bims-mikwok 2024-07-28 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒07‒28
25 papers selected by
Gavin McStay, Liverpool John Moores University

Germline regulation of the somatic mitochondrial stress response.
PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
Arginine methylation of DDX3 by PRMT1 mediates mitochondrial homeostasis to promote breast cancer metastasis.
BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.
Parkin, a Parkinson's disease-associated protein, mediates the mitophagy that plays a vital role in the pathophysiology of major depressive disorder.
Targeting cellular mitophagy as a strategy for human cancers.
ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse.
Ginsenoside Rb1 ameliorates heart failure through DUSP-1-TMBIM-6-mediated mitochondrial quality control and gut flora interactions.
Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.
Differential Effects of Three Medium-Chain Fatty Acids on Mitochondrial Quality Control and Skeletal Muscle Maturation.
Celastrol alleviates atopic dermatitis by regulating Ezrin-mediated mitochondrial fission and fusion.
Korean red ginseng alleviates benign prostatic hyperplasia by dysregulating androgen receptor signaling and inhibiting DRP1-mediated mitochondrial fission.
New sesquiterpenes and viridin derivatives from Penicillium sp. Ameliorates NAFLD by regulating the PINK1/Parkin mitophagy pathway.
Autophagy aggravates multi-walled carbon nanotube-induced ferroptosis by suppressing PGC-1 dependent-mitochondrial biogenesis in lung epithelial cells.
Diphenylbutadiene Fluorescent Analogues in Sub-cellular Imaging and Monitoring Mitophagy.
Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.
High levels of mitochondrial dynamics, autophagy, and apoptosis contribute to stable testicular status in hibernating Daurian ground squirrels.
Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
Nur77 improves ovarian function in reproductive aging mice by activating mitophagy and inhibiting apoptosis.
Enhanced glioma cell death with ZnO nanorod flowers and temozolomide combination therapy through autophagy and mitophagy pathways.
Epigallocatechin gallate attenuated high glucose-induced pancreatic beta cell dysfunction by modulating DRP1-mediated mitochondrial apoptosis pathways.
The Role of Polyphenols in Modulating Mitophagy: Implications for Therapeutic Interventions.
Mitochondrial inorganic polyphosphate is required to maintain proteostasis within the organelle.
Rhopaloic acid A triggers mitochondria damage-induced apoptosis in oral cancer by JNK/BNIP3/Nix-mediated mitophagy.
Amentoflavone regulates the miR-124-3p/CAPN2 axis to promote mitochondrial autophagy in HCC cells.

Trends Cell Biol. 2024 Jul 20. pii: S0962-8924(24)00142-9. [Epub ahead of print]

Germline regulation of the somatic mitochondrial stress response.

Liankui Zhou, Ying Liu.

  Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans.

Keywords:  UPR(mt); cell-nonautonomous; germline; mitochondria; stress response

DOI:  https://doi.org/10.1016/j.tcb.2024.07.004
Int J Mol Sci. 2024 Jul 15. pii: 7738. [Epub ahead of print]25(14):

PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.

Fedho Kusuma, Soyoung Park, Kim Anh Nguyen, Rosalie Elvira, Duckgue Lee, Jaeseok Han.

  Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPRMT), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPRMT induction in C. elegans, the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined. Here, we explored the role of protein kinase R (PKR), an eIF2α kinase activated by double-stranded RNAs (dsRNAs), in mitochondrial stress signaling. We found that UPRMT does not occur in cells lacking PKR, indicating its crucial role in this process. Mechanistically, we observed that dsRNAs accumulate within mitochondria under stress conditions, along with unprocessed mitochondrial transcripts. Furthermore, we demonstrated that accumulated mitochondrial dsRNAs in mouse embryonic fibroblasts (MEFs) deficient in the Bax/Bak channels are not released into the cytosol and do not induce the UPRMT upon mitochondrial stress, suggesting a potential role of the Bax/Bak channels in mediating the mitochondrial stress response. These discoveries enhance our understanding of how cells maintain mitochondrial integrity, respond to mitochondrial dysfunction, and communicate stress signals to the nucleus through retrograde signaling. This knowledge provides valuable insights into prospective therapeutic targets for diseases associated with mitochondrial stress.

Keywords:  PKR; UPRMT; integrated stress response; mitochondrial dsRNAs; mitochondrial stress

DOI:  https://doi.org/10.3390/ijms25147738
Cancer Res. 2024 Jul 23.

Arginine methylation of DDX3 by PRMT1 mediates mitochondrial homeostasis to promote breast cancer metastasis.

Wen-Jing Hsu, Ming-Chen Chiang, Yi-Chun Chao, Yu-Chu Chang, Ming-Chien Hsu, Chu-Hung Chung, I-Lin Tsai, Cheng-Ying Chu, Han-Chung Wu, Ching-Chieh Yang, Chi-Ching Lee, Cheng-Wei Lin.

Dysregulated mitochondrial dynamics and metabolism play important roles in tumorigenesis. Metastasizing tumor cells predominantly utilize mitochondrial metabolism, and regulators of metabolic reprogramming may provide reliable biomarkers for diagnosing cancer metastasis. Here, we identified a PRMT1-DDX3 axis that promotes breast cancer metastasis by coordinating mitochondrial biogenesis and mitophagy to ensure mitochondrial quality control. Mechanistically, PRMT1 induces arginine methylation of DDX3, which enhances its protein stability and prevents proteasomal degradation. DDX3 mediates mitochondrial homeostasis by translocating to mitochondria where it facilitates PINK1 translation in response to mitochondrial stress. Inhibition of DDX3 suppresses mitochondrial biogenesis and mitophagy, resulting in diminished cancer stemness and metastatic properties. Overall, this study uncovers a mechanism by which the PRMT1-DDX3 axis regulates mitochondrial homeostasis to support breast cancer metastasis, suggesting strategies for targeting metabolic vulnerabilities to treat metastatic breast cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3829
Brain. 2024 Jul 25. pii: awae241. [Epub ahead of print]

BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.

Yang Yang, Hui Chen, Shuwen Huang, Hao Chen, Alexei Verkhratsky, Jianqin Niu, Yibo Qu, Chenju Yi.

  Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer's disease (AD). Promoting mitophagy has been shown to improve cognitive function in AD animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in AD patients and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned AD-related changes. Our findings uncover a novel mechanism of BOK signaling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in AD, thus representing a promising therapeutic target.

Keywords:  amyloid-β; cognitive decline; mitochondrial dysfunction; mitophagy; synaptophysin loss

DOI:  https://doi.org/10.1093/brain/awae241
Neurochem Int. 2024 Jul 22. pii: S0197-0186(24)00135-9. [Epub ahead of print]179 105808

Parkin, a Parkinson's disease-associated protein, mediates the mitophagy that plays a vital role in the pathophysiology of major depressive disorder.

Yi Zhang.

  Depression is a complex mood disorder with multifactorial etiology and is also the most frequent non-motor symptom of Parkinson's disease. Emerging research suggests a potential link between mitochondrial dysfunction and the pathophysiology of major depressive disorder. By synthesizing current knowledge and research findings, this review sheds light on the intricate relationship between Parkin, a protein classically associated with Parkinson's disease, and mitochondrial quality control mechanisms (e.g., mitophagy, mitochondrial biogenesis, and mitochondrial dynamic), specifically focusing on their relevance in the context of depression. Additionally, the present review discusses therapeutic strategies targeting Parkin-medicated mitophagy and calls for further research in this field. These findings suggest promise for the development of novel depression treatments through modulating Parkin-mediated mitophagy.

Keywords:  Major depressive disorder; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Parkin

DOI:  https://doi.org/10.1016/j.neuint.2024.105808
Front Cell Dev Biol. 2024 ;12 1431968

Targeting cellular mitophagy as a strategy for human cancers.

Yuming Dong, Xue Zhang.

  Mitophagy is the cellular process to selectively eliminate dysfunctional mitochondria, governing the number and quality of mitochondria. Dysregulation of mitophagy may lead to the accumulation of damaged mitochondria, which plays an important role in the initiation and development of tumors. Mitophagy includes ubiquitin-dependent pathways mediated by PINK1/Parkin and non-ubiquitin dependent pathways mediated by mitochondrial autophagic receptors including NIX, BNIP3, and FUNDC1. Cellular mitophagy widely participates in multiple cellular process including metabolic reprogramming, anti-tumor immunity, ferroptosis, as well as the interaction between tumor cells and tumor-microenvironment. And cellular mitophagy also regulates tumor proliferation and metastasis, stemness, chemoresistance, resistance to targeted therapy and radiotherapy. In this review, we summarized the underlying molecular mechanisms of mitophagy and discussed the complex role of mitophagy in diverse contexts of tumors, indicating it as a promising target in the mitophagy-related anti-tumor therapy.

Keywords:  PINK1; cancer; mitochondria; mitophagy; stemness

DOI:  https://doi.org/10.3389/fcell.2024.1431968
J Neurosci. 2024 Jul 25. pii: e0879242024. [Epub ahead of print]

ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse.

Hiu-Tung C Wong, Angelica E Lang, Chris Stein, Catherine M Drerup.

Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can function to facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial fission and fusion dynamics. VapB is an ER membrane protein present at a subset of ER-mitochondria contact sites. Mutations in VapB cause neurodegenerative disease. Specifically, a proline-to-serine mutation at amino acid 56 (P56S), correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrate that transgenic expression of VapBP56S in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis in zebrafish neurons, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapBP56S transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondria tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.Significance statement Mitochondrial population dysfunction is tightly tied to neurodegenerative diseases, including ALS. Maintenance of the mitochondrial population in neurons requires the birth of new mitochondria and the degradation of damaged organelles. ER-mitochondrial contact site proteins are in a position to regulate both processes in neurons. Our work demonstrates that an ALS-associated mutation in the contact site protein VapB disrupts both processes, identifying VapB as a mediator of regulated mitochondrial turnover to maintain a steady-state mitochondrial population.

DOI: https://doi.org/10.1523/JNEUROSCI.0879-24.2024
Phytomedicine. 2024 Jul 20. pii: S0944-7113(24)00538-5. [Epub ahead of print]132 155880

Ginsenoside Rb1 ameliorates heart failure through DUSP-1-TMBIM-6-mediated mitochondrial quality control and gut flora interactions.

Xiangyi Pu, Qin Zhang, Jinfeng Liu, Yanli Wang, Xuanke Guan, Qiaomin Wu, Zhiming Liu, Ruxiu Liu, Xing Chang.

  BACKGROUND: There is currently no specific therapeutic drug available for heart failure in clinical practice. Numerous studies have validated the efficacy of Ginsenoside Rb1, an active component found in various herbal remedies used for heart failure treatment, in effectively ameliorating myocardial ischemia. However, the precise mechanism of action and molecular targets of Ginsenoside Rb1 remain unclear.PURPOSE: This study aims to explore the molecular mechanisms through which Ginsenoside Rb1 synergistically modulates the gut flora and mitochondrial quality control network in heart failure by targeting the DUSP-1-TMBIM-6-VDAC1 axis.
STUDY DESIGN: This study utilized DUSP-1/VDAC1 knockout (DUSP-1-/-/VDAC1-/-) and DUSP-1/VDAC1 transgenic (DUSP-1+/+/VDAC1+/+) mouse models of heart failure, established through Transverse Aortic Constriction (TAC) surgery and genetic modification techniques. The mice were subsequently subjected to treatment with Ginsenoside Rb1.
METHODS: A series of follow-up multi-omics analyses were conducted, including assessments of intestinal flora, gene transcription sequencing, single-cell databases, and molecular biology assays of primary cardiomyocytes, to investigate the mechanism of action of Ginsenoside Rb1.
RESULTS: Ginsenoside Rb1 was found to have multiple regulatory mechanisms on mitochondria. Notably, DUSP-1 was discovered to be a crucial molecular target of Ginsenoside Rb1, controlling both intestinal flora and mitochondrial function. The regulatory effects of DUSP-1 on inflammation and mitochondrial quality control were mediated by changes in TMBIM-6 and VDAC1. Furthermore, NLRP3-mediated inflammatory responses were found to interact with mitochondrial quality control, exacerbating myocardial injury under stress conditions. Ginsenoside Rb1 modulated the DUSP-1-TMBIM-6-VDAC1 axis, inhibited the release of pro-inflammatory factors, altered the structural composition of the gut flora, and protected impaired heart function. These effects indirectly influenced the crosstalk between inflammation, mitochondria, and gut flora.
CONCLUSION: The DUSP-1-TMBIM-6-VDAC1 axis, an upstream pathway regulated by Ginsenoside Rb1, is a profound mechanism through which Ginsenoside Rb1 improves cardiac function in heart failure by modulating inflammation, mitochondria, and gut flora.

Keywords:  Cellular pyroptosis; DUSP-1; Ginsenoside Rb1; Intestinal flora; Mitochondrial quality control; TMBIM-6-VDAC1

DOI:  https://doi.org/10.1016/j.phymed.2024.155880
Autophagy. 2024 Jul 25.

Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.

Juan Yi, He-Ling Wang, Guang Lu, Hailong Zhang, Lina Wang, Zhen-Yu Li, Liming Wang, Yihua Wu, Dajing Xia, Evandro F Fang, Han-Ming Shen.

  Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Caenorhabditis elegans (C. elegans) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) C. elegans model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.

Keywords:  Alzheimer’s disease; PINK1; TOMM complex; autophagy; mitophagy; spautin-1

DOI:  https://doi.org/10.1080/15548627.2024.2383145
Antioxidants (Basel). 2024 Jul 09. pii: 821. [Epub ahead of print]13(7):

Differential Effects of Three Medium-Chain Fatty Acids on Mitochondrial Quality Control and Skeletal Muscle Maturation.

Ryoichi Nishida, Shota Nukaga, Isao Kawahara, Yoshihiro Miyagawa, Kei Goto, Chie Nakashima, Yi Luo, Takamitsu Sasaki, Kiyomu Fujii, Hitoshi Ohmori, Ruiko Ogata, Shiori Mori, Rina Fujiwara-Tani, Hiroki Kuniyasu.

  Nutritional interventions are one focus of sarcopenia treatment. As medium-chain fatty acids (MCFAs) are oxidized in the mitochondria and produce energy through oxidative phosphorylation (OXPHOS), they are key parts of nutritional interventions. We investigated the in vitro effects of three types of MCFA, caprylic acid (C8), capric acid (C10), and lauric acid (C12), in skeletal muscle cells. Compared with C10 and C12, C8 promoted mitophagy through the phosphatase and tensin homolog (PTEN)-induced kinase 1-Parkin pathway and increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-α and dynamin-related protein 1 to reduce mitochondrial oxidative stress and promote OXPHOS. Furthermore, the expression of myogenic differentiation 1 and myosin heavy chain increased in myotubes, thus promoting muscle differentiation and maturation. These results suggest that C8 improves mitochondrial quality and promotes skeletal muscle maturation; in contrast, C10 and C12 poorly promoted mitochondrial quality control and oxidative stress and suppressed energy production. Future animal experiments are required to establish the usefulness of C8 for nutritional interventions for sarcopenia.

Keywords:  medium-chain fatty acids; mitochondrial quality control; mitophagy; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.3390/antiox13070821
J Cell Mol Med. 2024 Jul;28(14): e18375

Celastrol alleviates atopic dermatitis by regulating Ezrin-mediated mitochondrial fission and fusion.

Dandan Wang, Shan Jin, Hanye Liu, Xinyi Song, Hongyu Jin, Yilan Song, Hongwei Zhao, Liangchang Li, Guanghai Yan.

  Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1β, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.

Keywords:  Drp1; atopic dermatitis; celastrol; ezrin; mitochondrial fission and fusion

DOI:  https://doi.org/10.1111/jcmm.18375
Chin J Nat Med. 2024 Jul;pii: S1875-5364(24)60671-0. [Epub ahead of print]22(7): 599-607

Korean red ginseng alleviates benign prostatic hyperplasia by dysregulating androgen receptor signaling and inhibiting DRP1-mediated mitochondrial fission.

Geum-Lan Hong, Kyung-Hyun Kim, Sung-Pil Cho, Hui-Ju Lee, Yae-Ji Kim, Ju-Young Jung.

  Panax ginseng (C.A. Mey.) has been traditionally employed in Korea and China to alleviate fatigue and digestive disorders. In particular, Korean red ginseng (KRG), derived from streamed and dried P. ginseng, is known for its anti-aging and anti-inflammatory properties. However, its effects on benign prostatic hyperplasia (BPH), a representative aging-related disease, and the underlying mechanisms remain unclear. This study aims to elucidate the therapeutic effects of KRG on BPH, with a particular focus on mitochondrial dynamics, including fission and fusion processes. The effects of KRG on cell proliferation, apoptosis, and mitochondrial dynamics and morphology were evaluated in a rat model of testosterone propionate (TP)-induced BPH and TP-treated LNCaP cells, with mdivi-1 as a control. The results revealed that KRG treatment reduced the levels of androgen receptors (AR) and prostate-specific antigens in the BPH group. KRG inhibited cell proliferation by downregulating cyclin D and proliferating cell nuclear antigen (PCNA) levels, and it promoted apoptosis by increasing the ratio of B-cell lymphoma protein 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 expression. Notably, KRG treatment enhanced the phosphorylation of dynamin-related protein 1 (DRP-1, serine 637) compared with that in the BPH group, which inhibited mitochondrial fission and led to mitochondrial elongation. This modulation of mitochondrial dynamics was associated with decreased cell proliferation and increased apoptosis. By dysregulating AR signaling and inhibiting mitochondrial fission through enhanced DRP-1 (ser637) phosphorylation, KRG effectively reduced cell proliferation and induced apoptosis. These findings suggest that KRG's regulation of mitochondrial dynamics offers a promising clinical approach for the treatment of BPH.

Keywords:  Androgen; Benign prostatic hyperplasia; Fission; Korean red ginseng; Mitochondria

DOI:  https://doi.org/10.1016/S1875-5364(24)60671-0
Bioorg Chem. 2024 Jul 16. pii: S0045-2068(24)00561-3. [Epub ahead of print]151 107656

New sesquiterpenes and viridin derivatives from Penicillium sp. Ameliorates NAFLD by regulating the PINK1/Parkin mitophagy pathway.

Hang Zhang, Yanting You, Jingyang Xu, Haimei Jiang, Jinyan Jiang, Zijie Su, Zhi Chao, Qingfeng Du, Fei He.

  Fungi from the plant rhizosphere microbiome are considered an important source of bioactive novel natural compounds. In this study, three new sesquiterpenes, penisterpenoids A-C (1-3), and three new viridin derivatives, peniviridiols A-C (4-6), along with twenty one known compounds (7-27), were isolated from the rhizosphere fungus Penicillium sp. SMU0102 of medicinal plant Bupleurum chinense DC. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1-6 were determined by experimental and calculated ECD spectra, DP4 + probability analysis, modified Mosher's method, and X-ray crystallography. All new compounds were screened for their cytotoxic and lipid-lowering activities in vitro. Among them, compound 1 (20 μM) remarkably alleviated lipid accumulation both in FFA-induced LO2 cells and TAA-induced zebrafish NAFLD models. Furthermore, compound 1 enhanced ATP production and mitochondrial membrane potential (MMP), suppressed reactive oxygen species (ROS) formation, restored mitochondrial structure, and induced autophagosome formation. Moreover, compound 1 significantly upregulated the expression of representative proteins for the mitochondrial homeostasis, including OPA1, DRP1, MFF, and Fis1, as well as mitophagy representative proteins PINK1, Parkin, and P62. Further mechanistic investigations indicated that compound 1 primarily alleviated lipid accumulation through selective activation of the PINK1/Parkin mitophagy signaling pathway.

Keywords:  Absolute configurations; Mitochondria; Mitophagy; NAFLD; Sesquiterpene; Viridian

DOI:  https://doi.org/10.1016/j.bioorg.2024.107656
Chem Biol Interact. 2024 Jul 19. pii: S0009-2797(24)00304-1. [Epub ahead of print]400 111158

Autophagy aggravates multi-walled carbon nanotube-induced ferroptosis by suppressing PGC-1 dependent-mitochondrial biogenesis in lung epithelial cells.

Lin Zhu, Deyu Zhu, Jiahui Ran, Maojie Li, Zhebin Lai, Yan Zhou, Lei Luo, Xiliang Liu, Kanmin Mao, Kunming Tian.

  Multi-walled carbon nanotube (MWCNT) induced respiratory toxicity has become a growing concern, with ferroptosis emerging as a novel mechanism implicated in various respiratory diseases. However, whether ferroptosis is involved in MWCNT-elicited lung injury and the underlying molecular mechanisms warrant further exploration. In this study, we found that MWCNT-induced ferroptosis is autophagy-dependent, contributing to its cellular toxicity. Inhibiting of autophagy by pharmacological inhibitors 3-MA or ATG5 gene knockdown significantly attenuated MWCNT-induced ferroptosis, concomitant with rescued mitochondrial biogenesis. Rapamycin, the autophagy agonist, exacerbated the mitochondrial damage and MWCNT-induced ferroptosis. Moreover, lentivirus-mediated overexpression of PGC-1α inhibited ferroptosis, while inhibition of PGC-1α aggravated ferroptosis. In summary, our study unveils ferroptosis as a novel mechanism underlying MWCNT-induced respiratory toxicity, with autophagy promoting MWCNT-induced ferroptosis by hindering PGC-1α-dependent mitochondrial biogenesis.

Keywords:  Autophagy; BEAS-2B cells; Ferroptosis; Mitochondria biogenesis; Multi-walled carbon nanotube

DOI:  https://doi.org/10.1016/j.cbi.2024.111158
Chem Asian J. 2024 Jul 25. e202400600

Diphenylbutadiene Fluorescent Analogues in Sub-cellular Imaging and Monitoring Mitophagy.

Mohini Ghorpade, Abdulkhalik Mansuri, Ashutosh Kumar, Sriram Kanvah.

  A series of donor-acceptor (D-π-A) substituted diphenylbutadienes exhibiting solvatochromic emission and a large Stokes shift (100-200 nm) were designed and synthesized for distinctive organelle labelling, enabling real-time monitoring of organelle behaviour such as lysosomal dynamics, mitophagy monitoring, and stress responses. The morpholine-substituted D-A-D diphenylbutadiene (M2) was employed to investigate selective imaging of lysosomes, the uptake of damaged mitochondria through mitophagy, and monitoring lysosomal viscosity or pH changes. Other diphenylbutadiene derivatives (M1, M3, M4) selectively accumulated in lipid droplets. All the synthesized derivatives demonstrated significant uptake in 5-day post-fertilization zebrafish larvae, with M2 showing maximum uptake in the enterocyte-containing heart and intestinal regions, which include the lysosomes.

Keywords:  Fluorescence Microscopy; Live-Cell Imaging; Mitophagy; Zebrafish; diarylbutadienes

DOI:  https://doi.org/10.1002/asia.202400600
iScience. 2024 Jul 19. 27(7): 110280

Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.

Yan-Dong Sun, Qing-Guo Xu, De-Shu Dai, Shu-Xian Wang, Xin-Qiang Li, Shang-Heng Shi, Peng Jiang, Yan Jin, Xin Wang, Yong Zhang, Feng Wang, Peng Liu, Bing-Liang Zhang, Tian-Xiang Li, Chuan-Shen Xu, Bin Wu, Jin-Zhen Cai.

  Hepatic ischemia-reperfusion (IR) injury significantly impacts liver transplantation success, yet current treatments remain inadequate. This study explores the role of Proto-oncogene serine/threonine-protein kinase (Pim-1) in liver IR, an area previously unexplored. Utilizing a mouse liver IR in vivo model and a MIHA cell hypoxia-reoxygenation in vitro model, we observed that Pim-1 expression increases following IR, inversely correlating with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased Pim-1 expression stabilizes mitochondrial membranes by modifying Drp1 phosphorylation, reducing mitochondrial fission and apoptosis, thereby mitigating liver damage. Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.

Keywords:  Cellular physiology; Endocrinology

DOI:  https://doi.org/10.1016/j.isci.2024.110280
Comp Biochem Physiol A Mol Integr Physiol. 2024 Jul 20. pii: S1095-6433(24)00132-6. [Epub ahead of print]297 111705

High levels of mitochondrial dynamics, autophagy, and apoptosis contribute to stable testicular status in hibernating Daurian ground squirrels.

Zhe Wang, Ming-Di Wang, Xing-Chen Wang, Le Chen, Lu-Fan Li, Li-Na Jiang, Jin-Hui Xu, Kai Dang.

  Daurian ground squirrels (Spermophilus dauricus) experience various stress states during winter hibernation, but the impact on testicular function remains unclear. This study focused on the effects of changes in testicular autophagy, apoptosis, and mitochondrial homeostasis signaling pathways at various stages on the testes of Daurian ground squirrels. Results indicated that: (1) During winter hibernation, there was a significant increase in seminiferous tubule diameter and seminiferous epithelium thickness compared to summer. Spermatogonia number and testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were higher during inter-bout arousal, suggesting that the testes remained stable during hibernation. (2) An increased number of mitochondria with intact morphology were observed during hibernation, indicating that mitochondrial homeostasis may contribute to testicular stability. (3) DNA fragmentation was evident in the testes during the hibernation and inter-bout arousal stages, with the highest level of caspase3 enzyme activity detected during inter-bout arousal, together with elevated levels of Bax/Bcl-2 and Lc3 II/Lc3 I, indicating an up-regulation of apoptosis and autophagy signaling pathways during hibernation. (4) The abundance of DRP1, MFF, OPA1, and MFN2 proteins was increased, suggesting an up-regulation of mitochondrial dynamics-related pathways. Overall, testicular autophagy, apoptosis, and mitochondrial homeostasis-related signaling pathways were notably active in the extreme winter environment. The well-maintained mitochondrial morphology may favor the production of reproductive hormones and support stable testicular morphology.

Keywords:  Apoptosis; Autophagy; Hibernation; Spermophilus dauricus; Testis

DOI:  https://doi.org/10.1016/j.cbpa.2024.111705
Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595

Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.

Antigoni Diokmetzidou, Luca Scorrano.

In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.

DOI: https://doi.org/10.1016/j.molcel.2024.06.035
Reprod Biol Endocrinol. 2024 Jul 23. 22(1): 86

Nur77 improves ovarian function in reproductive aging mice by activating mitophagy and inhibiting apoptosis.

Ying Yao, Bin Wang, Kaihua Yu, Ji Song, Liyan Wang, Xuehong Zhang, Yulan Li.

  Reproductive aging not only affects the fertility and physical and mental health of women but also accelerates the aging process of other organs. There is an urgent need newfor novel mechanisms, targets, and drugs to break the vicious cycle of mitochondrial dysfunction, redox imbalance, and germ cell apoptosis associated with ovarian aging. Autophagy, recognized as a longevity mechanism, has recently become a focal point in anti-aging research. Although mitophagy is a type of autophagy, its role and regulatory mechanisms in ovarian aging, particularly in age-related ovarian function decline, remain unclear. Nerve growth factor inducible gene B (Nur77) is an early response gene that can be stimulated by oxidative stress, DNA damage, metabolism, and inflammation. Recent evidence recommends that decreased expression of Nur77 is associated with age-related myocardial fibrosis, renal dysfunction, and Parkinson's disease; however, its association with ovarian aging has not been studied yet. We herein identified Nur77 as a regulator of germ cell senescence, apoptosis, and mitophagy and found that overexpression of Nur77 can activate mitophagy, improve oxidative stress, reduce apoptosis, and ultimately enhance ovarian reserve in aged mice ovaries. Furthermore, we discovered an association between Nur77 and the AKT pathway through String and molecular docking analyses. Experimental confirmation revealed that the AKT/mTOR signaling pathway is involved in the regulation of Nur77 in ovarian function. In conclusion, our results suggest Nur77 as a promising target for preventing and treating ovarian function decline related to reproductive aging.

Keywords:  Aging; Apoptosis; Granulosa cells; Mitophagy; Nur77; PINK1/Parkin

DOI:  https://doi.org/10.1186/s12958-024-01250-6
Biomed Pharmacother. 2024 Jul 23. pii: S0753-3322(24)01033-3. [Epub ahead of print]178 117149

Enhanced glioma cell death with ZnO nanorod flowers and temozolomide combination therapy through autophagy and mitophagy pathways.

Yuanyuan Li, Yonghua Ma, Jingjing Li, Yan Lu, Haiying Liu, Min Gao, Junqin Cao.

  In recent years, the application of engineered NMts has significantly contributed to various biomedical fields. ZnO NMts (ZnO NMts) are widely utilized due to their biocompatibility, unique physical and chemical properties, stability, and cost-effectiveness for large-scale production. They have emerged as potential materials for anti-cancer applications. This study aims to study the impact of ZnO Nanorod flowers (ZnO NRfs) and their combination with temozolomide (TMZ) on glioma cells. Normal mouse microglia (BV2) will be used as a control to assess the effects on mouse glioma cells (G422) and human glioma cells (LN229). The effects of these substances were evaluated on G422 and LN229 cells through various parameters such as IC50 value, Zn2+ accumulation, ROS production, apoptosis, mitochondrial membrane potential (MMP) depolarization, and examination of organelles like mitochondria and lysosomes. Additionally, hypoxia-inducible factor-1α (HIF-1α), endothelial cell PAS domain protein 1 (EPAS1), autophagy markers (LC3), mitophagy and phagocytosis marker (BNIP3) were assessed. The results demonstrated that the combination of ZnO NRfs and TMZ could influence the expression of HIF-1α, EPAS1, LC3, and BNIP3 proteins, leading to mitophagy in glioma cells. This combination treatment has the potential to effectively eliminate glioma cells by activating the mitophagy pathway, which provides a good prospect for the clinical treatment of glioma.

Keywords:  Apoptosis; Autophagy; Glioma; Mitophagy; Temozolomide; ZnO nanorod flowers

DOI:  https://doi.org/10.1016/j.biopha.2024.117149
Sci Rep. 2024 Jul 22. 14(1): 16809

Epigallocatechin gallate attenuated high glucose-induced pancreatic beta cell dysfunction by modulating DRP1-mediated mitochondrial apoptosis pathways.

Xu Jia, Danting Mao, Jianwei Guo, Jiangyu Ke, Yanlin Zhu, Xiaoyang Zhao, Ziren Luo, Xinghai Liu, Rui Tang, Ruihan Hou, Haitao Lan, Qian Zheng.

  Long-term exposure to hyperglycemic conditions leads to β-cell dysfunction, particularly mitochondrial dysfunction, and inflammatory and oxidative stress responses, which are considered the primary causes of β-cell death and the hallmarks of diabetes. Plant-active ingredients may play a key role in glycemic control. Epigallocatechin gallate (EGCG) is a characteristic catechin derived from tea that possesses anti-diabetic properties. Nonetheless, its underlying mechanisms remain elusive. Herein, the protective role of EGCG on high glucose (33 mM)-induced pancreatic beta cell dysfunction and its possible molecular mechanisms were investigated. Briefly, MIN6 cells were treated with glucose and EGCG (10 µM, 20 µM, and 40 µM) for 48 h. Our results revealed that EGCG dose-dependently restored mitochondrial membrane potential and concomitantly alleviated cell apoptosis. Mechanistically, the expression level of apoptotic protein BAX and Dynamic related protein 1 (DRP1) was significantly downregulated following EGCG treatment, whereas that of the anti-apoptotic protein BCL-2 was significantly upregulated. Taken together, EGCG alleviated high glucose-induced pancreatic beta cell dysfunction by targeting the DRP1-related mitochondrial apoptosis pathway and thus can serve as a nutritional intervention for the preservation of beta cell dysfunction in patients with type 2 diabetes mellitus.

Keywords:  Diabetes; Dynamic related protein1; Epigollatecatechin gallate; Mitochondrial apoptosis; β-cells

DOI:  https://doi.org/10.1038/s41598-024-67867-0
Pharmacol Res. 2024 Jul 24. pii: S1043-6618(24)00269-X. [Epub ahead of print] 107324

The Role of Polyphenols in Modulating Mitophagy: Implications for Therapeutic Interventions.

Xinyu Lin, Wenkai Liu, Xizhuo Hu, Zhiqiang Liu, Fang Wang, Jinlian Wang.

  This review rigorously assesses the burgeoning research into the role of polyphenols in modulating mitophagy, an essential cellular mechanism for the targeted removal of impaired mitochondria. These natural compounds, known for their low toxicity, are underscored for their potential in therapeutic strategies against a diverse array of diseases, such as neurodegenerative, cardiovascular, and musculoskeletal disorders. The analysis penetrates deeply into the molecular mechanisms whereby polyphenols promote mitophagy, particularly by influencing crucial signaling pathways and transcriptional regulators, including the phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/parkin and forkhead box O3 (FOXO3a) pathways. Noteworthy discoveries include the neuroprotective properties of resveratrol and curcumin, which affect both autophagic pathways and mitochondrial dynamics, and the pioneering integration of polyphenols with other natural substances to amplify therapeutic effectiveness. Furthermore, the review confronts the issue of polyphenol bioavailability and emphasizes the imperative for clinical trials to corroborate their therapeutic viability. By delivering an exhaustive synthesis of contemporary insights and recent advancements in polyphenol and mitophagy research, this review endeavors to catalyze additional research and foster the creation of innovative therapeutic modalities that exploit the distinctive attributes of polyphenols to manage and prevent disease.

Keywords:  Mitophagy; Natural products; Polyphenols; Signaling pathways; Therapeutic interventions

DOI:  https://doi.org/10.1016/j.phrs.2024.107324
Front Cell Dev Biol. 2024 ;12 1423208

Mitochondrial inorganic polyphosphate is required to maintain proteostasis within the organelle.

Renata T Da Costa, Pedro Urquiza, Matheus M Perez, YunGuang Du, Mei Li Khong, Haiyan Zheng, Mariona Guitart-Mampel, Pia A Elustondo, Ernest R Scoma, Vedangi Hambardikar, Beatrix Ueberheide, Julian A Tanner, Alejandro Cohen, Evgeny V Pavlov, Cole M Haynes, Maria E Solesio.

  The existing literature points towards the presence of robust mitochondrial mechanisms aimed at mitigating protein dyshomeostasis within the organelle. However, the precise molecular composition of these mechanisms remains unclear. Our data show that inorganic polyphosphate (polyP), a polymer well-conserved throughout evolution, is a component of these mechanisms. In mammals, mitochondria exhibit a significant abundance of polyP, and both our research and that of others have already highlighted its potent regulatory effect on bioenergetics. Given the intimate connection between energy metabolism and protein homeostasis, the involvement of polyP in proteostasis has also been demonstrated in several organisms. For example, polyP is a bacterial primordial chaperone, and its role in amyloidogenesis has already been established. Here, using mammalian models, our study reveals that the depletion of mitochondrial polyP leads to increased protein aggregation within the organelle, following stress exposure. Furthermore, mitochondrial polyP is able to bind to proteins, and these proteins differ under control and stress conditions. The depletion of mitochondrial polyP significantly affects the proteome under both control and stress conditions, while also exerting regulatory control over gene expression. Our findings suggest that mitochondrial polyP is a previously unrecognized, and potent component of mitochondrial proteostasis.

Keywords:  mitochondria; mitochondrial inorganic polyphosphate; polyP; protein homeostasis; proteostasis

DOI:  https://doi.org/10.3389/fcell.2024.1423208
Phytomedicine. 2024 Jul 04. pii: S0944-7113(24)00513-0. [Epub ahead of print]132 155855

Rhopaloic acid A triggers mitochondria damage-induced apoptosis in oral cancer by JNK/BNIP3/Nix-mediated mitophagy.

Wu-Fu Chen, Sheng-Chieh Tsai, Ya-Hui Zhang, Hui-Min Chang, Wan-Ju Wu, Jui-Hsin Su, Bin-Nan Wu, Chung-Yi Chen, Mei-Ying Lin, Hsien-Lin Chen, Chien-Hsing Lee.

  BACKGROUND: Oral squamous cell carcinoma (OSCC) is a frequently occurring type of head and neck cancer with a high mortality and morbidity rate. Rhopaloic acid A (RA), a terpenoid derived from sponges, has demonstrated a promising anti-tumor activity, but its effectiveness for treating OSCC remains unknown.PURPOSE: The aim of this study was to investigate whether RA inhibits the growth of OSCC.
METHODS: Cell viability was evaluated using CCK-8 assays in OSCC cells (Ca9-22, HSC-3 and SAS) and in normal cells (HGF-1) treated with RA. DAPI staining, AO staining, JC-1 staining and immunofluorescence were used to determine apoptosis, mitochondrial membrane potential and autophagy in RA-treated OSCC cells. Protein expression levels were determined by western blotting. Furthermore, the anti-tumor effect of RA was confirmed in vivo using a zebrafish oral cancer xenotransplantation model.
RESULTS: OSCC cells had a significantly reduced viability after RA treatment, but normal cells were not affected. Treatment with RA caused chromatin condensation in OSCC cells, which increased their expression of autophagy- and apoptosis-related proteins. Furthermore, RA caused mitochondrial damage and increased autophagosome formation. Mitophagy was also induced by RA through the JNK/BNIP3/Nix/LC3B pathway. The JNK inhibitor SP600125 prevented both RA-mediated cell death and mitophagy of OSCC cells. A zebrafish xenograft model demonstrated that RA inhibits OSCC growth.
CONCLUSION: In conclusion, RA showed a potent anticancer activity in in vitro and in in vivo oral cancer models by promoting mitochondrial damage-induced apoptosis and mitophagy, which suggests that RA may be useful as a novel and effective treatment for OSCC.

Keywords:  Apoptosis; Mitophagy; Oral squamous cell carcinoma

DOI:  https://doi.org/10.1016/j.phymed.2024.155855
Toxicol Res (Camb). 2024 Aug;13(4): tfae110

Amentoflavone regulates the miR-124-3p/CAPN2 axis to promote mitochondrial autophagy in HCC cells.

Fengting Zhu, Jingwen Jiang, Xuewu Chen, Lei Fu, Hui Liu, Hui Zhang.

  BACKGROUND: Hepatocellular carcinoma (HCC) is a disease with poor prognosis and high mortality. Amentoflavone (AF) possesses the characteristics of marginal toxicity, stable curative effect, and good anti-HCC activity. This study aimed to evaluate the molecular mechanism of AF inhibiting HCC and provide a new idea for HCC treatment.METHODS: Clinical tissue of HCC was collected. AF was given with HCC cells, and transfected with corresponding vectors. MiR-124-3p expression in HCC clinical samples and cells was ascertained by qRT-PCR assay. HCC cells viability was identified by CCK-8 assay. LC3 protein expression was ascertained by immunofluorescence assay. The expressions of CAPN2, β-catenin and mitochondrial autophagy-related proteins were detected by western blot. Dual-luciferase reporter gene assay confirmed the targeting relationship of miR-124-3p and CAPN2.
RESULTS: MiR-124-3p expression was inhibited and CAPN2 expression was increased in HCC tissues and cells. AF decreased HCC cell viability, up-regulated miR-124-3p expression, and inhibited CAPN2 expression and β-catenin nuclear transcription. Moreover, AF could activate the mitochondrial autophagy of HCC cells. MiR-124-3p specifically regulated CAPN2 expression. This study found that CAPN2 could promote β-catenin nuclear translocation, thus activating wnt/β-catenin pathway to inhibit mitochondrial autophagy in HCC cells. MiR-124-3p mimics enhanced AF function in promoting mitochondrial autophagy in HCC cells. However, CAPN2 overexpression, miR-124-3p inhibitor and SKL2001 attenuated the effectiveness of AF.
CONCLUSION: This study confirmed that AF regulated miR-124-3p/CAPN2 axis to restraint β-catenin nuclear translocation and then inhibit the wnt/β-catenin pathway, thereby promoting mitochondrial autophagy in HCC.

Keywords:  Amentoflavone; CAPN2; hepatocellular carcinoma; miR-124-3p; mitochondrial autophagy

DOI:  https://doi.org/10.1093/toxres/tfae110