and autophagy by disrupting the mitochondrial dynamics in mice kidneys.

Keywords:  Apoptosis; Autophagy; Battery wastewater; Mitochondrial dynamics; Nephrotoxicity

DOI:  https://doi.org/10.1016/j.chemosphere.2022.135018
Phytother Res. 2022 May 27.

Cardioprotective effects of gypenoside XVII against ischemia/reperfusion injury: Role of endoplasmic reticulum stress, autophagy, and mitochondrial fusion fission balance.

Shijia Su, Jiarui Wang, Jing Wang, Ruili Yu, Likang Sun, Yue Zhang, Lei Song, Weiling Pu, Yi Tang, Yingli Yu, Kun Zhou.

  Gypenoside XVII (GP-17), a tetracyclic triterpene saponin isolated from the functional food Gynostemma pentaphyllum, has been demonstrated protective effects against cerebrovascular and cardiovascular diseases on multiple disease models. In this study, we established a myocardial infarction (MI) model by ligating the left anterior descending coronary artery, and explored whether GP-17 prevent myocardial ischemia/reperfusion (I/R) injuries in mice. Compared with the I/R group, GP-17 significantly improved the cardiac function, reduced the MI, decreased myocardial pathology, activated superoxide dismutase and catalase, and reduced the content of lactate dehydrogenase, creatine kinase, malondialdehyde, and inflammatory factor. The proteomic analysis showed multiple differential proteins between the GP-17 and I/R groups enriched in endoplasmic reticulum and mitochondria. Western-Blot showed that GP-17 significantly decreased the expression of GRP78, ATF6, CHOP, and phosphorylation of PERK, indicating the inhibition of ERS. GP-17 inhibited the expression of ATG5, LC3A/B, and BAX, illustrating the suppression of autophagy and apoptosis. Moreover, both GP-17 and 4-PBA could improve the downregulated Mfn2, meaning that inhibition of ERS regulated the mitochondrial fusion fission balance, thus protected the function of mitochondria. In conclusion, we found that GP-17 prevented against myocardial I/R injury by inhibit ERS-induced cell apoptosis, autophagy, oxidative stress, and mitochondrial division.

Keywords:  autophagy; endoplasmic reticulum stress; gypenoside XVII; ischemia/reperfusion; mitochondria; oxidative stress

DOI:  https://doi.org/10.1002/ptr.7493