bims-mikwok 2024-12-08 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–12–08
34 papers selected by
Gavin McStay, Liverpool John Moores University

Enhancement of Mitochondrial Homeostasis: A Novel Approach to Attenuate Hypoxic Myocardial Injury.
Mitophagy in gynecological malignancies: roles, advances, and therapeutic potential.
SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia.
Protective effect of astragaloside IV against zinc oxide nanoparticles induced human neuroblastoma SH-SY5Y cell death: a focus on mitochondrial quality control.
Mito-TEMPO Ameliorates Sodium Palmitate Induced Ferroptosis in MIN6 Cells through PINK1/Parkin-Mediated Mitophagy.
Correction to: Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells.
Cyclovirobuxine D inhibits triple-negative breast cancer via YAP/TAZ suppression and activation of the FOXO3a/PINK1-Parkin pathway-induced mitophagy.
Structural Basis for the Pathogenicity of Parkin Catalytic Domain Mutants.
The role of HIF-1α/Bnip3/mitophagy in acrylonitrile-induced neuronal death in HT22 cells and mice: a potential neuroprotection target.
The Mitochondrial Fusion Promoter M1 Mitigates Cigarette Smoke-Induced Airway Inflammation and Oxidative Stress via the PI3K-AKT Signaling Pathway.
Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation.
The Role and Applied Value of Mitochondria in Glioma-Related Research.
OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.
MAM-mediated mitophagy and endoplasmic reticulum stress: the hidden regulators of ischemic stroke.
Remote ischemic preconditioning plays a neuroprotective role in cerebral ischemia-reperfusion mice by inhibiting mitophagy.
Rebalance of mitophagy by inhibiting LRRK2 improves colon alterations in an MPTP in vivo model.
5'tiRNA-33-CysACA-1 promotes septic cardiomyopathy by targeting PGC-1α-mediated mitochondrial biogenesis.
Pink1/Parkin signaling mediates pineal mitochondrial autophagy dysfunction and its biological role in a comorbid rat model of depression and insomnia.
Loss of PTPN21 disrupted mitochondrial metabolic homeostasis and aggravated experimental pulmonary fibrosis.
Macrophage S1PR2 Drives Sepsis-induced Immunosuppression by Exacerbating Mitochondrial Fragmentation.
Comparative mitochondrial proteomic: PGAM5-mediated necroptosis through excessive mitophagy in sheep livers under molybdenum and cadmium co-exposure.
OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase.
5-Methoxytryptophan Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Regulating Nrf2-Mediated Mitophagy.
Coordination of cytochrome bc1 complex assembly at MICOS.
Ischemic Stroke Induces ROS Accumulation, Maladaptive Mitophagy, and Neuronal Apoptosis in Minipigs.
Sonoactivated Z-Scheme Heterojunction for Enhanced Sonodynamic Mitophagy Inhibition and Triple Negative Breast Cancer Treatment.
Allogeneic platelet lysate activates the SIRT1-PINK1/Parkin pathway: A promising approach for improving mitochondrial function in an in vitro model of intervertebral disc degeneration.
Mitochondria-based holistic 3PM approach as the 'game-changer' for individualised rehabilitation-the proof-of-principle model by treated breast cancer survivors.
DMT1 Maintains Iron Homeostasis to Regulate Mitochondrial Function in Porcine Oocytes.
2-Hydroxyisobutyric acid targeted binding to MT-ND3 boosts mitochondrial respiratory chain homeostasis in hippocampus to rescue diabetic cognitive impairment.
Dissociation of mitochondrial and ribosomal biogenesis during thallium administration in rat kidney.
Aflatoxin B1 Promotes Pyroptosis in IPEC-J2 Cells by Disrupting Mitochondrial Dynamics through the AMPK/NLRP3 Pathway.
Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4+ T cell for inflammatory bowel diseases treatment.

Int J Med Sci. 2024 ;21(15): 2897-2911

Enhancement of Mitochondrial Homeostasis: A Novel Approach to Attenuate Hypoxic Myocardial Injury.

Zhijiang Guo, Yingjie Tian, Jing Gao, Bei Zhou, XiuTeng Zhou, Xing Chang, Hao Zhou.

  Cardiomyocytes are highly oxygen-dependent cells, relying on oxygen-driven oxidative phosphorylation to maintain their function. During hypoxia, mitochondrial ATP production decreases, leading to calcium overload, acidosis, and oxidative stress, which collectively trigger myocardial injury. Ischemic heart disease, caused by coronary atherosclerosis, results in myocardial ischemia and hypoxia, leading to ischemia-reperfusion (I/R) injury. Early myocardial injury is attributed to ischemia and hypoxia, but even after thrombolytic therapy, interventional surgery, or coronary artery bypass grafting (CABG) restores local blood flow and oxygen supply, myocardial reperfusion injury (I/R) may still occur. Mitochondria, often referred to as the "powerhouses" of the cell, play a crucial role in cellular energy production. In the early stages of ischemia and hypoxia, mitochondrial dysfunction disrupts mitochondrial homeostasis, causing the accumulation of unfolded or misfolded proteins in the mitochondria. This activates the mitochondrial unfolded protein response (mtUPR) and mitophagy, which work to clear damaged proteins and mitochondria, playing a key role during this period. This review focuses on mitochondrial mechanisms during the ischemic phase of ischemia-reperfusion injury, aiming to provide new theoretical foundations and potential therapeutic strategies to reduce myocardial damage.

Keywords:  hypoxic myocardial injury; mitophagy; unfolded protein response (UPR)

DOI:  https://doi.org/10.7150/ijms.103986
Cell Death Discov. 2024 Dec 05. 10(1): 488

Mitophagy in gynecological malignancies: roles, advances, and therapeutic potential.

Jiao Wang, Dandan Wang.

Mitophagy is a process in which impaired or dysfunctional mitochondria are selectively eliminated through the autophagy mechanism to maintain mitochondrial quality control and cellular homeostasis. Based on specific target signals, several mitophagy processes have been identified. Defects in mitophagy are associated with various pathological conditions, including neurodegenerative disorders, cardiovascular diseases, metabolic diseases, and cancer. Mitophagy has been shown to play a critical role in the pathogenesis of gynecological malignancies and the development of drug resistance. In this review, we have summarized and discussed the role and recent advances in understanding the therapeutic potential of mitophagy in the development of gynecological malignancies. Therefore, the valuable insights provided in this review may serve as a basis for further studies that contribute to the development of novel treatment strategies and improved patient outcomes.

DOI: https://doi.org/10.1038/s41420-024-02259-x
Cell Death Dis. 2024 Dec 05. 15(12): 881

SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia.

Alice Zhao, Laura Maple, Juwei Jiang, Katie N Myers, Callum G Jones, Hannah Gagg, Connor McGarrity-Cottrell, Ola Rominiyi, Spencer J Collis, Greg Wells, Marufur Rahman, Sarah J Danson, Darren Robinson, Carl Smythe, Chun Guo.

SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress.

DOI: https://doi.org/10.1038/s41419-024-07271-8
Mol Cell Biochem. 2024 Dec 04.

Protective effect of astragaloside IV against zinc oxide nanoparticles induced human neuroblastoma SH-SY5Y cell death: a focus on mitochondrial quality control.

Liwei Wang, Lu Zhang, Yang Yun, Tingting Liang, Chaoqun Yan, Zhuoya Mao, Jingfang Zhang, Baoshe Liu, Jian Zhang, Taigang Liang.

  Occupational and unintentional exposure of zinc oxide nanoparticles (ZnONPs) raises concerns regarding their neurotoxic potential and there is an urgent need for the development of effective agents to protect against the toxic effects of ZnONPs. Astragalus memeranaceus (AM), a famous Traditional Chinese Medicine, as well as its bioactive components, showing a potential neuroprotective function. This study aims to investigate the neuroprotective effects of bioactive components of AM against ZnONPs-induced toxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. The cell apoptosis, ROS generation, MMP changes, mitochondrial fission/fusion, biogenesis, and mitophagy were assessed. In this study, AM treatment inhibited ZnONPs-induced cell apoptosis and ROS overproduction in SH-SY5Y cells. And astragaloside IV (ASIV) played a dominant role in the attenuation of cytotoxicity after ZnONPs exposure, rather than flavonoids and polysaccharides. ASIV treatment significantly reduced ROS generation and MMP collapse in ZnONPs-exposed cells. Furthermore, the protein expressions of mitochondrial biogenesis (PGC-1α), fusion (Mfn1 and Mfn2), and fission (Drp1) were markedly increased. Meanwhile, the PINK1/Parkin-mediated mitophagy was activated after ASIV administration, which ameliorated ZnONPs-induced SH-SY5Y cell death. Collectively, ASIV administration mitigated ZnONPs-induced cytotoxicity in SH-SY5Y cells through restoring mitochondrial quality control process, which hinted the protective role of ASIV in ZnONPs-induced neurotoxicity.

Keywords:  Astragaloside IV; Human neuroblastoma SH-SY5Y cells; Mitochondrial quality control; Neuroprotective; Zinc oxide nanoparticles

DOI:  https://doi.org/10.1007/s11010-024-05172-0
Biomed Environ Sci. 2024 Oct 20. 37(10): 1128-1141

Mito-TEMPO Ameliorates Sodium Palmitate Induced Ferroptosis in MIN6 Cells through PINK1/Parkin-Mediated Mitophagy.

Baolei Chang, Yanyu Su, Tingting Li, Yanxia Zheng, Ruirui Yang, Heng Lu, Hao Wang, Yusong Ding.

   Objective: Mitochondrial reactive oxygen species (mtROS) could cause damage to pancreatic β-cells, rendering them susceptible to oxidative damage. Hence, investigating the potential of the mitochondria-targeted antioxidant (Mito-TEMPO) to protect pancreatic β-cells from ferroptosis by mitigating lipid peroxidation becomes crucial.
Methods: MIN6 cells were cultured in vitro with 100 μmol/L sodium palmitate (SP) to simulate diabetes. FerroOrange was utilized for the detection of Fe 2+ fluorescence staining, BODIPY581/591C11 for lipid reactive oxygen species, and MitoSox-Red for mtROS. Alterations in mitophagy levels were assessed through the co-localization of lysosomal and mitochondrial fluorescence. Western blotting was employed to quantify protein levels of Acsl4, GPX4, FSP1, FE, PINK1, Parkin, TOMM20, P62, and LC3. Subsequently, interventions were implemented using Mito-TEMPO and Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) to observe changes in ferroptosis and mitophagy within MIN6 cells.
Results: We found that SP induced a dose-dependent increase in Fe 2+ and lipid ROS in MIN6 cells while decreasing the expression levels of GPX4 and FSP1 proteins. Through bioinformatics analysis, it has been uncovered that mitophagy assumes a crucial role within the ferroptosis pathway associated with diabetes. Additionally, SP decreased the expression of mitophagy-related proteins PINK1 and Parkin, leading to mtROS overproduction. Conversely, Mito-TEMPO effectively eliminated mtROS while activating the mitophagy pathways involving PINK1 and Parkin, thereby reducing the occurrence of ferroptosis in MIN6 cells. CCCP also demonstrated efficacy in reducing ferroptosis in MIN6 cells.
Conclusion: In summary, Mito-TEMPO proved effective in attenuating mtROS production and initiating mitophagy pathways mediated by PINK1 and Parkin in MIN6 cells. Consequently, this decreased iron overload and lipid peroxidation, ultimately safeguarding the cells from ferroptosis.

Keywords:  Bioinformatical analysis; Ferroptosis; MIN6; Mitophagy; MtROS; Type 2 diabetes

DOI:  https://doi.org/10.3967/bes2024.111
Circ Res. 2024 Dec 06. 135(12): e154

Correction to: Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.

DOI: https://doi.org/10.1161/RES.0000000000000702
J Pathol. 2024 Dec 03.

Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells.

Jaeeun Lee, Hayoung Woo, Hyunju Kang, Young-Ki Park, Ji-Young Lee.

  The pathogenesis of alcohol-related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPRmt) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPRmt is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD+ precursor, could mitigate ethanol-triggered cellular damage. When ImKCs were exposed to 80 mm ethanol for 72 h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPRmt genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol-induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPRmt, to the nucleus from the mitochondria was abolished by NR. The induction of UPRmt genes by ethanol was significantly repressed when Atf5 was knocked down, indicating the role of ATF5 in the induction of UPRmt genes in ImKCs exposed to ethanol. We also confirmed the induction of UPRmt gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5-dependent UPRmt pathway in ImKCs, suggesting its potential for ALD therapy. © 2024 The Pathological Society of Great Britain and Ireland.

Keywords:  Kupffer cells; ethanol metabolism; mitochondrial unfolded protein response; nicotinamide riboside

DOI:  https://doi.org/10.1002/path.6372
Phytomedicine. 2024 Nov 26. pii: S0944-7113(24)00943-7. [Epub ahead of print]136 156287

Cyclovirobuxine D inhibits triple-negative breast cancer via YAP/TAZ suppression and activation of the FOXO3a/PINK1-Parkin pathway-induced mitophagy.

Zi-Qiong Wang, Zhi-Xuan Wu, Jia-Wei Chen, Hong-Feng Li, Hao-Dong Wu, Jing-Xia Bao, Yao Cheng, Yin-Wei Dai, Ou-Chen Wang, Xuan-Xuan Dai.

   BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by its rapid progression and aggressive nature, with limited effective therapeutic interventions currently available. Cyclovirobuxine D (CVB-D), a natural alkaloid extracted from the traditional Chinese herb Buxus sinica, is renowned for its cardioprotective and anti-ischemic effects, demonstrating notable anti-cancer properties. Nevertheless, the anti-tumor effects of CVB-D on TNBC remain unverified.
PURPOSE: This study seeks to investigate the effects of CVB-D on TNBC and to uncover the underlying mechanisms.
STUDY DESIGN: Network pharmacology, SPR, DSF, and cell-based functional assays were conducted on TNBC cells to assess the impact of CVB-D. Findings were further corroborated using xenograft mouse models.
METHODS: Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, transwell assays, flow cytometry, wound healing assays, immunofluorescence, and immunoblotting were employed to evaluate CVB-D's influence on TNBC cell lines. SPR, DSF and molecular docking techniques were utilized to assess the binding affinity of CVB-D to Yes-associated protein (YAP). The interaction between CVB-D and autophagy/mitophagy was further analyzed through plasmid transient transfection, JC-1 assay, TUNEL assay, and the use of autophagy inhibitors. The anti-TNBC mechanism of CVB-D was elucidated by overexpressing YAP in MDA-MB-231 cells. Additionally, the in vivo efficacy and safety of CVB-D were assessed in a xenograft mouse model.
RESULTS: In vitro analyses revealed that CVB-D effectively suppressed G1 phase arrest and inhibited TNBC cell proliferation. Moreover, CVB-D induced mitochondrial-dependent apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, CVB-D exerted its anti-cancer effects by directly binding to YAP, thereby inhibiting the nuclear translocation of YAP/TAZ and suppressing the transcription of downstream oncogenic target genes. Furthermore, CVB-D triggered excessive mitophagy by activating the FOXO3a/PINK1-Parkin axis, promoting apoptosis and leading to mitochondrial dysfunction in TNBC cells. Elevated YAP expression counteracted the effects of CVB-D on TNBC, including the suppression of mitophagy-related protein expression induced by CVB-D, suggesting that YAP modulates mitophagy through the FOXO3a/PINK1-Parkin axis. The anti-tumor efficacy of CVB-D and its underlying mechanisms were further substantiated using a subcutaneous xenograft model.
CONCLUSIONS: This study is the first to demonstrate that CVB-D can directly bind to the YAP target, proposing a novel therapeutic strategy for TNBC. CVB-D may serve both as a YAP/TAZ inhibitor and as an activator of the FOXO3a/PINK1-Parkin axis, leading to excessive mitophagy.

Keywords:  Autophagy; Chinese traditional medicine; Mitophagy; Triple negative breast neoplasms; YAP-Signaling Proteins

DOI:  https://doi.org/10.1016/j.phymed.2024.156287
J Biol Chem. 2024 Dec 02. pii: S0021-9258(24)02553-5. [Epub ahead of print] 108051

Structural Basis for the Pathogenicity of Parkin Catalytic Domain Mutants.

Julian P Wagner, Véronique Sauvé, Anshu Saran, Kalle Gehring.

Mutations in the E3 ubiquitin ligase parkin cause a familial form of Parkinson's disease (PD). Parkin and the mitochondrial kinase PINK1 assure quality control of mitochondria through selective autophagy of mitochondria (mitophagy). Whereas numerous parkin mutations have been functionally and structurally characterized, several PD mutations found in the catalytic Rcat domain of parkin remain poorly understood. Here, we characterize two pathogenic Rcat mutants, T415N and P437L. We demonstrate that both mutants exhibit impaired activity using autoubiquitination and ubiquitin vinyl sulfone assays. We determine the minimal ubiquitin binding segment and show that both mutants display impaired binding of ubiquitin charged on the E2 enzyme. Finally, we use AlphaFold 3 to predict a model of the phospho-parkin:phospho-ubiquitin:ubiquitin-charged E2 complex. The model shows the repressor-element of parkin (REP) and the N-terminal residues of the catalytic domain form a helix to position ubiquitin for transfer from the E2 to parkin. Our results rationalize the pathogenicity of the parkin mutations and deepen our understanding of the active parkin-E2∼Ub complex.

DOI: https://doi.org/10.1016/j.jbc.2024.108051
Chem Biol Interact. 2024 Nov 28. pii: S0009-2797(24)00473-3. [Epub ahead of print] 111327

The role of HIF-1α/Bnip3/mitophagy in acrylonitrile-induced neuronal death in HT22 cells and mice: a potential neuroprotection target.

Jing Hu, Bobo Yang, Zehua Tao, Jian Chen, Xinyu Zhang, Suhua Wang, Guangwei Xing, Ngwa Adeline Ngeng, Abdul Malik, Kwaku Appiah-Kubi, Marcelo Farina, Anatoly V Skalny, Alexey Tinkov, Michael Aschner, Rongzhu Lu.

  Acrylonitrile (AN) is a widely utilized organic compound in the production of diverse industrial synthetic materials. While acute exposure to AN can cause neurotoxicity, the precise mechanism remains unclear. Hypoxia-inducible factor 1 alpha (HIF-1α) is a pivotal transcription factor that coordinates and orchestrates multiple physiological processes to adapt to hypoxic conditions, ensuring cellular survival and homeostasis. In this study, we used in vitro (cultured mouse hippocampal neuronal cell line, HT22) and in vivo (AN exposed mice) approaches to investigate the potential modulator effects of HIF-1α in AN-induced neurotoxicity. In vitro, AN exposure caused concentration-dependent toxicity in HT22 cells, which was paralleled by increased Bax levels while decreasing Bcl-2. Exposure to AN resulted in reduced protein levels of HIF-1α, Bcl-2 19-kDa interacting protein 3 (BNIP3), microtubule-associated protein 1 light chain 3 beta (LC3) and Beclin1, while increased the protein levels of the translocase of outer mitochondrial membrane 20 (TOM20). Furthermore, mitochondrial morphology and function were compromised, suggesting that AN impaired HIF-1α/BNIP3-mediated mitochondrial autophagy and promoted apoptosis. Treatment with a HIF-1α activator, cobalt chloride (CoCl2), reversed these effects, while pretreatment with a HIF-1α inhibitor, 2-methoxyestradiol (2-MeOE2), augmented them. In BNIP3 overexpressing HT22 cells, enhanced cell viability and reduced apoptosis rates were observed. Furthermore, the HIF-1α/BNIP3 pathway was activated by the prolyl hydroxylase (PHD2) inhibitor, deferoxamine (DFO), which increased HT22 cell viability. Similarly, the activation of HIF-1α by administering 20 mg/kg of CoCl2 was found to alleviate neurotoxicity in mice. This treatment enhanced elevations of autophagy protein expression and co-localization of BNIP3 and LC3. In summary, under normal conditions, AN induced neurotoxicity by promoting PHD2-mediated HIF-1α degradation, disrupted the BNIP3-mediated mitophagy pathway, and enhanced apoptosis. Our findings underscore the effect of the HIF-1α/BNIP3-mediated mitochondrial autophagy in AN-induced neurotoxicity and suggest potential therapeutic strategies involving HIF-1α activation or BNIP3 overexpression for AN poisoning treatment.

Keywords:  Acrylonitrile; Apoptosis; BNIP3; HIF-1α; Mitophagy; Neurotoxicity

DOI:  https://doi.org/10.1016/j.cbi.2024.111327
Lung. 2024 Dec 03. 203(1): 12

The Mitochondrial Fusion Promoter M1 Mitigates Cigarette Smoke-Induced Airway Inflammation and Oxidative Stress via the PI3K-AKT Signaling Pathway.

Tingting Zeng, Lian Liu, Dan Xu, Tao Wang, Yanqiu Wu, Jiangyue Qin, Lijuan Gao, Mei Chen, Xiaohua Li, Diandian Li, Jun Chen, Yongchun Shen, Fuqiang Wen.

   PURPOSE: This study investigated the efficacy and underlying mechanism of the mitochondrial fusion promoter M1 in mitigating cigarette smoking (CS)-induced airway inflammation and oxidative stress both in vitro and in vivo models.
METHODS: Cigarette smoke extract (CSE)-treated airway epithelial cells (BEAS-2B) and CS-exposed mice were pretreated with M1, followed by the measurement of proinflammatory cytokines, oxidative stress, mitochondrial fusion proteins (MFN2 and OPA1) and fission proteins (DRP1 and MFF). Molecular pathways were elucidated through transcriptomic analysis and Western blotting.
RESULTS: M1 pretreatment in CSE-treated cells significantly reduced the release of inflammatory cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α); reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels; increased superoxide dismutase (SOD) activity; protected mitochondrial function by increasing the expression of mitochondrial fusion proteins (MFN2 and OPA1) and decreasing the expression of mitochondrial fission proteins (DRP1 and MFF). M1 attenuated CS-induced lung histologic damage and mucus hypersecretion in mice, relieved high oxidative stress and reduced the release of IL-6 and IL-8 in BALF. Similarly, it also protected mitochondrial function by regulating the CS-induced imbalance of mitochondrial dynamic proteins. Transcriptome sequencing and Western blotting showed that M1 inhibited CSE- or CS-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway.
CONCLUSION: M1 plays a protective role in inflammation, oxidative stress and mitochondrial dynamics dysfunction caused by CS by inhibiting the PI3K-AKT signaling pathway; thus, it has therapeutic potential for the treatment of CS-induced airway disorders.

Keywords:  Airway inflammation; Chronic obstructive pulmonary disease; Mitochondrial fusion promoter M1; Oxidative stress

DOI:  https://doi.org/10.1007/s00408-024-00766-3
Nat Commun. 2024 Dec 04. 15(1): 10582

Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation.

Yating Liu, Qian Li, Guojing Tian, Xinyi Zhou, Panpan Chen, Bo Chen, Zhao Shan, Bin Qi.

All organisms depend on food digestion for survival, yet the brain-gut signaling mechanisms that regulate this process are not fully understood. Here, using an established C. elegans digestion model, we uncover a pathway in which neuronal ROS (free radicals) signal the intestine to suppress digestion. Genetic screening reveals that reducing genes responsible for maintaining ROS balance increases free radicals and decreases digestion. PRDX-2 knockout in olfactory neurons (AWC) elevates ROS and reduces digestive capacity, mediated by the neuropeptide NLP-1 and activation of the mitochondrial unfolded protein response (UPRmt) in the intestine. Additionally, over-expressing nlp-1 or ablating AWC neurons both trigger UPRmt and inhibit digestion. These findings reveal a brain-gut connection in which neuronal PRDX-2-mediated ROS signaling modulates food digestion, highlighting a critical role of free radicals in shutting down digestion to alleviate stress and reduce food consumption.

DOI: https://doi.org/10.1038/s41467-024-55013-3
CNS Neurosci Ther. 2024 Dec;30(12): e70121

The Role and Applied Value of Mitochondria in Glioma-Related Research.

Liwen Chen, Hui Zhang, Chao Shang, Yang Hong.

  Mitochondria, known as the "energy factory" of cells, are essential organelles with a double membrane structure and genetic material found in most eukaryotic cells. They play a crucial role in tumorigenesis and development, with alterations in mitochondrial structure and function in tumor cells leading to characteristics such as rapid proliferation, invasion, and drug resistance. Glioma, the most common brain tumor with a high recurrence rate and limited treatment options, has been linked to changes in mitochondrial structure and function. This review focuses on the bioenergetics, dynamics, metastasis, and autophagy of mitochondria in relation to glioma proliferation, as well as the potential use of mitochondria-targeting drugs in glioma treatment.

Keywords:  glioma; glioma therapy; mitochondria; mitochondrial bioenergetics; mitochondrial dynamics; mitochondrial metastasis; mitophagy

DOI:  https://doi.org/10.1111/cns.70121
Cell Death Dis. 2024 Nov 30. 15(11): 870

OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.

J Macuada, I Molina-Riquelme, G Vidal, N Pérez-Bravo, C Vásquez-Trincado, G Aedo, D Lagos, P Yu-Wai-Man, R Horvath, T J Rudge, B Cartes-Saavedra, V Eisner.

Optic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on nucleoid distribution using high-resolution confocal microscopy. We applied a novel model incorporating the mitochondrial context, separating nucleoid distribution into the array in the mitochondrial population and intramitochondrial longitudinal distribution. Opa1-null cells showed decreased mtDNA levels and nucleoid abundance. Also, loss of Opa1 led to an altered distribution of nucleoids in the mitochondrial population, loss of cristae periodicity, and altered nucleoids to cristae proximity partly rescued by OPA1 isoform 1. Overexpression of WT OPA1 or ADOA-causing mutants c.870+5 G > A or c.2713 C > T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization, which was partly reproduced in Skeletal muscle-derived fibroblasts from ADOA patients harboring the same mutants. Opa1-null and cells overexpressing ADOA mutants accumulated mitochondria without nucleoids. Interestingly, intramitochondrial nucleoid distribution was only altered in Opa1-null cells. Altogether, our results highlight the relevance of OPA1 in nucleoid distribution in the mitochondrial landscape and at a single-organelle level and shed light on new components of ADOA etiology.

DOI: https://doi.org/10.1038/s41419-024-07165-9
Front Cell Neurosci. 2024 ;18 1470144

MAM-mediated mitophagy and endoplasmic reticulum stress: the hidden regulators of ischemic stroke.

Ziyi Jia, Hongtao Li, Ke Xu, Ruobing Li, Siyu Yang, Long Chen, Qianwen Zhang, Shulin Li, Xiaowei Sun.

  Ischemic stroke (IS) is the predominant subtype of stroke and a leading contributor to global mortality. The mitochondrial-associated endoplasmic reticulum membrane (MAM) is a specialized region that facilitates communication between the endoplasmic reticulum and mitochondria, and has been extensively investigated in the context of neurodegenerative diseases. Nevertheless, its precise involvement in IS remains elusive. This literature review elucidates the intricate involvement of MAM in mitophagy and endoplasmic reticulum stress during IS. PINK1, FUNDC1, Beclin1, and Mfn2 are highly concentrated in the MAM and play a crucial role in regulating mitochondrial autophagy. GRP78, IRE1, PERK, and Sig-1R participate in the unfolded protein response (UPR) within the MAM, regulating endoplasmic reticulum stress during IS. Hence, the diverse molecules on MAM operate independently and interact with each other, collectively contributing to the pathogenesis of IS as the covert orchestrator.

Keywords:  endoplasmic reticulum stress; ischemic stroke (IS); mitochondrial-associated endoplasmic reticulum membrane (MAM); mitophagy; unfolded protein response (UPR)

DOI:  https://doi.org/10.3389/fncel.2024.1470144
Heliyon. 2024 Oct 30. 10(20): e39076

Remote ischemic preconditioning plays a neuroprotective role in cerebral ischemia-reperfusion mice by inhibiting mitophagy.

Jiayi Zhu, Na Xu, Heng Lin, Li Deng, Bingqing Xie, Xiaoqian Jiang, Runde Liao, Chaoxian Yang.

  Remote ischemic preconditioning (RIPC) represents a clinically feasible method for safeguarding vital organs against ischemic injury. However, its specific role in cerebral ischemia-reperfusion (I/R) injury remains to be definitively elucidated. In this study, we investigated the neuroprotective effects of RIPC on mice at 7 days post-cerebral I/R and its involvement in mitophagy and mitochondrial dysfunction. Cerebral I/R led to impaired brain function, as well as structural and functional damage to mitochondria. Notably, RIPC treatment ameliorated the neurological dysfunction induced by cerebral I/R. Compared with the I/R group, the expression levels of NeuN, MBP, PDH, and Tom20 were significantly elevated in the RIPC + I/R group. Furthermore, mitochondria in the RIPC + I/R group exhibited more intact structure compared to those in the I/R group. In mice subjected to I/R injury, RIPC treatment markedly increased ATP content, ADP content, TAN level and glucose uptake while upregulating expression levels of Parkin, Pink1 and P62 proteins; it also reduced both the volume of ischemic foci and the number of mitochondrial autophagosomes along with decreasing LC3B II/I ratio. In conclusion, RIPC may exert a neuroprotective role by inhibiting excessive mitophagy during subacute stages following an ischemic stroke.

Keywords:  Cerebral ischemia-reperfusion; Mitophagy; Remote ischemic preconditioning

DOI:  https://doi.org/10.1016/j.heliyon.2024.e39076
iScience. 2024 Oct 18. 27(10): 110980

Rebalance of mitophagy by inhibiting LRRK2 improves colon alterations in an MPTP in vivo model.

Alessia Filippone, Deborah Mannino, Laura Cucinotta, Fabrizio Calapai, Lelio Crupi, Irene Paterniti, Emanuela Esposito.

  Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common genetic causes of Parkinson's disease (PD). Studies demonstrated that variants in LRRK2 genetically link intestinal disorders to PD. We aimed to evaluate whether the selective inhibitor of LRRK2, PF-06447475 (PF-475), attenuates the PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in central nervous system (CNS) and in the gastrointestinal system. CD1 mice received four intraperitoneal injections of MPTP (20 mg/kg, total dose of 80 mg/kg) at 2 h intervals (day 1). After 24 h PF-475 was administered intraperitoneally at the doses of 2.5, 5, and 10 mg/kg for seven days. LRRK2 inhibition reduced brain α-synuclein and modulated mitophagy pathway and reduced pro-inflammatory markers and α-synuclein aggregates in colonic tissues through the modulation of mitophagy proteins. LRRK2 inhibition suppressed MPTP-induced enteric dopaminergic neuronal injury and protected tight junction in the colon. Results suggested that PF-475 may attenuate gastrointestinal dysfunction associated to PD.

Keywords:  Biochemistry; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110980
Int J Biochem Cell Biol. 2024 Dec 02. pii: S1357-2725(24)00207-3. [Epub ahead of print] 106714

5'tiRNA-33-CysACA-1 promotes septic cardiomyopathy by targeting PGC-1α-mediated mitochondrial biogenesis.

Ludong Yuan, Jing Li, Leijing Yin, Xiaofang Lin, Dan Ni, Chuanhuan Deng, Pengfei Liang, Bimei Jiang.

   BACKGROUND: We revealed for the first time that the expression of 158 tRNA-derived small RNAs (tsRNAs) was altered in septic cardiomyopathy (SCM) by microarray analysis, and we selected 5'tiRNA-33-CysACA-1, which was the most significantly up-regulated, as a representative to explore the roles and mechanisms of tsRNAs in SCM.
METHODS: We constructed a sepsis model by cecum ligation and puncture (CLP) in mice and detected the expression of 5'tiRNA-33-CysACA-1 using quantitative real-time PCR (qRT-PCR). The supernatant generated after LPS stimulation of macrophages was used as the conditional medium (CM) to stimulate H9C2 and established the injured cell model. CCK-8 and LDH release assays were used to detect cell viability and cell death. Mitochondrial membrane potential (MMP), ATP production, ROS production, and Mitotracker Red mitochondrial morphology were assayed to assess mitochondrial function. Expression of mRNA for molecules related to the mitochondrial quality control system was verified by qRT-PCR. The mechanism by which 5'tiRNA-33-CysACA-1 regulates peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) expression was examined by western blot, mRNA stability analysis, and rescue experiments.
RESULTS: Expression of 5'tiRNA-33-CysACA-1 was elevated in cardiac tissue and H9C2 cells during septic myocardial injury. Stimulation of the CM resulted in cardiomyocyte injury and impaired mitochondrial function. Transfection of 5'tiRNA-33-CysACA-1 mimic in CM further downregulated PGC-1α expression, inhibited mitochondrial biogenesis thereby impairing mitochondrial function and leading to decreased cardiomyocyte activity and increased cell death. In contrast, transfection of the inhibitor ameliorated the above biological processes. In addition, mRNA stability assay and bioinformatics analysis showed that 5'tiRNA-33-CysACA-1 led to a decrease in the stability of PGC-1α mRNA, which in turn downregulated the expression of PGC-1α and promoted the development of SCM.
CONCLUSIONS: 5'tiRNA-33-CysACA-1 expression is upregulated in SCM and inhibits mitochondrial biogenesis by targeting PGC-1α and decreasing the stability of PGC-1α mRNA, leading to mitochondrial dysfunction and promoting the development of SCM.

Keywords:  5'tiRNA-33-CysACA-1; Septic cardiomyopathy (SCM); cardiomyocytes; mitochondrial biogenesis; tRNA-derived small RNAs (tsRNAs)

DOI:  https://doi.org/10.1016/j.biocel.2024.106714
Brain Res Bull. 2024 Dec 03. pii: S0361-9230(24)00275-2. [Epub ahead of print] 111141

Pink1/Parkin signaling mediates pineal mitochondrial autophagy dysfunction and its biological role in a comorbid rat model of depression and insomnia.

Zirong Li, Yi Shu, Deguo Liu, Sheng Xie, Liangbo Xian, Jiaqi Luo, Xiuwen Huang, Haixing Jiang.

  Using a chronic unpredictable mild stress (CUMS) combined with multi-platform water environment sleep deprivation (SD) as an animal model, the occurrence and development of human depression combined with insomnia were simulated. The abnormal mitochondrial autophagy signaling caused by the putative kinase 1/Parkin E3 ubiquitin protein ligase (Pink1/Parkin) signaling pathway directly affects the normal secretion of melatonin by the pineal gland, which may explain the pathogenesis of depression combined with insomnia. This study aims to explore the depression-like behavior, sleep changes, central oxidative stress response, pineal mitochondrial autophagy damage, melatonin secretion, histopathological changes of the pineal gland, and the expression of Pink1/Parkin signaling-related factors in CUMS+SD rats. The results showed that the levels of reactive oxygen species (ROS) in cerebrospinal fluid of CUMS+SD rats significantly increased along with the inflammatory factors Interleukin-1β (IL-1β) and nuclear factor kappa-B (NF-κB) in cerebrospinal fluid. In addition, the number of pineal gland cells significantly decreased, cell boundaries became blurred, cell volume shrank, and apoptotic bodies appeared in the pineal gland tissue under HE staining, indicating pineal gland inflammation. Sleep deprivation further disrupted the levels of autophagy damage factors, including histamine (MDA), glutathione (GSH), and catalase (CAT), in the cerebrospinal fluid of CUMS + SD rats. Transmission electron microscopy of the pineal gland in CUMS+SD rats revealed damage to mitochondrial autophagy. The levels of 5-hydroxytryptamine (5-HT) and aromatic amine-N-acetyltransferase (AANAT) in the cerebrospinal fluid, as well as melatonin levels in the pineal gland, were significantly decreased. Additionally, the expression of IL-1β, NF-κB, Pink1, and Parkin in the pineal gland of CUMS+SD rats significantly increased. The expression of microtubule-associated protein 1 light chain 3-β (LC3), selective autophagy adaptor protein (P62), cytochrome c oxidase IV (COXIV), and mitochondrial outer membrane translocation enzyme 20 (TOM20) proteins downstream of the Pink1/Parkin signaling pathway was enhanced, while the expression of downstream brain-derived neurotrophic factor (BDNF), Beclin 1, and BCL2 interacting protein 3 (BNIP3) proteins was negatively regulated. Pink1/Parkin signaling may specifically respond to mitochondrial autophagy damage in the pineal gland, affecting the normal synthesis and secretion of melatonin in the pineal gland. In summary, mitochondrial autophagy damage in the pineal gland affects the normal secretion of melatonin in CUMS+SD rats, which is closely related to the specific autophagy signaling impairment of Pink1/Parkin pathway, which may mediate the occurrence of depression combined with insomnia.

Keywords:  Depression+insomnia; Hippocampus; Mitochondrial Autophagy; Pineal Gland

DOI:  https://doi.org/10.1016/j.brainresbull.2024.111141
Respir Res. 2024 Dec 04. 25(1): 426

Loss of PTPN21 disrupted mitochondrial metabolic homeostasis and aggravated experimental pulmonary fibrosis.

Hui Lian, Kai Xu, Airu Chang, Yaxuan Wang, Shuaichen Ma, Lianhui Cheng, Wenyu Zhao, Cong Xia, Lan Wang, Guoying Yu.

  Idiopathic pulmonary fibrosis (IPF) is a high-mortality lung disease with unclear pathogenesis. Convincing evidence suggests that an imbalance in mitochondrial homeostasis resulting from repeated injury to alveolar epithelial type 2 cells (AEC2) underlies IPF. Non-receptor protein tyrosine phosphatase 21 (PTPN21) performs various functions in cancer; however, its role in IPF has not been studied. This study aimed to investigate the role of PTPN21 in lung fibrosis. The experimental results showed that loss of PTPN21 exacerbated lung fibrosis by increasing cell numbers in bronchoalveolar lavage fluid, lung hydroxyproline content, and extracellular matrix protein expression of fibronectin and α-smooth muscle actin (α-SMA) in bleomycin-challenged mouse lungs. In A549 cells (AEC2), knockdown of PTPN21 suppressed focal adhesion and migration, reduced mitochondrial fission and increased fusion, increased the level of mitochondrial superoxide, decreased mitochondrial membrane potential and ATP levels. Simultaneously, knockdown of PTPN21 impaired autophagy, and increased intracellular reactive oxygen species levels. Treatment of fibroblasts (MRC-5) and primary human lung fibroblasts (PHLF)) with the supernatant from PTPN21-knockdown A549 cells increased the expression of fibronectin, collagen 1 and α-SMA. Conversely, overexpression of PTPN21 in A549 cells produced opposite effects. However, treatment of MRC-5 and PHLF with the supernatant from PTPN21-overexpressing A549 cells only slightly reduced the expression of fibronectin, collagen 1 in MRC-5 cells, but did not change the expression of α-SMA. In summary, this study revealed that the loss of PTPN21 in epithelial cells disrupted mitochondrial metabolic homeostasis, leading to epithelial cell inactivation and increased the deposition of extracellular matrix proteins in fibroblasts, thereby exacerbating experimental pulmonary fibrosis.

Keywords:  Alveolar epithelial cells; Autophagy; Idiopathic pulmonary fibrosis; Mitochondrial homeostasis; PTPN21

DOI:  https://doi.org/10.1186/s12931-024-03041-4
Am J Respir Cell Mol Biol. 2024 Dec 03.

Macrophage S1PR2 Drives Sepsis-induced Immunosuppression by Exacerbating Mitochondrial Fragmentation.

Xiangyang Yu, Xin Hu, Dongdong Wang, Ping Cui, Min Zeng, Min Li, Chenchen Gong, Dongqin Huang, Yan Wang, Kai Zhang, Xiangming Fang.

  Macrophage mitochondrial dysfunction is associated with immunosuppression and poor prognosis of septic patients. Mitochondrial fragmentation drives mitochondrial dysfunction. Our previous study has found that S1PR2 regulates macrophage phagocytosis during sepsis, while the role of S1PR2 in immunosuppression and the mechanisms remain further studied. This study aimed to unveil the relationship between macrophage mitochondrial fragmentation and sepsis-induced immunosuppression, as well as the S1PR2-related mechanisms thereof. Peripheral blood monocytes were collected from healthy controls (n = 12), nonseptic critical controls (n = 13) and septic patients (n = 19). Peritoneal macrophages were harvested from wildtype and S1pr2-/- mice (MMRRC strain iD, 12830) after cecal ligation and puncture (CLP). Mitochondrial ultrastructure was evaluated using transmission electron microscopy. The impact of mitochondrial ultrastructure alteration on immunosuppression of monocytes-macrophages was evaluated. Compared with nonseptic and healthy controls, peripheral blood monocytes from septic patients exhibited increased S1PR2 expression, mitochondrial fragmentation, and mitochondrial dysfunction. Mitochondrial fragmentation was negatively associated with HLA-DR expression. S1PR2 expression was positively correlated with mitochondrial fragmentation and negatively correlated with HLA-DR expression. In mice subjected to CLP, S1PR2 depletion ameliorated macrophage mitochondrial fragmentation and dysfunction, boosted immunity, and improved survival. Mechanistically, in response to sepsis, S1PR2 activates ROCK I to induce Drp1 phosphorylation, resulting in Drp1-dependent mitochondrial fragmentation of macrophages. Drp1 inhibition by Mdivi-1 mitigated S1PR2-induced macrophage immunosuppression and improved the prognosis of mice following CLP. In conclusion, S1PR2-induced mitochondrial fragmentation is a crucial factor mediating septic immunosuppression, highlighting its potential as a promising therapeutic target in sepsis.

Keywords:  Immunosuppression; Macrophages; Mitochondrial fragmentation; S1PR2; Sepsis

DOI:  https://doi.org/10.1165/rcmb.2024-0161OC
J Hazard Mater. 2024 Nov 26. pii: S0304-3894(24)03267-9. [Epub ahead of print]483 136686

Comparative mitochondrial proteomic: PGAM5-mediated necroptosis through excessive mitophagy in sheep livers under molybdenum and cadmium co-exposure.

Zhiwei Xiong, Fan Yang, Xueyan Dai, Chenghong Xing, He Bai, Lingli Liu, Yun Wang, Huabin Cao.

  Accumulation of excessive molybdenum (Mo) and cadmium (Cd) in the environment poses detrimental effects on organisms. The precise mechanisms of hepatotoxicity that are involved with mitochondria, resulting from the co-exposure to Mo and Cd, remain poorly understood and elusive. To fill the gap, a total of 24 sheep were stratified into two groups: control group and Mo + Cd group (45 mg Mo·kg⁻¹·B.W. and 1 mg Cd·kg⁻¹·B.W.). Results showed that exposure to Mo and Cd adversely co-induced the liver function related biochemical marker alterations in serum, histopathological abnormalities, mitochondrial ultrastructure damage and oxidative stress in the livers of sheep. Sequencing results from isolated mitochondria indicated that a total of approximately 4788 mitochondria-localized proteins were identified, of which 360 exhibited significant differential expression. GO and KEGG database analysis demonstrated excessive Mo and Cd primarily induced hepatotoxicity by affecting mitochondria-mediated oxidation-reduction processes, single-organism metabolic processes, and enhancing the TNF signaling pathway. Mo and Cd co-exposure increased the levels of mitophagy- and necroptosis- related factors regulated by PGAM5 in the livers. Consistently, our findings highlight the co-exposure of Mo and Cd induced necroptosis triggered by PGAM5-mediated mitophagy, which offers valuable insights into the toxicological mechanisms underlying the combined effects of Mo and Cd.

Keywords:  Cadmium; Liver; Mitochondrial proteomics; Molybdenum; PGAM5

DOI:  https://doi.org/10.1016/j.jhazmat.2024.136686
Cell Rep. 2024 Dec 03. pii: S2211-1247(24)01389-5. [Epub ahead of print]43(12): 115038

OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase.

Praveenraj Elancheliyan, Klaudia K Maruszczak, Remigiusz Adam Serwa, Till Stephan, Ahmet Sadik Gulgec, Mayra A Borrero-Landazabal, Sonia Ngati, Aleksandra Gosk, Stefan Jakobs, Michal Wasilewski, Agnieszka Chacinska.

  Mitochondrial proteins are transported and sorted to the matrix or inner mitochondrial membrane by the presequence translocase TIM23. In yeast, this essential and highly conserved machinery is composed of the core subunits Tim23 and Tim17. The architecture, assembly, and regulation of the human TIM23 complex are poorly characterized. The human genome encodes two paralogs, TIMM17A and TIMM17B. Here, we describe an unexpected role of the ovarian cancer immunoreactive antigen domain-containing protein 1 (OCIAD1) and the prohibitin complex in the biogenesis of human TIM23. Prohibitins were required to stabilize both the TIMM17A- and TIMM17B-containing variants of the translocase. Interestingly, OCIAD1 assembled with the prohibitin complex to protect the TIMM17A variant from degradation by the YME1L protease. The expression of OCIAD1 was in turn regulated by the status of the TIM23 complex. We postulate that OCIAD1 together with prohibitins constitute a regulatory axis that differentially regulates variants of human TIM23.

Keywords:  CP: Cell biology; OCIAD1; TIM23 translocase; biogenesis; mitochondria; prohibitin

DOI:  https://doi.org/10.1016/j.celrep.2024.115038
J Inflamm Res. 2024 ;17 9857-9873

5-Methoxytryptophan Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Regulating Nrf2-Mediated Mitophagy.

Xue Sun, Hanyu Wang, Yang Liu, Yanyan Yang, Yanjun Wang, Yan Liu, Shaozheng Ai, Zhenzhen Shan, Pengli Luo.

   Purpose: The effects of 5-methoxytryptophan (5-MTP) on mitophagy in sepsis-induced acute kidney injury (S-AKI) and its possible role in the Nrf2/HO-1 signaling pathway are unclear. In this study, we aimed to examine the levels of serum 5-MTP and mitophagy in patients with S-AKI and to evaluate the influence of 5-MTP on a lipopolysaccharide(LPS)-induced AKI model. Additionally, we sought to elucidate the mechanisms by which 5-MTP regulates mitophagy via Nrf2 mediation.
Patients and Methods: We initially included 52 patients with sepsis, 25 of whom were diagnosed with AKI, and used metabolomics to analyze the serum levels of 5-MTP. We investigated the effects of exogenous 5-MTP on the kidneys of a mouse model with LPS-induced AKI. We explored the underlying mechanisms by assessing oxidative stress and mitophagy in the kidneys following the administration of different doses of 5-MTP to S-AKI mice. In addition, we used ML385 to inhibit Nrf2 expression and assessed mitophagy levels in kidney damage to investigate the specific mechanism by which 5-MTP mitigates S-AKI.
Results: The plasma 5-MTP levels were significantly higher in patients with S-AKI than in those with sepsis, showing a correlation with renal function. Administration of 5-MTP led to a decrease in inflammatory and oxidative stress reactions and stimulated the Nrf2 signaling pathway to alleviate kidney injury following the induction of sepsis. However, this protective effect was reversed by ML385. In S-AKI, 5-MTP therapy enhanced mitophagy and decreased kidney injury by upregulating the Nrf2/HO-1 pathway.
Conclusion: Serum 5-MTP levels correlate with renal function and upregulate Nrf2 expression by activating the Nrf2 signaling pathway, thereby promoting renal tubular mitophagy and alleviating S-AKI.

Keywords:  5-methoxytryptophan2; Nrf23; mitophagy4; oxidative stress5; sepsis-induced acute kidney injury1

DOI:  https://doi.org/10.2147/JIR.S474040
EMBO Rep. 2024 Dec 02.

Coordination of cytochrome bc1 complex assembly at MICOS.

Ralf M Zerbes, Lilia Colina-Tenorio, Maria Bohnert, Karina von der Malsburg, Christian D Peikert, Carola S Mehnert, Inge Perschil, Rhena F U Klar, Rinse de Boer, Anita Kram, Ida van der Klei, Silke Oeljeklaus, Bettina Warscheid, Heike Rampelt, Martin van der Laan.

  The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for the formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as a determinant in the biogenesis of the cytochrome bc1 complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruiting complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, contributes to the spatial and temporal coordination of respiratory chain biogenesis.

Keywords:   bc 1 Complex; Cristae; MICOS; Mitochondria; Respiratory Chain

DOI:  https://doi.org/10.1038/s44319-024-00336-x
J Microbiol Biotechnol. 2024 Nov 14. 34(12): 2651-2664

Ischemic Stroke Induces ROS Accumulation, Maladaptive Mitophagy, and Neuronal Apoptosis in Minipigs.

Jie Chen, Yanan Bie, Yajin Guan, Wen Liu, Fei Xu, Tianping Liu, Zilong Meng, Mengqi Gao, Jiawei Liu, Shuilin Xie, Weiwang Gu.

  Reactive oxygen species (ROS)-induced adaptive/maladaptive mitophagy plays an essential role in the pathophysiology of acute ischemic stroke (AIS). However, most studies have been conducted using rodent models, which limits their clinical application. In this study, we aimed to develop porcine models of permanent stroke and observe the pathophysiological alterations caused by acute ischemic stroke, focusing on ROS-induced mitophagy. Miniature pigs were subjected to lateral frontotemporal electrocoagulation, which resulted in permanent middle cerebral artery occlusion. We investigated global brain damage and mechanisms of adaptive/maladaptive mitophagy caused by ROS and global brain inflammation after AIS. An early neuroinflammatory response was observed in the ipsilateral hemisphere. ROS levels were significantly elevated in the ipsilateral hemisphere and slightly elevated in the contralateral hemisphere. ROS accumulation may be attributed to the increased production and impaired elimination of ROS. In addition, mitophagy and apoptosis were detected in the ischemic core, which may be attributed to ROS accumulation. We propose "distinct-area targeting" interventions aimed at maladaptive mitophagy within the ischemic core of the infarct hemisphere, which may provide new therapeutic targets for the treatment of AIS.

Keywords:  acute ischemic stroke; maladaptive mitophagy; minipig; neuronal apoptosis; reactive oxygen species accumulation

DOI:  https://doi.org/10.4014/jmb.2409.09003
Adv Mater. 2024 Dec 01. e2413601

Sonoactivated Z-Scheme Heterojunction for Enhanced Sonodynamic Mitophagy Inhibition and Triple Negative Breast Cancer Treatment.

Yi Zheng, Tianhu Zhang, Meiqi Chang, Lili Xia, Liang Chen, Li Ding, Yu Chen, Rong Wu.

  Sonodynamic therapy (SDT) has emerged as a potent therapeutic modality to generate intratumoral toxic reactive oxygen species (ROS) in combating refractory triple-negative breast cancer (TNBC). However, its therapeutic efficacy is compromised due to pro-survival cancer-cell mitophagy to mitigate mitochondrial oxidative damage. Here, an "all-in-one" tumor-therapeutic strategy that integrates nanosonosensitizer-augmented noninvasive SDT with mitophagy inhibition is reported. This is achieved using a rationally constructed sonoactivated liquid Z-scheme heterojunction that connects sonosensitizer PtCu3 nanocages and mitophagy-blocking sonosensitizer BP nanosheets via an amphipathic organic linker (PEI-PEG5000-C18). The conjugated electron mediator (M, Cp*Rh(phen)Cl) is strategically positioned between the 2 sonosensitizers to facilitate electron transfer. This M-based Z-scheme configuration prolongs the separation of sonoactivated electron-hole pairs, leading to efficient ROS generation upon ultrasound stimulation. Importantly, Cu2+ released from PtCu3 expedites BP degradation by reducing phosphorus vacancy formation energy, improving the overall biodegradability of BP-M-PtCu3 and favoring phosphate ions production. These ions elevate lysosomal pH, inhibiting the hydrolysis of damaged mitochondria within autophagic lysosomes, thus preventing cancer cell self-preservation under oxidative stress and effectively eliminating TNBC. It is believe that the M-based sonoactivated Z-scheme heterojunction will be a promising sonosensitizer structure, and the sonodynamic mitophagy inhibition strategy offers valuable prospects for cancer treatment.

Keywords:  cancer therapy; liquid Z‐scheme heterojunction; mitophagy inhibition; nanomedicine; sonodynamic therapy

DOI:  https://doi.org/10.1002/adma.202413601
Int Immunopharmacol. 2024 Dec 02. pii: S1567-5769(24)02222-7. [Epub ahead of print]144 113700

Allogeneic platelet lysate activates the SIRT1-PINK1/Parkin pathway: A promising approach for improving mitochondrial function in an in vitro model of intervertebral disc degeneration.

Zhili Ding, Wei Du, Jie Huang, Jiaheng Han, Jie Bai, Guangnan Yang, Yan Zhang, Yu Ding.

   BACKGROUND: Intervertebral disc degeneration (IVDD) is a common cause of low back pain and spinal issues. Allogeneic platelet lysate (APL) is a blood product for several growth agents. However, only a few studies have revealed that APL can increase autophagy in defective mitochondria by activating the SIRT1-PINK1/parkin pathway while enhancing mitochondrial function to decrease reactive oxygen species (ROS) levels.
OBJECTIVE: To elucidate the mechanism by which APL mediates mitochondrial autophagy via the SIRT1-PINK1/Parkin pathway in the treatment of IVDD in vitro.
METHODS: Pure platelet-rich plasma (P-PRP) was prepared by two-step centrifugation, and APL was prepared via freeze-thaw cycles. The nucleus pulposus cells of New Zealand white rabbits were harvested and grown. After the third generation, four groups of cells were cultured: (1) control group: standard culture conditions; (2) IL-1β group: intervention; (3) APL group: 24-hour IL-1β intervention followed by 24-hour APL treatment; and (4) APL + EX527 group: SIRT1 inhibitor EX527 24-hour treatment after 24-hour IL-1β and APL treatment. After interventions, cell activity was measured by Trypan blue staining. Apoptosis was measured by flow cytometry in each group. Immunofluorescence labeling measured mitochondrial permeability, ROS, and ROS. RT-PCR evaluated autophagy and inflammation-related gene mRNA expression. Western blot analysis revealed the protein levels of these genes. Electron microscopy reveals mitochondrial autophagy.
RESULTS: APL from P-PRP decreased ROS levels in an IVDD in vitro model, mediated autophagy in dysfunctional mitochondria, and alleviated inflammation via the SIRT1-PINK1/Parkin pathway.

Keywords:  Allogeneic platelet lysate; Intervertebral disc degeneration; Platelet-rich plasma; Pyroptosis; Reactive oxygen species; SIRT1

DOI:  https://doi.org/10.1016/j.intimp.2024.113700
EPMA J. 2024 Dec;15(4): 559-571

Mitochondria-based holistic 3PM approach as the 'game-changer' for individualised rehabilitation-the proof-of-principle model by treated breast cancer survivors.

Martin Pesta, Barbara Mrazova, Marko Kapalla, Vlastimil Kulda, Eleni Gkika, Olga Golubnitschaja.

  Breast cancer belongs to the most commonly diagnosed malignancies worldwide, with its increasing incidence paralleled by advances in early diagnostics and effective treatments resulting in significantly improved survival rates. However, breast cancer survivors often experience significantly reduced quality of life linked to the long-term health burden as a consequence of aggressive oncological treatments applied. Their most frequently recorded complains include chronic fatigue, reduced physical activity, disordered sleep, chronification of pain, and severe mental health impairments-all per evidence are associated with compromised mitochondrial health and impaired homeostasis. Self-report of a breast cancer survivor is included in this article to illustrate currently uncovered patient needs. This article highlights mechanisms behind the suboptimal health of breast cancer survivors associated with mitochondrial damage, and introduces a novel, mitochondria-based holistic approach addressing rehabilitation concepts for breast cancer survivors following advanced principles of predictive, preventive and personalised medicine (3PM). By operating via mitochondrial function, the proposed holistic approach triggers systemic effects at molecular, sub/cellular and organismal levels positively affecting energy metabolism, repair mechanisms as well as physical and mental health creating, therefore, highly effective rehabilitation algorithms tailored to an individualised patient profile. The proposed methodology integrates mitochondrial health assessments utilising mitochondrial homeostasis biomarkers in tear fluid as a non-invasive diagnostic tool, tailored nutraceuticals and lifestyle adjustments. The introduced approach aligns with advanced principles of 3PM, offering a holistic and proactive framework for managing persistent post-treatment symptoms of suboptimal health in the cohort of cancer survivors. Furthermore, presented approach is also applicable to pre-habilitation programmes considering needs of other patient cohorts affected by chronic diseases such as CVD and orthopaedic disorders with planned major surgical incisions, who require individually adapted pre- and rehabilitation programmes. Implementing such innovative pre- and rehabilitation strategies may lead to a full recovery, sustainable health conditions and, therefore, facilitating patients' comeback to normal daily activities, family and professional life. Contextually, presented approach is considered a 'proof-of-principle' model for the 3PM-related paradigm shift from reactive medicine to a cost-effective holistic health management in both primary and secondary care benefiting a large spectrum of affected patient cohorts, individuals in suboptimal health conditions as well as society at large.

Keywords:  Behavioural patterns; Breast cancer survivors; Expert recommendations; Health policy; Health risk assessment; Healthcare economy; Homeostasis; Individualised patient profile; Life quality; Mitochondrial health; Mitophagy; Patient self-report; Patient-friendly non-invasive approach; Predictive preventive personalised medicine (PPPM / 3PM); Rehabilitation; Chronic fatigue; Secondary care; Sleep medicine; Tear fluid analysis

DOI:  https://doi.org/10.1007/s13167-024-00386-0
J Cell Physiol. 2024 Dec 05.

DMT1 Maintains Iron Homeostasis to Regulate Mitochondrial Function in Porcine Oocytes.

Jin-Xin Zhang, Meng-Fan Lan, Jian-Zhou Shang, Xin-Le Lai, Li-Shu Li, Tong-Tong Duan, Ru-Hai Xu, Kun-Lin Chen, Xing Duan.

  Iron plays critical roles in many cellular functions, including energy production, metabolism, and cell proliferation. However, the role of iron in maintaining oocyte quality remains unclear. In this study, DMT1 was identified as a key iron transporter during porcine oocyte maturation. The results demonstrated that iron deficiency in porcine oocyte led to aberrant meiotic progression, accompanied by increased gene expression of DMT1. Inhibition of DMT1 resulted in the failure of cumulus cell expansion and oocyte maturation, along by the abnormal actin and microtubule assembly. Furthermore, loss of DMT1 function caused disruption in mitochondrial function and dynamics, resulting in oxidative stress and Ca2+ dyshomeostasis. Additionally, the absence of DMT1 function activated PINK1/Parkin-dependent mitophagy in porcine oocyte. These findings suggested that DMT1 played a crucial role in safeguarding oocyte quality by protecting against iron-deficiency-induced mitochondrial dysfunction and autophagy. This study provided compelling evidence that DMT1 and iron homeostasis were crucial for maintaining the capacity of porcine oocyte maturation. Moreover, the results hinted at the potential of DMT1 as a novel therapeutic target for treating iron deficiency-related female reproductive disorders.

Keywords:  DMT1; iron; mitochondria; mitophagy; porcine oocyte

DOI:  https://doi.org/10.1002/jcp.31494
Redox Biol. 2024 Nov 28. pii: S2213-2317(24)00424-5. [Epub ahead of print]79 103446

2-Hydroxyisobutyric acid targeted binding to MT-ND3 boosts mitochondrial respiratory chain homeostasis in hippocampus to rescue diabetic cognitive impairment.

Minzhen Xie, Siqi Gu, Yan Liu, Haolin Yang, Yuqi Wang, Wei Yin, Yang Hong, Wanying Lu, Chengbing He, Lin Li, Limin Zhao, Jianjia Zhang, Heng Liu, Tian Lan, Shuijie Li, Qi Wang.

   BACKGROUND: The prevalence of diabetic cognitive impairment (DCI) is significant, some studies have shown that it is related to mitochondrial respiratory chain homeostasis, but the specific mechanism is not clear. 2-hydroxyisobutyric acid (2-HIBA) is a novel short-chain fatty acid with potential applications in the treatment of metabolic diseases because it can regulate mitochondrial disorders. Our aim was to explore a novel mechanism of action for 2-HIBA in the treatment of DCI in mitochondrial respiratory chain homeostasis.
METHODS: Metabolic substances and differentially active metabolic pathways in the serum of diseased mice were identified based on multi-omics analysis. The nanoLC-Obitrap-MS technology was utilized to detect the content of selected small molecules with differential metabolic activity in the hippocampus and mitochondria of mice to evaluate their permeability through the blood-brain barrier (BBB) and outer mitochondrial membrane. A combination of behavioral, proteomic, and molecular biology approaches was used to explore specific regulatory mechanisms and identify potential pharmacological targets. Additionally, using techniques such as protein thermal shift, drug affinity responsive target stability (DARTS), hydrolase stability, and surface plasmon resonance (SPR) experiments, we demonstrated the direct binding effects of small molecule metabolites with protein targets.
RESULTS: 2-HIBA was found to directly ameliorate cognitive dysfunction in db/db mice by penetrating the blood-brain barrier and reversing the decrease in the protein content of NADH dehydrogenase 3 (MT-ND3) in the hippocampus through direct binding to ND3. This action helps maintain the stability of NAD+/NADH and regulate the mitochondrial respiratory chain balance. Furthermore, a combined medication plant agonist of 2-HIBA can enhance the expression of MT-ND3, thereby improving cognitive dysfunction in mice.
CONCLUSION: MT-ND3 is a crucial target for improving diabetic cognitive dysfunction, and 2-HIBA can directly bind to the MT-ND3 protein to alleviate the functional impairment of the mitochondrial respiratory chain in mice to treat DCI.

Keywords:  2-Hydroxyisobutyric acid; Cognitive impairment; Diabetic; MT-ND3; Metabonomics; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.redox.2024.103446
PLoS One. 2024 ;19(12): e0311884

Dissociation of mitochondrial and ribosomal biogenesis during thallium administration in rat kidney.

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

Thallium (Tl) is a heavy metal with toxicity comparative to other heavy metals such as As, Cd, and Hg. Nevertheless, fewer studies have been reported concerning the molecular mechanism of Tl toxicity as compared to other heavy metals. To obtain insight into Tl toxicity in the kidney, rats were intraperitoneally administered Tl2SO4 (30 mg/kg), and the kidneys were removed 2 or 5 days later to examine the effects of Tl. Transcriptome analysis using DNA microarray of the rat kidney 2 and 5 days after Tl administration showed that cytoplasmic ribosomal proteins are the most upregulated category; many of the genes involved in ribosome biosynthesis were upregulated by Tl administration. This upregulation was associated with the activation of eukaryotic transcription initiation factor 2α (eIF2α), implying that increased ribosome biogenesis was linked to the subsequent activation of protein translation. In contrast, decreased mitochondrial biogenesis was revealed via proteomic analysis. Although we found an increase in Myc, a positive regulator of both ribosomal and mitochondrial biogenesis, decreased levels of NRF1 and TFAM, positive regulators of mitochondrial biogenesis whose gene expression is directory activated by Myc, were paradoxically observed. Taken together, differing responses of ribosomes and mitochondria to Tl toxicity were observed. Failure of transmission of the Myc signal to NRF1/TFAM might be involved in the observed disruption of coordinated responses in mitochondria and ribosomes during Tl administration in rat kidney.

DOI: https://doi.org/10.1371/journal.pone.0311884
J Agric Food Chem. 2024 Dec 04.

Aflatoxin B1 Promotes Pyroptosis in IPEC-J2 Cells by Disrupting Mitochondrial Dynamics through the AMPK/NLRP3 Pathway.

Jiayi Ding, Xinyi Cheng, Chun Zeng, Qintao Zhao, Chenghong Xing, Caiying Zhang, Huabin Cao, Xiaoquan Guo, Guoliang Hu, Yu Zhuang.

  Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins in food and feed, seriously jeopardizing the intestinal health, while the effects of AFB1 on intestinal damage remain to be well understood. This study aims to evaluate the effect of AFB1 on intestinal injury by regulating AMP-activated protein kinase (AMPK)-mediated pyroptosis in vitro. The present study showed that AFB1 led to the formation of large number of bubble-like protrusions on the cell membrane, releasing lactate dehydrogenase (LDH) and interleukin-1β (IL-1β). Stimulation with AFB1 resulted in the activation of the NOD-like receptor protein 3 (NLRP3) pathway, as indicated by the increased expression of pyroptosis-associated factor mRNAs and proteins, which ultimately led to a significant upregulation of the pyroptosis rate. Meanwhile, AFB1 caused dysfunction of mitochondrial dynamics by activating the AMPK signaling pathway as mainly evidenced by upregulating dynamin-1-like protein 1 (Drp1) mRNA and protein expression. Moreover, inhibition of NLRP3 and AMPK pathways by MCC950 and compound C, respectively, significantly alleviated AFB1-induced damage in IPEC-J2 cells, evidenced by suppressed NLRP3-mediated pyroptosis, and ameliorated AMPK-mediated mitochondrial dynamics imbalance. In conclusion, these results demonstrated that AFB1 promoted pyroptosis of IPEC-J2 cells by interfering with mitochondrial dynamics by activating the AMPK/NRLP3 pathway.

Keywords:  AMPK; NLRP3; aflatoxin B1; mitochondrial dynamics; pyroptosis

DOI:  https://doi.org/10.1021/acs.jafc.4c05876
Cell Rep Med. 2024 Nov 23. pii: S2666-3791(24)00611-6. [Epub ahead of print] 101840

Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4+ T cell for inflammatory bowel diseases treatment.

Jiangnan Zhang, Yunhan Jiang, Dongmei Fan, Zhiqiang Qiu, Xinlian He, Song Liu, Linjie Li, Zhengyi Dai, Lidan Zhang, Ziyi Shu, Lili Li, Hu Zhang, Tao Yang, Youfu Luo.

  Inflammatory bowel disease (IBD) is an autoimmune disorder, and despite the availability of multiple Food and Drug Administration (FDA)-approved therapies, current clinical needs remain unmet. In this study, we find that caseinolytic protease P (ClpP) expression is markedly upregulated in colonic tissues from IBD patients and preclinical colitis models, particularly in CD4+ T cells. Subsequently, a small molecule, namely NCA029, is identified, and its therapeutic efficacy and mechanism of action are investigated both in vitro and in vivo. Oral administration of NCA029 significantly alleviates symptoms associated with dextran sulfate sodium (DSS)-induced acute and interleukin (IL)-10-deficient chronic colitis. The effects of NCA029 are largely dependent on its selective binding to ClpP in CD4+ T cells, thereby mitigating inflammation and restoring intestinal barrier function. Furthermore, NCA029 activates ClpP to promote oxidative phosphorylation (OXPHOS) inhibition and concomitantly modulate the Th17/Treg balance. In conclusion, our study develops a therapeutic strategy for treating IBD through the chemical activation of ClpP.

Keywords:  ClpP; OXPHOS; inflammatory bowel diseases; mitochondrial

DOI:  https://doi.org/10.1016/j.xcrm.2024.101840