bims-mikwok 2025-01-05 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2025–01–05
thirty-six papers selected by
Gavin McStay, Liverpool John Moores University

Nuclear receptor 4A1 Regulates Mitochondrial Homeostasis in Cardiac Post-Ischemic Injury by Controlling Mitochondrial Fission 1 Protein-Mediated Fragmentation and Parkin-Dependent Mitophagy.
Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.
Protective effect of compound K against podocyte injury in chronic kidney disease by maintaining mitochondrial homeostasis.
Curcumin liposomes alleviate senescence of bone marrow mesenchymal stem cells by activating mitophagy.
Yanghe decoction alleviates osteoarthritis by AMPK-SIRT3 positive feedback loop-mediated Mitochondrial autophagy.
The role of TBC1D15 in sepsis-induced acute lung injury: Regulation of mitochondrial homeostasis and mitophagy.
MANF overexpression ameliorates oxidative stress-induced apoptosis of human nucleus pulposus cells by facilitating mitophagy through promoting MFN2 expression.
Mitophagy in ischemic heart disease: molecular mechanisms and clinical management.
Mitochondrial Quality Control: A New Perspective in Skeletal Muscle Dysfunction of Chronic Obstructive Pulmonary Disease.
Lipotoxicity-induced upregulation of FIS1 exacerbates mitochondrial fragmentation and promotes NLRP3-dependent pyroptosis in diabetic cardiomyopathy.
CREG1 attenuates intervertebral disc degeneration by alleviating nucleus pulposus cell pyroptosis via the PINK1/Parkin-related mitophagy pathway.
Metabolic plasticity in pancreatic cancer: The mitochondrial connection.
Icariside II relieves radiation enteritis by regulating PINK/Parkin-mediated mitophagy.
Harmine-Induced Disruption of the Blood-Brain Barrier via Excessive Mitophagy in Zebrafish.
LncRNA Tug1 Regulates Post-Stroke Microglial Pyroptosis via PINK1/Parkin-Mediated Mitophagy.
Aberrant activation of adenine nucleotide translocase 3 promotes progression and chemoresistance in multiple myeloma dependent on PINK1 transport.
Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.
Rg1 Improves Alzheimer's disease by Regulating Mitochondrial Dynamics Mediated by the AMPK/Drp1 Signaling Pathway.
ATP5J regulates microglial activation via mitochondrial dysfunction, exacerbating neuroinflammation in intracerebral hemorrhage.
Deciphering Glioblastoma Pathogenesis: Insights from Mitophagy Dysregulation and SNX7 as a Therapeutic Target.
DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.
Rostellularia procumbens (L) Nees. extract attenuates adriamycin-induced nephropathy by maintaining mitochondrial dynamics balance via SIRT1/PGC-1α signaling pathway activation.
Beyond static snapshots: Mitochondria in action.
Aldehyde Dehydrogenase 2 Lactylation Aggravates Mitochondrial Dysfunction by Disrupting PHB2 Mediated Mitophagy in Acute Kidney Injury.
Hippocampal SIRT1 signaling mediates the ameliorative effect of treadmill exercise on anxiety- and depression-like behavior in APP/PS1 mice.
Cardiomyocyte-specific Piezo1 deficiency mitigates ischemia-reperfusion injury by preserving mitochondrial homeostasis.
Loss of Mfn1 but not Mfn2 enhances adipogenesis.
Resolvin D1 combined with exercise rehabilitation alleviates neurological injury in mice with intracranial hemorrhage via the BDNF/TrkB/PI3K/AKT pathway.
Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.
CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy.
AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.
[Mitochondrial transfer contributes to the odontogenic differentiation of dental mesenchymal stem cells].
Receptor-Interacting Protein Kinase 3-Mediated Modulation of Endothelial Cell Necroptosis and Mitochondrial Dysfunction through AMPK/Drp1 Signaling Pathway: Insights into the Pathophysiological Mechanisms of Lipopolysaccharide-Induced Acute Lung Injury.
Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.
HMOX1-LDHB interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis.
Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice.

Int J Biol Sci. 2025 ;21(1): 400-414

Nuclear receptor 4A1 Regulates Mitochondrial Homeostasis in Cardiac Post-Ischemic Injury by Controlling Mitochondrial Fission 1 Protein-Mediated Fragmentation and Parkin-Dependent Mitophagy.

Haoran Ye, Jialong Lin, Hui Zhang, Jing Wang, Yuan Fu, Zhaopei Zeng, Junmeng Zheng, Jun Tao, Junxiong Qiu.

  The close interaction of mitochondrial fission and mitophagy, two crucial mechanisms, is key in the progression of myocardial ischemia-reperfusion (IR) injury. However, the upstream regulatory mechanisms governing these processes remain poorly understood. Here, we demonstrate a marked elevation in Nr4a1 expression following myocardial IR injury, which is associated with impaired cardiac function, heightened cardiomyocyte apoptosis, exacerbated inflammatory responses, and endothelial dysfunction. Notably, Nr4a1-knockout mice exhibited remarkable resistance to acute myocardial IR injury, characterized by preserved mitochondrial integrity relative to their wild-type counterparts. Functional analyses revealed that elevated Nr4a1 expression after IR injury promotes Fis1-mediated mitochondrial fission while suppressing Parkin-driven mitophagy. Importantly, interventions that inhibit mitochondrial fission or enhance mitophagy effectively ameliorated IR-induced cardiomyocyte and endothelial dysfunction. Collectively, these results highlight that the absence of Nr4a1 provides a shield against cardiac post-ischemic damage by reinstating balance within the mitochondria through inhibiting Fis1-induced fission and promoting Parkin-triggered mitophagy. Furthermore, therapeutic strategies targeting the Nr4a1/mitochondria axis may offer promising avenues for improving cardiac outcomes under myocardial IR stress.

Keywords:  Cardiac post-ischemic damage; Fis1; Mitochondrial fission and Mitophagy; Nr4a1; Parkin

DOI:  https://doi.org/10.7150/ijbs.104680
Int J Med Sci. 2025 ;22(1): 188-196

Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.

Yang Shen, Xin Gao, Ying Xiang, Hao Zhou, Hang Zhu, Qiang Wu, Jinfeng Liu.

  This study investigates the role of Fundc1 in cardiac protection under high-altitude hypoxic conditions and elucidates its underlying molecular mechanisms. Using cardiomyocyte-specific Fundc1 knockout (Fundc1CKO ) mice, we demonstrated that Fundc1 deficiency exacerbates cardiac dysfunction under simulated high-altitude hypoxia, manifesting as impaired systolic and diastolic function. Mechanistically, we identified that Fundc1 regulates cardiac function through the mitochondrial unfolded protein response (mito-UPR) pathway. Fundc1 deficiency led to significant downregulation of multiple mito-UPR-related factors, including ATF5, Chop, and PITRM1. Further investigation revealed that Fundc1 deficiency results in increased cardiomyocyte apoptosis, calcium dysregulation, reduced cell viability, and impaired mitochondrial function, characterized by decreased ATP production, reduced membrane potential, and increased ROS production. Notably, activation of mito-UPR with oligomycin significantly ameliorated these cardiac abnormalities in Fundc1-deficient mice. We identified ATF5 as a key downstream effector of Fundc1, as ATF5 overexpression effectively reversed cardiac dysfunction and restored mito-UPR-related gene expression in Fundc1-deficient hearts. Additionally, we discovered that Fundc1-mediated cardioprotection involves regulation of mitophagy, where its activation improved cardiac function and mitochondrial homeostasis in Fundc1-deficient mice. Our findings reveal a novel Fundc1-ATF5-mito-UPR axis in cardioprotection against high-altitude hypoxia and highlight the crucial role of mitophagy in this protective mechanism, providing new insights into potential therapeutic strategies for high-altitude heart disease.

Keywords:  ATF5; FUNDC1; mito-UPR; mitochondria.

DOI:  https://doi.org/10.7150/ijms.100523
Sci Rep. 2025 Jan 02. 15(1): 435

Protective effect of compound K against podocyte injury in chronic kidney disease by maintaining mitochondrial homeostasis.

Fugang Huang, Shuo Huang, Ke Sun, Yanhao Chen, Guanqun Xie, Jie Bao, Yongsheng Fan.

  Chronic kidney disease (CKD) stands as a formidable global health challenge, often advancing to end-stage renal disease (ESRD) with devastating morbidity and mortality. At the central of this progression lies podocyte injury, a critical determinant of glomerular dysfunction. Compound K (CK), a bioactive metabolite derived from ginsenoside, has emerged as a compelling candidate for nephroprotective therapy. Here, we unveil the profound therapeutic potential of CK in a folic acid (FA)-induced CKD mouse model, demonstrating its ability to restore renal function and mitigate podocyte injury. CK exerted its nephroprotective effects by reinforcing inter-podocyte junctions, suppressing aberrant podocyte motility, and preventing podocyte detachment and apoptosis, thereby safeguarding the glomerular filtration barrier. Mechanistically, we identified mitochondrial dysregulation as a key driver of excessive oxidative stress, which is commonly associated with podocyte damage. CK remarkably restored mitochondrial homeostasis by attenuating pathological mitochondrial fission and enhancing mitophagy, thereby rebalancing the delicate mitochondrial network. Intriguingly, CK may disrupt the formation of the Drp1-Bax dimer, a crucial mediator of mitochondrial apoptosis, further averting podocyte loss. Collectively, our findings highlight CK as a potent nephroprotective agent, offering a novel therapeutic avenue for CKD management and redefining possibilities in the battle against progressive renal disease.

Keywords:  Apoptosis; Chronic kidney disease; Compound K; Mitochondrial homeostasis; Podocyte Injury

DOI:  https://doi.org/10.1038/s41598-024-84704-6
Sci Rep. 2024 Dec 28. 14(1): 31291

Curcumin liposomes alleviate senescence of bone marrow mesenchymal stem cells by activating mitophagy.

Weiyao Li, Yixin Huang, Lei Fan, Dekyi Yangzom, Kun Zhang, Liuhong Shen, Suizhong Cao, Congwei Gu, Shumin Yu.

  The senescence of mesenchymal stem cells (MSCs) is closely related to aging and degenerative diseases. Curcumin exhibits antioxidant and anti-inflammatory effects and has been extensively used in anti-cancer and anti-aging applications. Studies have shown that curcumin can promote osteogenic differentiation, autophagy and proliferation of MSCs. Liposome, as a nano-carrier, provides a feasible strategy for improving the bioavailability and controlled-release profile of curcumin.This study aimed to evaluate the effects of curcumin liposomes (Cur-Lip) on the senescence of rat bone marrow mesenchymal stem cells (rBMSCs). Based on network pharmacology, we predicted the targets and mechanisms of curcumin on senescence of MSC. 23 key targets of Cur were associated with MSC senescence were screened out and mitophagy signaling was significantly enriched. Cur-Lip treatment alleviated senescence of D-galactose (D-gal)-induced rBMSCs, protected mitochondrial function, and activated mitophagy, which may be related to mitochondrial fission. Inhibition of mitophagy attenuated the protective effects of Cur-lip on mitochondrial function and senescence of rBMSCs. Our findings suggested that Cur-Lip could alleviate senescence of rBMSC and improve mitochondrial function by activating mitophagy.

Keywords:  Curcumin liposomes; Mitophagy; Network pharmacology; Senescence; rBMSCs

DOI:  https://doi.org/10.1038/s41598-024-82614-1
J Ethnopharmacol. 2024 Dec 31. pii: S0378-8741(24)01593-9. [Epub ahead of print] 119294

Yanghe decoction alleviates osteoarthritis by AMPK-SIRT3 positive feedback loop-mediated Mitochondrial autophagy.

Peng-Bo Shi, Meng-Meng Du, Peng Yu, Xian-Zhong Bu, Dong-Fang Meng, Wei-Ping Qiao, Li-He Wang, Hui-Ying Li.

   ETHNOPHARMACOLOGICAL RELEVANCE: Yanghe Decoction(YHD) is a traditional Chinese medicine compound known for its efficacy in treating osteoarthritis (OA).
AIM OF THE STUDY: We aimed to explore the underlying mechanisms of YHD in relation to OA.
MATERIALS AND METHODS: UHPLC-MS technology was used to identify the material basis of YHD. In vivo, OA rat model was induced by the modified Hulth method and then treated with YHD at three different doses (0.625, 1.3 and 2.6g/kg/d). In vitro,YHD-Contained serum was prepared and administrated into rat chondrocytes, followed by simulation of Lipopolysaccharide(LPS). The protective mechanism was determined by observation of morphology, Flow cytometry and Protein level detection.
RESULTS: In vivo, YHD reduced chondrocyte apoptosis and joint inflammation while promoting mitophagy. It also elevated the protein levels of p-AMPK, SIRT3, PINK1, Parkin, and LC3II/I. In vitro, YHD-Contained Serum reduced chondrocyte apoptosis, decreased mitochondrial ROS, enhanced mitochondrial membrane potential, and upregulated the protein expressions of p-AMPK, SIRT3, PINK1, Parkin, and LC3II/I.
CONCLUSION: Through this study, we demonstrated YHD protect chondrocytes against apoptosis, and its underlying mechanisms may involve the regulation of AMPK-SIRT3 positive feedback loop and activation of PINK1/Parkin mediated mitophagy.

Keywords:  AMPK-SIRT3 Feedback Loop; Chondrocytes; Mitophagy; Osteoarthritis; Yanghe Decoction

DOI:  https://doi.org/10.1016/j.jep.2024.119294
Int J Biol Macromol. 2024 Dec 29. pii: S0141-8130(24)10100-6. [Epub ahead of print] 139289

The role of TBC1D15 in sepsis-induced acute lung injury: Regulation of mitochondrial homeostasis and mitophagy.

Hanghang Han, Yingying Zhang, Enhao Huang, Siyu Zhou, Zijin Huang, Ke Qin, Xueke Du.

  Mitochondrial quality control is crucial in sepsis-induced acute lung injury (SI-ALI). Our study investigates how the intracellular protein TBC1D15 regulates mitochondrial quality to improve SI-ALI. We found TBC1D15 levels significantly decreased in the whole blood of sepsis patients, monocytes, lung tissue from SI-ALI mice, and the MLE-12 cellular model (mouse lung epithelial cells). Overexpression of TBC1D15 using adeno-associated viral and lentiviral vectors alleviated lung injury and inflammation in both mouse models and MLE-12 cells, while silencing TBC1D15 exacerbated inflammatory responses. Mechanistically, TBC1D15 overexpression dissociated mitochondria-lysosome contact duration, promoted mitophagy, and restored mitochondrial function. The protective effects of TBC1D15 were reversed by the mitophagy inhibitor Bafilomycin A1. Additionally, TBC1D15 knockdown prolonged mitochondria-lysosome contact time, resulting in worsened mitochondrial dysfunction and increased oxidative stress. Our findings indicate that SI-ALI is characterized by prolonged mitochondria-lysosome contact and impaired mitophagy. Thus, TBC1D15 overexpression presents a promising therapeutic strategy to mitigate mitochondrial dysfunction and reduce lung injury in septic conditions, suggesting potential clinical applications for SI-ALI treatment.

Keywords:  Mitochondrial homeostasis; Sepsis induced acute lung injury; TBC1D15

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.139289
Sci Rep. 2025 Jan 02. 15(1): 476

MANF overexpression ameliorates oxidative stress-induced apoptosis of human nucleus pulposus cells by facilitating mitophagy through promoting MFN2 expression.

Liang Ma, Xiangyu Meng, Tuerhongjiang Abudurexiti, Yuntao Liu, Jiang Gao, Weibin Sheng.

  Intervertebral disc degeneration (IDD) is a degenerative condition associated with impaired mitophagy. MANF has been shown to promote mitophagy in murine kidneys; however, its role in IDD remains unexplored. This study aimed to elucidate the mechanism by which MANF influences IDD development through the regulation of mitophagy. Human nucleus pulposus (NP) cells were exposed to tert-butyl hydroperoxide (TBHP) to establish an oxidative stress-induced cellular model. The expression levels of MANF in NP cells were quantified using quantitative real-time PCR (qPCR) and Western blotting. The impact of MANF on TBHP-induced NP cells was evaluated by assessing cell viability, apoptosis, and the levels of mitophagy-related proteins. The underlying mechanisms were further investigated using RNA-binding protein immunoprecipitation (RIP), dual-luciferase reporter assays, qPCR, and Western blotting. Results indicated that MANF expression was significantly downregulated in both IDD patients and TBHP-induced NP cells. Overexpression of MANF inhibited apoptosis, enhanced cell viability, and promoted mitophagy in TBHP-treated NP cells. MFN2 was identified as a downstream target of MANF, and MANF overexpression upregulated MFN2 expression in NP cells, whereas TBHP markedly suppressed MFN2 expression. Furthermore, knockdown of MFN2 partially reversed the effects of MANF overexpression on apoptosis, cell viability, and mitophagy in TBHP-treated NP cells. Collectively, these findings demonstrate that MANF overexpression enhances mitophagy by upregulating MFN2 expression, thereby mitigating oxidative stress-induced apoptosis in NP cells. These results provide novel insights into the pathogenesis of IDD.

Keywords:  Intervertebral disc degeneration; MANF; MFN2; Mitophagy

DOI:  https://doi.org/10.1038/s41598-024-84167-9
Cell Death Dis. 2024 Dec 30. 15(12): 934

Mitophagy in ischemic heart disease: molecular mechanisms and clinical management.

Shujuan Xu, Zihan Wang, Fan Guo, Yehao Zhang, Han Peng, Huiyu Zhang, Zixin Liu, Ce Cao, Gaojie Xin, Yuan Yuan Chen, Jianhua Fu.

The influence of the mitochondrial control system on ischemic heart disease has become a major focus of current research. Mitophagy, as a very crucial part of the mitochondrial control system, plays a special role in ischemic heart disease, unlike mitochondrial dynamics. The published reviews have not explored in detail the unique function of mitophagy in ischemic heart disease, therefore, the aim of this paper is to summarize how mitophagy regulates the progression of ischemic heart disease. We conclude that mitophagy affects ischemic heart disease by promoting cardiomyocyte hypertrophy and fibrosis, the progression of oxidative stress, the development of inflammation, and cardiomyocyte death, and that the specific mechanisms of mitophagy are worthy of further investigation.

DOI: https://doi.org/10.1038/s41419-024-07303-3
Aging Dis. 2024 Dec 21.

Mitochondrial Quality Control: A New Perspective in Skeletal Muscle Dysfunction of Chronic Obstructive Pulmonary Disease.

Yanxia Song, Xiaoyu Han, Yingqi Wang, Kangxia Li, Huanping Li, Yizhu Tian, Xiaoqing Ma, Weibing Wu, Jihong Wang.

Skeletal muscle dysfunction (SMD), one of the extrapulmonary complications in patients with chronic obstructive pulmonary disease (COPD), considerably influences patient prognosis. Mitochondria regulates their dynamic networks through a mitochondria quality control (MQC) mechanism, involving mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. The MQC is crucial for mitochondrial homeostasis and health, and disruption of it can lead to mitochondrial damage, which is a key factor in the structural and functional impairment of skeletal muscle in COPD. The mitochondria in the skeletal muscles of these patients undergo changes, mainly including decrease in mitochondrial density and biogenesis levels, imbalanced mitochondrial fission and fusion, and altered mitophagy status. However, the potential mechanisms linking MQC to the damaged structure and function of skeletal muscles in COPD have not been fully clarified. Therefore, this review highlights the effects and potential pathways of the MQC system on the dysfunction of skeletal muscle (muscle atrophy, impaired myogenesis and regeneration, and aerobic endurance) in patients with COPD, and summarizes potential interventions targeted MQC, intending to provide a theoretical basis for further research on COPD, improve SMD, and enhance the quality of life.

DOI: https://doi.org/10.14336/AD.2024.1129
Free Radic Biol Med. 2024 Dec 27. pii: S0891-5849(24)01158-4. [Epub ahead of print]

Lipotoxicity-induced upregulation of FIS1 exacerbates mitochondrial fragmentation and promotes NLRP3-dependent pyroptosis in diabetic cardiomyopathy.

Libo Luo, Qingrui Wu, Qingyu Xiao, Yuqiong Chen, Zhanxiang Deng, Chunren Cen, Jijin Lin.

   BACKGROUND: Lipotoxicity is a significant factor in the pathogenesis of diabetic cardiomyopathy (DbCM), a condition characterized by mitochondrial fragmentation and pyroptosis. Mitochondrial fission protein 1 (FIS1) plays a role in mitochondrial fission by anchoring dynamin-related protein 1 (DRP1). However, the specific contribution of FIS1 to DbCM remains unclear. This study aims to clarify how lipotoxicity-induced upregulation of FIS1 affects mitochondrial fragmentation and the mechanisms linking this fragmentation to NLRP3-dependent pyroptosis in DbCM.
METHODS: To model lipotoxicity in DbCM, we used db/db mice and primary neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA) and conducted a series of in vivo and in vitro experiments. Gain- and loss-of-function studies on NRCMs were performed using pharmacological inhibitors and small interfering RNA (siRNA) transfection, and we assessed the expression and function of FIS1, mitochondrial dynamics, mitochondrial reactive oxygen species (mitoROS) production, NLRP3-dependent pyroptosis, and their interrelationships.
RESULTS: Our results show that in the myocardium of db/db mice, NLRP3-dependent pyroptosis is associated with upregulation of FIS1, mitochondrial fragmentation, and increased oxidative stress. In NRCMs subjected to PA, the application of VX-765 and MCC950 to inhibit caspase-1 and NLRP3, respectively, significantly reduced pyroptosis. Additionally, pretreatment with Mito-TEMPO (MT) demonstrated that mitoROS are critical initiators for NLRP3 inflammasome activation and subsequent pyroptosis. Furthermore, PA-induced upregulation of FIS1 exacerbates mitochondrial fragmentation. Downregulation of FIS1 or inhibition of FIS1/DRP1 interaction reversed mitochondrial fragmentation, reduced mitoROS levels, and mitigated pyroptosis.
CONCLUSIONS: Lipotoxicity-induced FIS1 upregulation exacerbates mitochondrial fragmentation through its interaction with DRP1, leading to increased mitoROS production and the initiation of NLRP3-dependent pyroptosis in DbCM. Therefore, targeting FIS1 emerges as a potential therapeutic approach for managing DbCM.

Keywords:  Diabetic cardiomyopathy; FIS1; Inflammation; Lipotoxicity; Mitochondrial fragmentation; Pyroptosis; mitoROS

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.049
Int Immunopharmacol. 2025 Jan 01. pii: S1567-5769(24)02496-2. [Epub ahead of print]147 113974

CREG1 attenuates intervertebral disc degeneration by alleviating nucleus pulposus cell pyroptosis via the PINK1/Parkin-related mitophagy pathway.

Yang Zhang, Deguo Xing, Yi Liu, Shiyu Sha, Yueying Xiao, Zhonghao Liu, Qingfeng Yin, Zengxin Gao, Wenguang Liu.

  Intervertebral disc degeneration (IVDD) is a chronic degenerative disease with a complex pathophysiological mechanism. Increasing evidence suggests that the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis of nucleus pulposus cells (NPCs) plays a crucial role in the pathological progression of IVDD. Pyroptosis is a novel form of programmed cell death characterized by the formation of plasma membrane pores by gasdermin family proteins, leading to cell swelling, membrane rupture, and the release of inflammatory cytokines, which trigger an inflammatory response. The close relationship between pyroptosis and mitophagy has been previously described in various diseases, but the crosstalk between pyroptosis and mitophagy in IVDD remains unexplored. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and homeostasis regulation and has been shown to promote lysosomal biogenesis and function. However, the potential role and underlying mechanisms of CREG1 in the progression of IVDD have not yet been reported. In this study, we first observed that CREG1 is downregulated following IVDD and that pyroptosis occurs. Furthermore, CREG1 knockdown inhibited NPC proliferation and exacerbated apoptosis and degeneration. Moreover, we confirmed that CREG1 knockdown induced NLRP3 activation while also leading to mitophagy inhibition and mitochondrial dysfunction in NPCs. CREG1 overexpression ameliorated LPS-induced mitophagy inhibition and mitochondrial dysfunction by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. However, these protective effects were reversed by pretreatment with the mitophagy inhibitor cyclosporin A (CsA). In a rat model of IVDD, imaging and histological assessments revealed that CREG1 overexpression effectively alleviated the progression of IVDD. Additionally, CREG1 overexpression reduced the expression of NLRP3, caspase-1, and IL-1β while increasing the expression of collagen II, PINK1 and LC3, delaying the course of IVDD. Overall, this study highlights the importance of the interplay between CREG1-mediated regulation of mitophagy and pyroptosis in the pathogenesis of IVDD, identifying CREG1 as a promising therapeutic target for IVDD treatment.

Keywords:  CREG1; IVDD; Mitophagy; NLRP3 inflammasome; Pyroptosis

DOI:  https://doi.org/10.1016/j.intimp.2024.113974
Mol Metab. 2024 Dec 28. pii: S2212-8778(24)00220-5. [Epub ahead of print] 102089

Metabolic plasticity in pancreatic cancer: The mitochondrial connection.

Noemi Ghiglione, Damiano Abbo, Anastasia Bushunova, Andrea Costamagna, Paolo Ettore Porporato, Miriam Martini.

  Cellular metabolism plays a pivotal role in the development and progression of pancreatic ductal adenocarcinoma (PDAC), with dysregulated metabolic pathways contributing to tumorigenesis and therapeutic resistance. Distinct metabolic heterogeneity exists in pancreatic cancer, impacting patient prognosis, as variations in metabolic profiles influence tumor behavior and treatment responses. Here, we review the intricate interplay between mitochondrial dynamics, mitophagy, and cellular metabolism in PDAC. We highlight the significance of mitophagy dysregulation in PDAC pathogenesis, impacting treatment response and prognosis. Additionally, we examine the impact of mitochondrial dynamics alterations on PDAC progression, focusing on the role of fission and fusion processes in tumorigenesis. Ongoing trials have demonstrated the potential therapeutic value of targeting key regulators of mitochondrial dynamics and mitophagy. Despite challenges, targeting mitochondrial metabolism offers diverse strategies to enhance PDAC treatment efficacy, underscoring its potential in advancing cancer therapeutics.

Keywords:  Metabolism; Mitochondria; Mitophagy; Oxidative phosphorylation; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.molmet.2024.102089
Int Immunopharmacol. 2024 Dec 28. pii: S1567-5769(24)02383-X. [Epub ahead of print]146 113861

Icariside II relieves radiation enteritis by regulating PINK/Parkin-mediated mitophagy.

Shuangyan He, Chengqiu Yan, Zhuo Wang, Yinhui Mao, Kunjian Liu, Juntao Sun, Yueyue Zang, Mingxing Wang, Guofeng Li, Yong Yang.

  Radiation enteritis (RE) is one of the major side effects of radiotherapy. So far, there are no effective drugs for preventing the disease process. Icariside II (ICS II) is a highly efficient monomer compound extracted and purified from the classic Chinese medicinal herb Epimedium. It has anti-inflammatory, antioxidant, and immunomodulatory effects. However, the role and mechanism of ICS II on radiation enteritis are not clear. Here, we reveal the role of ICS II in radiation enteritis by using an irradiation-induced rat model and a human colorectal cancer cell (CaCo2). After intragastric administration, HE staining and Tunel staining to observe the histopathological changes in the colon, and TEM to observe the ultrastructure of mitochondria; The antioxidant indexes and mitochondrial function-related markers of colon tissues were determined; DCFH-DA fluorescent probe were used to detect the cellular ROS level, JC-1 staining was used to detect the changes in mitochondrial membrane potential, and Western Blot was used to detect related protein expression. The results showed that ICS II could reduce intestinal injury and attenuate the radiation-induced oxidative stress and inflammatory response. In addition, ICS II could effectively attenuate mitochondrial damage and activate mitochondrial autophagy in rats. Mechanistically, ICS II activates mitochondrial autophagy-related protein expression to rescue radiation-induced damage to mitophagy. We found that by inhibiting mitophagy, the therapeutic effect of ICS II can be eliminated and our data suggest that ICS II may be a new and effective drug candidate for the treatment of radiation enteritis.

Keywords:  Icariside II; Intestinal barrier function; Mitophagy; ROS; Radiation enteritis

DOI:  https://doi.org/10.1016/j.intimp.2024.113861
Eur J Pharmacol. 2024 Dec 30. pii: S0014-2999(24)00913-0. [Epub ahead of print] 177223

Harmine-Induced Disruption of the Blood-Brain Barrier via Excessive Mitophagy in Zebrafish.

Yi Wu, Menghui He, Ying He, Tingting Jin, Siju Li, Feng He.

  Stroke is a serious condition with sudden onset, high severity, and significant rates of mortality and disability, ranking as the second leading cause of death globally at 11.6%. Hemorrhagic stroke, characterized by non-traumatic rupture of cerebral vessels, can cause secondary brain injury such as neurotoxicity, inflammation, reactive oxygen species, and blood-brain barrier (BBB) damage. The integrity of the BBB plays a crucial role in stroke outcomes, as its disruption can exacerbate injury. Harmine, a natural β-carboline alkaloid, has been studied for various pharmacological effects, including its potential benefits in protecting cardiac and cognitive functions. However, its impact on cerebrovascular conditions, particularly in the context of stroke, remains underexplored. This study investigates harmine's effects on BBB integrity and its role in inducing cerebral hemorrhage in zebrafish. We found that harmine disrupts BBB permeability, leading to cerebral hemorrhage through modulation of tight junction protein Claudin-5 and cytoskeletal protein F-actin expression. Furthermore, harmine altered mitochondrial morphology, causing structural imbalance, excessive mitophagy, and cell death. Together, these data indicate that harmine can induce BBB damage and intracerebral hemorrhage in zebrafish, and provide a possible mechanism and explanation for this effect.

Keywords:  BBB; Cerebral hemorrhage; Harmine; M-L contact; mitophagy

DOI:  https://doi.org/10.1016/j.ejphar.2024.177223
Inflammation. 2024 Dec 30.

LncRNA Tug1 Regulates Post-Stroke Microglial Pyroptosis via PINK1/Parkin-Mediated Mitophagy.

Meiling Yao, Xiaobei Wang, Hao Lin, Hui Shu, Zongtang Xu, Ling Tang, Wenyuan Guo, Pingyi Xu.

  Microglia, the central nervous system's primary immune cells, play a key role in the progression of cerebral ischemic stroke, particularly through their involvement in pyroptosis. The long non-coding RNA taurine up-regulated gene 1 (Tug1) is elevated during ischemic stroke and is critical in driving post-stroke neuroinflammation. However, the underlying molecular mechanisms remain unclear. This study explores the biological role of Tug1 and its potential mechanisms in regulating pyroptosis in microglia. We utilized an in vivo photothrombosis (PT) mice model and an in vitro oxygen-glucose deprivation and reperfusion (OGD/R) BV2 cell model to explore the mechanisms underlying ischemic stroke. Initially, we assessed the expression levels of Tug1 in the OGD/R model in vitro and the PT model in vivo. Subsequently, we investigated the impact of Tug1 on microglial pyroptosis by knocking down Tug1, silencing the PTEN-induced putative kinase 1 (Pink1) expression, and employing the mitophagy inhibitor mdivi-1. Tug1 exacerbated microglial pyroptosis by inhibiting mitophagy in both in vivo and in vitro models. The increase in mitophagy observed following Tug1 knockdown was reversed by either silencing Pink1 expression or using the mitophagy inhibitor mdivi-1. This reversal resulted in exacerbated pyroptosis and worsened neurological damage. Further mechanistic studies revealed that Tug1 knockdown significantly reduced microglial pyroptosis and alleviated neuronal damage by enhancing PINK1/Parkin-mediated mitophagy. For the first time, this study reveals that Tug1 promotes hypoxia-induced microglial pyroptosis by inhibiting PINK1/Parkin-mediated mitophagy, potentially providing a promising therapeutic target for ischemic inflammatory injury.

Keywords:  Autophagy; Ischemic Stroke; LncRNA Tug1 ; Pyroptosis

DOI:  https://doi.org/10.1007/s10753-024-02219-8
Int J Biol Sci. 2025 ;21(1): 233-250

Aberrant activation of adenine nucleotide translocase 3 promotes progression and chemoresistance in multiple myeloma dependent on PINK1 transport.

Ke Hu, Yue Lai, Jinfeng Zhou, Chaolu Hu, Shushan Guo, Hui Zhang, Guanli Wang, Qikai Zhang, Xuejie Gao, Zhuning Wang, Yujie Liu, Qilin Feng, Hongfei Yi, Yu Peng, Yifei Zhang, Xiaosong Wu, Haiyan Cai, Jumei Shi.

  Chemoresistance is an important factor in multiple myeloma (MM) relapse and overall survival. However, the mechanism underlying resistance remains unclear. In this study, we identified adenine nucleotide translocase 3 (ANT3) as a novel biomarker and therapeutic target for MM progression and resistance to the proteasome inhibitor bortezomib (BTZ). The oncogenic functions of ANT3 in MM were verified using MM sensitive/drug-resistant cells, bone marrow tissues from patients with MM, orthotopic MM model, and subcutaneous tumor model. ANT3 knockdown impaired MM cell proliferation owing to a lack of cellular ATP levels, causing cell cycle arrest in the G0/G1 phase. Moreover, our study showed that ANT3 leads to BTZ resistance by promoting mitophagy. Notably, ANT3-mediated mitophagy is independent of its biological function as an ADP/ATP translocase. Mechanistically, ANT3 interacts with mitochondrial inner and outer membrane transporters, including Timm22 and Tomm20, thus restricting PINK1 import to the inner membrane of mitochondria. In this case, PINK1 is stabilized in the outer membrane of the mitochondria and recruits Parkin, resulting in mitophagy. Furthermore, targeted intervention with ANT3 combined with BTZ limited the growth of BTZ-resistant myeloma in vivo. This study identified ANT3 as a novel biomarker and therapeutic target for MM.

Keywords:  Adenine nucleotide translocase 3; Bortezomib resistance; Mitophagy; Multiple myeloma

DOI:  https://doi.org/10.7150/ijbs.101850
Arch Biochem Biophys. 2024 Dec 30. pii: S0003-9861(24)00405-3. [Epub ahead of print]764 110283

Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.

Yixin Li, Wanying Zhang, Qihang Zhang, Yunzhe Li, Chonghui Xin, Rongze Tu, Haijing Yan.

  Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.

Keywords:  Carnosine; Mitophagy; Neurodegenerative disease; Oxidative stress

DOI:  https://doi.org/10.1016/j.abb.2024.110283
J Ethnopharmacol. 2024 Dec 27. pii: S0378-8741(24)01584-8. [Epub ahead of print] 119285

Rg1 Improves Alzheimer's disease by Regulating Mitochondrial Dynamics Mediated by the AMPK/Drp1 Signaling Pathway.

Yini Zhang, Shangzhi Liu, Di Cao, Min Zhao, Haifei Lu, Ping Wang.

   ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by a complex pathogenesis that includes Aβ deposition, abnormal phosphorylation of tau protein, chronic neuroinflammation, and mitochondrial dysfunction. In traditional medicine, ginseng is revered as the 'king of herbs'. Ginseng has the effects of greatly tonifying vital energy, strengthening the spleen and benefiting the lungs, generating fluids and nourishing the blood, and calming the mind while enhancing intelligence. Ginsenoside Rg1 (Rg1) is a well-defined major active component found in ginseng, known for its relatively high content. It has been demonstrated to exhibit neuroprotective effects in both in vivo and in vitro models, capable of ameliorating Aβ and tau pathology, regulating synaptic function, and reducing inflammation, oxidative stress, and apoptosis. However, the potential of Rg1 to improve AD pathology through the regulation of mitochondrial dynamics is still uncertain.
AIM OF THE STUDY: Despite the active research efforts on drugs for AD, the currently available anti-AD medications can only slow disease progression and manage symptoms, yet unable to provide a cure for AD. Furthermore, some anti-AD drugs failed phase III and IV clinical trials due to significant side effects. Therefore, there is an urgent need to further investigate the pathogenesis of AD, to identify new therapeutic targets, and to explore more effective therapies. The aim of this study is to evaluate the potential therapeutic effects of Rg1 on APP/PS1 double transgenic mice and Aβ42-induced HT22 cell models, and to investigate the potential mechanisms through which it provides neuroprotective effects.
MATERIALS AND METHODS: This study investigates the effects of Rg1 in treating AD on APP/PS1 double transgenic mice and Aβ42-induced HT22 cells. In the in vivo experiments, APP/PS1 mice were divided into a model group, Rg1-L group, Rg1-H group, and donepezil group, with C57BL/6 mice serving as the control group (n = 12 per group). The Rg1-L and Rg1-H groups were administered Rg1 at doses of 5 mg/kg/d and 10 mg/kg/d, respectively, while the donepezil group received donepezil at a dose of 1.3 mg/kg/d. Both the control and model groups received an equal volume of physiological saline daily for 28 days. Learning and spatial memory were assessed by the Morris water maze (MWM) and novel object recognition (NOR) tests, and neuronal damage by Nissl staining. Aβ deposition was analyzed through immunohistochemistry and Western blot, while the expression levels of synaptic proteins PSD95 and SYN were evaluated via immunofluorescence staining and Western blot. The dendritic spines of neurons was observed by Golgi staining .The ultrastructure of neuronal mitochondria and synapses was examined by transmission electron microscopy (TEM). Mitochondrial function was assessed through measurements of Reactive oxygen species (ROS), Superoxide Dismutase (SOD), and Adenosine Triphosphate (ATP), and Western blot analysis was performed to detect the expression levels of AMPK, p-AMPK, Drp1, p-Drp1, OPA1, Mfn1, and Mfn2, thereby investigating the protective effects of Rg1 on mitochondrial dysfunction and cognitive impairment in APP/PS1 double transgenic mice. In vitro experiments, HT22 cells were treated with Aβ42 of 10 μM for 24 hours to verify the therapeutic effects of Rg1. Flow cytometry was used to detect ROS and JC-1, biochemical methods were employed to measure SOD and ATP, immunofluorescence staining was used to detect the expression levels of PSD95 and SYN, and Western blot analysis was conducted to elucidate its potential mechanisms of action.
RESULTS: The findings suggest that after 28 days of Rg1 treatment, cognitive dysfunction in APP/PS1 mice was improved. Pathological and immunohistochemical analyses demonstrated that Rg1 treatment significantly reduced Aβ deposition and neuronal loss. Rg1 can improve synaptic dysfunction and mitochondrial function in APP/PS1 mice. Rg1 activated AMPK, enhanced p-AMPK expression, inhibited Drp1, and reduced p-Drp1 levels, which led to increased expression of OPA1, Mfn1, and Mfn2, thereby inhibiting mitochondrial fission and facilitating mitochondrial fusion. Additionally, Rg1 effectively reversed the decrease in mitochondrial membrane potential (MMP) and the increase in ROS production induced by Aβ42 in HT22 cells, restoring SOD and ATP levels. Furthermore, Rg1 regulated mitochondrial fission mediated by the AMPK/Drp1 signaling pathway, promoting mitochondrial fusion and improving synaptic dysfunction.
CONCLUSION: Our research provides evidence for the neuroprotective mechanisms of Rg1 in AD models. Rg1 modulates mitochondrial dynamics through the AMPK/Drp1 signaling pathway, thereby reducing synaptic and mitochondrial dysfunction in APP/PS1 mice and AD cell models.

Keywords:  AMPK/Drp1; Alzheimer’s disease (AD); Mitochondrial dynamics; Mitochondrial dysfunction; Rg1; synaptic dysfunction

DOI:  https://doi.org/10.1016/j.jep.2024.119285
Front Immunol. 2024 ;15 1509370

ATP5J regulates microglial activation via mitochondrial dysfunction, exacerbating neuroinflammation in intracerebral hemorrhage.

Naixin Ren, Hutao Zhang, Tao Li, Huafang Ji, Zhen Zhang, He Wu.

  Microglial-mediated neuroinflammation is crucial in the pathophysiological mechanisms of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Mitochondria are central regulators of inflammation, influencing key pathways such as alternative splicing, and play a critical role in cell differentiation and function. Mitochondrial ATP synthase coupling factor 6 (ATP5J) participates in various pathological processes, such as cell proliferation, migration, and inflammation. However, the role of ATP5J in microglial activation and neuroinflammation post-ICH is poorly understood. This study aimed to investigate the effects of ATP5J on microglial activation and subsequent neuroinflammation in ICH and to elucidate the underlying mechanisms. We observed that ATP5J was upregulated in microglia after ICH. AAV9-mediated ATP5J overexpression worsened neurobehavioral deficits, disrupted the blood-brain barrier, and increased brain water content in ICH mice. Conversely, ATP5J knockdown ameliorated these effects. ATP5J overexpression also intensified microglial activation, neuronal apoptosis, and inflammatory responses in surrounding tissues post-ICH. ATP5J impaired microglial dynamics and reduced the proliferation and migration of microglia to injury sites. We used oxyhemoglobin (OxyHb) to stimulate BV2 cells and model ICH in vitro. Further in vitro studies showed that ATP5J overexpression enhanced OxyHb-induced microglial functional transformation. Mechanistically, ATP5J silencing reversed dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) upregulation in microglia post-OxyHb induction; reduced mitochondrial overdivision, excessive mitochondrial permeability transition pore opening, and reactive oxygen species production; restored normal mitochondrial ridge morphology; and partially restored mitochondrial respiratory electron transport chain activity. ATP5J silencing further alleviated OxyHb-induced mitochondrial dysfunction by regulating mitochondrial metabolism. Our results indicate that ATP5J is a key factor in regulating microglial functional transformation post-ICH by modulating mitochondrial dysfunction and metabolism, thereby positively regulate neuroinflammation. By inhibiting ATP5J, SBI following ICH could be prevented. Therefore, ATP5J could be a candidate for molecular and therapeutic target exploration to alleviate neuroinflammation post-ICH.

Keywords:  ATP5J; intracerebral hemorrhage; microglia; mitochondrial reprogramming; secondary brain injury

DOI:  https://doi.org/10.3389/fimmu.2024.1509370
Brain Res Bull. 2024 Dec 28. pii: S0361-9230(24)00318-6. [Epub ahead of print] 111184

Deciphering Glioblastoma Pathogenesis: Insights from Mitophagy Dysregulation and SNX7 as a Therapeutic Target.

Yuanlong Zhang, Binghong Chen, Renfu Liu, Wenzhong Mei, Yuanxiang Lin.

   BACKGROUND: Glioblastoma is a highly aggressive and invasive brain tumor with an extremely poor prognosis. The aims of the present study are to investigate the pathogenesis of glioblastoma and identify potential therapeutic targets.
METHODS: We performed a systematic analysis of gene expression data from multiple datasets, including GEO and TCGA, to identify hub genes and pathways associated with glioblastoma progression. Bioinformatics tools were utilized to analyze differential gene expression, pathway enrichment and survival prognosis. Both in vitro and in vivo functional experiments were conducted to validate biological roles of SNX7.
RESULTS: Pathway analysis revealed significant enrichment of the mitophagy pathway in glioblastoma, indicating its critical role in tumor development. We identified 12 hub genes associated with glioblastoma prognosis, with high-risk patients having worse survival outcomes. Among the hub gene set, sorting nexin 7 (SNX7) was found to be the most significant regulator of glioblastoma progression. Our results also demonstrated that SNX7 expression is associated with tumor ferroptosis and genomic variations, representing potential biomarkers for clinical diagnosis and treatment. Furthermore, functional experiments confirmed that SNX7 promotes glioblastoma cell proliferation, invasion and survival by inhibiting protective mitophagy.
CONCLUSION: Our results highlight the importance of mitophagy dysregulation in the pathogenesis of glioblastoma and identify SNX7 as a novel therapeutic target. Further research is needed to elucidate the underlying mechanisms of SNX7 in glioblastoma and validate its clinical significance. These findings may facilitate the development of personalized treatment strategies and improve outcomes for glioblastoma patients.

Keywords:  Autophagy; Gene expression profiling; Glioblastoma; Mitophagy prognostic model; Sorting Nexin 7

DOI:  https://doi.org/10.1016/j.brainresbull.2024.111184
Nat Commun. 2024 Dec 30. 15(1): 10806

DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.

Jorge Gómez-Deza, Matthew Nebiyou, Mor R Alkaslasi, Francisco M Nadal-Nicolás, Preethi Somasundaram, Anastasia L Slavutsky, Wei Li, Michael E Ward, Trent A Watkins, Claire E Le Pichon.

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-024-54982-9
J Ethnopharmacol. 2024 Dec 27. pii: S0378-8741(24)01596-4. [Epub ahead of print]340 119297

Rostellularia procumbens (L) Nees. extract attenuates adriamycin-induced nephropathy by maintaining mitochondrial dynamics balance via SIRT1/PGC-1α signaling pathway activation.

Zhongzhu Ai, Dongfeng Yuan, Ruotong Dong, Shanshan Zhou, Jigang Cao.

   ETHNOPHARMACOLOGICAL RELEVANCE: Rostellularia procumbens (L) Nees. (R. procumbens) is a classical Chinese herbal medicine that has been used for effective treatment of kidney disease for nearly a thousand years in China. Recently, significant progress has been achieved in understanding the abnormal mitochondrial structure and function from chronic kidney disease (CKD). However, the regulatory mechanisms underlying R. procumbens treatment for CKD and its association with dysfunctional mitochondrial function remain elusive.
AIM OF THE STUDY: To study the protective effect of N-butanol extract from R. procumbens (J-NE) on chronic glomerulonephritis (CGN) mice using a mice model and mitochondrial function-related experiments.
MATERIALS AND METHODS: A renal injury mouse model was developed using a single tail vein injection of adriamycin (9 mg/kg). Renal pathology was analyzed through hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Cell apoptosis in kidney tissues was analyzed using TUNEL staining. Protein levels were measured via immunohistochemistry (HIF-1α, FN, α-SMA, and Collagen I) and Western blot (Mn-SOD, p-Drp-S637, MFN1, MFN2, OPA1, TFAM, Nrf1, ATP6, SIRT1, and PGC-1α) analysis. UHPLC-MS/MS was used to analyze the presence of bioactive phytocompounds in J-NE.
RESULTS: The results reported that the levels of kidney injury markers (urinary protein, glomerular atrophy, and renal cell apoptosis), mitochondrial dysfunction markers (mitochondrial ultrastructure, Mn-SOD, HIF-1α, FN and α-SMA),mitochondrial dynamic imbalance markers (p-Drp-S637, MFN1, MFN2 and OPA1) and SIRT1/PGC-1α signaling pathway markers (TFAM, Nrf1, ATP6, SIRT1, and PGC-1α) were settled to a significant improvement by the oral administration of J-NE.
CONCLUSIONS: In conclusion, R. procumbens could be able to protect the kidneys from podocyte injury caused mitochondrial dynamics and energy metabolism dysregulation by modulating the SIRT1/PGC-1α signaling pathway.

Keywords:  Adriamycin-induced nephropathy; Energy metabolism; Mitochondrial dynamics; Rostellularia procumbens (L) nees.; SIRT1/PGC-1α

DOI:  https://doi.org/10.1016/j.jep.2024.119297
Curr Opin Cell Biol. 2024 Dec 29. pii: S0955-0674(24)00139-X. [Epub ahead of print]92 102460

Beyond static snapshots: Mitochondria in action.

Julien Cicero, Uri Manor.

Mitochondria are dynamic organelles essential for cellular homeostasis, undergoing continuous fission and fusion processes that regulate their morphology, distribution, and function. Disruptions in these dynamics are linked to numerous diseases, including neurodegenerative disorders and cancer. Understanding these processes is vital for developing therapeutic strategies aimed at mitigating mitochondrial dysfunction. This review provides an overview of recent perspectives on mitochondrial dynamics, focusing on the need for live video microscopy imaging in order to fully understand mitochondrial phenotypes and pathology. Advanced imaging tools, such as machine learning-based segmentation and label-free microscopy approaches, have the potential to transform our ability to study mitochondrial dynamics in live cells.

DOI: https://doi.org/10.1016/j.ceb.2024.102460
Adv Sci (Weinh). 2024 Dec 31. e2411943

Aldehyde Dehydrogenase 2 Lactylation Aggravates Mitochondrial Dysfunction by Disrupting PHB2 Mediated Mitophagy in Acute Kidney Injury.

Jiaying Li, Xiaoxiao Shi, Jiatong Xu, Kaiyue Wang, Fangxing Hou, Xiaodong Luan, Limeng Chen.

  Mitochondrial dysfunction is a crucial event in acute kidney injury (AKI), leading to a metabolic shift toward glycolysis and increased lactate production. Lactylation, a posttranslational modification derived from lactate, plays a significant role in various cellular processes, yet its implications in AKI remain underexplored. Here, a marked increase in lactate levels and pan-Kla levels are observed in kidney tissue from AKI patients and mice, with pronounced lactylation activity in injured proximal tubular cells identified by single-cell RNA sequencing. The lactylation of aldehyde dehydrogenase 2 (ALDH2) is identified at lysine 52 (K52la), revealing that ALDH2 lactylation exacerbates tubular injury and mitochondrial dysfunction. Conversely, the ALDH2 K52R mutation alleviates these injuries in HK-2 cells and adeno-associated virus-infected kidney tissues in mice. Furthermore, ALDH2 lactylation can be modulated by upregulating SIRT3 in vivo and in vitro, which reduces ALDH2 lactylation, mitigating tubular injury and mitochondrial dysfunction. Mechanistically, immunoprecipitation-mass spectrometry analysis demonstrates an interaction between ALDH2 and prohibitin 2 (PHB2), a crucial mitophagy receptor. ALDH2 lactylation promotes the ubiquitination-proteasomal degradation of PHB2 to inhibit mitophagy and worsen mitochondrial dysfunction. These findings highlight the critical role of endogenous lactate in AKI and propose ALDH2 lactylation as a potential therapeutic target.

Keywords:  ALHD2; acute kidney injury; lactylation; mitochondrial function; mitophagy

DOI:  https://doi.org/10.1002/advs.202411943
Front Aging Neurosci. 2024 ;16 1489214

Hippocampal SIRT1 signaling mediates the ameliorative effect of treadmill exercise on anxiety- and depression-like behavior in APP/PS1 mice.

Yarong Wang, Rongxing Zhang, Yumin Jiang, Jingwen Liao, Lianwei Mu, Min Hu.

   Objective: Anxiety and depression-like symptoms occur in the early stages of Alzheimer's disease. Hippocampal Sirtuin 1 (SIRT1) signaling mediates anxiety- and depression-like behavior. Exercise training improves anxiety and depression-like behavior in various disease models, such as the rat chronic restraint stress model, rat model of posttraumatic stress disorder, and rat model of fetal alcohol spectrum disorders. Here, we aimed to investigate whether exercise ameliorates anxiety- and depression like behaviors in APP/PS1 mice and explore the potential mechanisms.
Methods: After eight weeks of exercise intervention, we assessed anxiety- and depression-like behaviors in Alzheimer's disease (AD) model mice. We then measured the levels of SIRT1, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and mitochondrial biogenesis (CO2, ATP6, and mitochondrial content) using immunofluorescence, reverse transcription-quantitative real-time PCR, and transmission electron microscopy. Finally, we investigated the effects of pharmacological activation of SIRT1 on anxiety- and depression-like behaviors, the SIRT1/PGC-1α/NRF1/TFAM signaling axis, and mitochondrial biogenesis.
Results: We first observed that treadmill exercise improved anxiety- and depression-like behaviors in six-month-old APP/PS1 mice and increased SIRT1 levels in the hippocampus. Pharmacological activation of hippocampal SIRT1 function also reduced anxiety and depression-like behaviors in APP/PS1 mice. Meanwhile, both treadmill exercise and pharmacological activation of hippocampal SIRT1 increased the levels of PGC1α, NRF1, TFAM, and enhanced mitochondrial biogenesis (CO2, ATP6, or mitochondrial content) in the hippocampus of APP/PS1 mice.
Conclusion: These findings reveal that treadmill exercise reduces anxiety- and depression-like behaviors in six-month-old APP/PS1 mice by enhancing the SIRT1-dependent PGC-1α/NRF1/TFAM axis, promoting mitochondrial biogenesis in the hippocampus.

Keywords:  APP/PS1 mice; SIRT1; anxiety-and depression-like behaviors; mitochondrial; treadmill exercise

DOI:  https://doi.org/10.3389/fnagi.2024.1489214
Redox Biol. 2024 Dec 27. pii: S2213-2317(24)00449-X. [Epub ahead of print]79 103471

Cardiomyocyte-specific Piezo1 deficiency mitigates ischemia-reperfusion injury by preserving mitochondrial homeostasis.

Honglin Xu, Xin Chen, Shangfei Luo, Jintao Jiang, Xianmei Pan, Yu He, Bo Deng, Silin Liu, Rentao Wan, Liwen Lin, Qiaorui Tan, Xiaoting Chen, Youfen Yao, Bin He, Yajuan An, Jing Li.

  Ca2+ overload and mitochondrial dysfunction play crucial roles in myocardial ischemia-reperfusion (I/R) injury. Piezo1, a mechanosensitive cation channel, is essential for intracellular Ca2+ homeostasis. The objective of this research was to explore the effects of Piezo1 on mitochondrial function during myocardial I/R injury. We showed that the expression of myocardial Piezo1 was elevated in the infracted area of I/R and cardiomyocyte-specific Piezo1 deficiency (Piezo1△Myh6) mice attenuated I/R by decreasing infarct size and cardiac dysfunction. Piezo1△Myh6 regulated mitochondrial fusion and fission to improve mitochondrial function and decrease inflammation and oxidative stress in vivo and in vitro. Mechanistically, myocardial Piezo1 knockout alleviated intracellular calcium overload to normalize calpain-associated mitochondrial homeostasis. Our findings indicated that Piezo1 depletion in cardiomyocytes partially restored mitochondrial homeostasis during cardiac ischemia/reperfusion (I/R) injury. This study suggests an innovative therapeutic strategy to alleviate cardiac I/R injury.

Keywords:  Calpain; Cardiomyocytes; I/R; Inflammation; Mitochondria; Piezo1

DOI:  https://doi.org/10.1016/j.redox.2024.103471
PLoS One. 2024 ;19(12): e0306243

Loss of Mfn1 but not Mfn2 enhances adipogenesis.

Jake P Mann, Luis Carlos Tábara, Satish Patel, Pushpa Pushpa, Anna Alvarez-Guaita, Liang Dong, Afreen Haider, Koini Lim, Panna Tandon, Fabio Scurria, James E N Minchin, Stephen O'Rahilly S, Daniel J Fazakerley, Julien Prudent, Robert K Semple, David B Savage.

OBJECTIVE: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells.
METHODS: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA.
RESULTS: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings.
CONCLUSIONS: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.

DOI: https://doi.org/10.1371/journal.pone.0306243
Sci Rep. 2024 Dec 28. 14(1): 31447

Resolvin D1 combined with exercise rehabilitation alleviates neurological injury in mice with intracranial hemorrhage via the BDNF/TrkB/PI3K/AKT pathway.

Lv Xiaoyu, Li Dandan, Ouyang Tianzhao, Zhang Ziyou, Liu Zhenlin, Li Zhuang, Liu Mingrui, He Yusong, Zhong Yangyang, Li Yanjiao, Shi Chun, Wang Siqi, Li Tong, Zhang Bensi.

  Resolvin D1 (RvD1) is an endogenous anti-inflammatory mediator that modulates the inflammatory response and promotes inflammation resolution. RvD1 has demonstrated neuroprotective effects in various central nervous system contexts; however, its role in the pathophysiological processes of intracerebral hemorrhage (ICH) and the potential protective mechanisms when combined with exercise rehabilitation remain unclear. A mouse model of ICH was established using collagenase, and treatment with RvD1 combined with three weeks of exercise rehabilitation significantly improved neurological deficits, muscle strength, learning, and memory in ICH mice while reducing anxiety-like behavior. RvD1 combined with exercise rehabilitation upregulated anti-inflammatory factors, inhibited the inflammatory state, and activated the BDNF/TrkB/PI3K/AKT pathway. TUNEL staining confirmed a decrease in residual apoptotic neurons, while transmission electron microscopy showed an increase in mitochondrial autophagosomes with combined treatment. Mendelian randomization and molecular docking further confirmed the association of RvD1 with targets related to mitophagy and inflammatory factors, clarifying the mechanism of RvD1 involvement. In summary, RvD1 combined with exercise rehabilitation activates the BDNF/TrkB/PI3K/AKT signaling pathway, effectively reduces neuronal apoptosis and inflammatory responses following ICH in mice, and participates in mitochondrial autophagy-related states. This comprehensive therapeutic strategy promotes neurological recovery and provides insights for clinical management of this condition.

Keywords:  Inflammation; Intracerebral hemorrhage; Mitophagy; Neuronal Apoptosis; RvD1; exercise rehabilitation

DOI:  https://doi.org/10.1038/s41598-024-83019-w
Sci Rep. 2024 Dec 28. 14(1): 31401

Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.

Ken Ohno, Hisashi Murakami, Naohisa Ogo, Akira Asai.

  The cell painting assay is useful for understanding cellular phenotypic changes and drug effects. To identify other aspects of well-known chemicals, we screened 258 compounds with the cell painting assay and focused on a mitochondrial punctate phenotype seen with disulfiram. To elucidate the reason for this punctate phenotype, we looked for clues by examining staining steps and gene knockdown as well as examining protein solubility and comparing cell lines. From these results, we found that the punctate phenotype was caused by protein insolubility in the mitochondrial matrix. Interestingly, the punctate phenotype of disulfiram was sensitive to the relative expression of LonP1, a protease in the mitochondrial matrix that regulates proteostasis, suggesting that the punctate phenotype manifests when the protein quality control capacity in the mitochondrial matrix is exceeded. Moreover, we discovered that disulfiram and its derivatives, which have all been reported to increase acetaldehyde in the blood after the in vivo intake of alcohol, induced a punctate phenotype as well. The investigated punctate phenotype not only provides a novel clue for elucidating the common mechanism of action among disulfiram derivatives but is also a novel example of chemical perturbation of proteostasis in the mitochondrial matrix.

Keywords:  Cell painting assay; Disulfiram; LonP1; Oligomycin A; Protein insolubility; Proteostasis

DOI:  https://doi.org/10.1038/s41598-024-82939-x
Am J Physiol Cell Physiol. 2024 Dec 31.

CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy.

Guiyin Zhu, Haiyang Yu, Xiaoming Li, Wenjing Ye, Xi Chen, Wen Gu.

  CD147 has the potential to serve as a specific target with therapeutic characteristics in several respiratory diseases. Studies have demonstrated that CD147 regulates levels of oxidative phosphorylation (OXPHOS) through the process of mitochondrial translocations. However, there is still limited insight in the distinct mechanism of CD147 in asthmatic macrophages. Here, we found that CD147 expression levels increased significantly both in vivo and in vitro. CD147 undergoes mitochondrial translocation in M2 macrophages. Reducing the expression of CD147 resulted in a decline in M2 polarization levels within macrophages, as well as a decrease in the levels of mitochondrial respiratory chain complex I, II, and IV proteins. This effect may be attained by interacting with ANT1, subsequently impacting the levels of mitophagy. We also discovered that CD147 knockdown significantly reduced airway remodeling and inflammation in addition to lowering the polarization level of M2 in the lung tissues of chronic asthmatic model mice. The findings represent the first evidence of the distinct function of CD147 in the process of airway remodeling in asthma.

Keywords:  CD147; M2 polarization; airway remodeling; macrophages; mitochondrial translocation

DOI:  https://doi.org/10.1152/ajpcell.00735.2024
Exp Hematol Oncol. 2024 Dec 28. 13(1): 123

AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.

HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen.

  Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. We report on AOH1996 (AOH), an oral compound targeting cancer-associated PCNA, which shows significant antileukemic activity. AOH inhibited growth in AML cell lines and primary CD34 + CD38 - blasts (LSC-enriched) in vitro while sparing normal hematopoietic stem cells (HSCs). In vivo, AOH-treated mice demonstrated prolonged survival compared to controls (50 vs. 35 days; p < 0.0001) with reduced LSC burden, as shown in secondary transplants (42 vs. 30 days, p < 0.0001). Mechanistically, AOH disrupted mitochondrial PCNA's binding to the OPA1 protein, enhancing OPA1's interaction with its E3 ligase, MARCH5, which led to OPA1 degradation. This process reduced mitochondrial length, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby inhibiting LSC expansion. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential.

Keywords:  AML; AOH1996; Leukemic stem cells; Mitochondrial metabolism; PCNA inhibitor

DOI:  https://doi.org/10.1186/s40164-024-00586-4
Zhonghua Kou Qiang Yi Xue Za Zhi. 2025 Jan 02. 60(1): 43-53

[Mitochondrial transfer contributes to the odontogenic differentiation of dental mesenchymal stem cells].

X Y Li, L Zhang, Y Sun.

Objective: To investigate whether there is mitochondrial transfer in dental mesenchymal stem cells (MSCs) and its significance for the odontogenic differentiation. Methods: Flow cytometry and immunohistochemical staining were used to isolate dental mesenchymal stem cells. Immunofluorescence staining and live cell imaging were applied to determine whether there is mitochondrial transfer in dental MSCs. Transcriptome sequencing data re-analysis of human dental pulp stem cells (DPSCs) and bone marrow mesenchymal stem cells (BMSCs) from gene expression omnibus (GEO) data base demonstrated the importance of mitochondrial transfer in dental MSCs. Cells were managed with mitochondrial transfer inhibitor ML141 with dimethyl sulfoxide as the control. Immunofluorescence staining, senescence-associated β-galactosidase (SA-β-gal) staining, reactive oxygen species (ROS) assay, 5-ethynyl-2'-deoxyuridine(Edu) labelling, cell counting kit-8 (CCK-8) assay, Western blotting, live cell imaging and transmission electron microscope were used to investigate cell morphology, ROS level, cellular senescence, cell proliferation, MSCs marker paired related homeobox 1 (Prrx1) and Sp7 transcription factor (Sp7) expression, mitochondrial transfer and mitochondrial morphology, respectively. Further, after using ML141 during the induction of odontogenic differentiation, alkaline phosphatase (ALP) chromogenic kit was used to detect ALP activity and real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expression of odontogenic differentiation-related genes Alp, Sp7, dentin matrix protein 1 (Dmp1), and dentin salivary phosphoprotein (Dspp), which were applied to investigate the effect of mitochondrial transfer on odontogenic differentiation. Results: An ultrafine tunneling nanotubes (TNTs) structure labelled with F-actin existed between dental MSCs, and the presence of transferring mitochondria in this structure was also confirmed. Transcriptome sequencing data suggested that the gene expression profiles were significantly different between DPSCs and BMSCs. Genes related to mitochondrial transfer and mitochondrial dynamic were significantly increased in DPSCs compared to BMSCs. Compared with the control group, treatment with 1, 5, 10 μmol/L ML141, the mitochondrial transfer inhibitor, had little significant effects on the cell morphology, cytoskeleton and ROS level. SA-β-gal activity and the proportion of SA-β-gal positive cells in the ML141-treated groups [(3.93±0.21)%, (3.23±0.42)%, (4.06±0.84)%] had no significant differences with the control group [(3.83±0.28)%] (all P>0.05). In the cell proliferation assay, the proportion of EdU positive cells in the ML141-treated groups [(20.00±3.82)%, (19.48±1.96)%, (12.55±2.86)%] had no significant differences (all P>0.05) with the control group [(18.57±0.87)%], whereas the CCK-8 assay showed similar results in ML141-treated group of 1, 5 μmol/L all P>0.05. Western blotting results showed that the protein expression levels of PRRX1 and SP7 in the ML141-treated group had no significant differences with the control group. Live cell imaging showed that compared with the control group [(31.42±4.01)%], the proportion of TNTs and mitochondrial transfer in the ML141-treated groups [(13.45±1.46)%, (10.36±3.47)%, (9.32±1.11)%] were significantly decreased in dental MSCs (all P<0.001). Scanning electron microscope showed that the mitochondrial morphology of dental MSCs in the ML141-treated group was similar to the control group, with globular and short-rod shape. After 7 days of odontogenic differentiation, the ALP staining intensity of the ML141-treated group was significantly lower than the control group. After 21 days of induction, RT-qPCR results showed that compared with control group, the relative mRNA expressions of Alp, Sp7, Dmp1 and Dspp were significantly decreased in the ML141-treated group (all P<0.05), indicating that the suppression of mitochondrial transfer in dental MSCs inhibited the odontogenic differentiation. Conclusions: Mitochondrial transfer exists between dental MSCs, and inhibition of mitochondrial transfer impairs the odontogenic differentiation.

DOI: https://doi.org/10.3760/cma.j.cn112144-20240926-00360
Int J Med Sci. 2025 ;22(1): 71-86

Receptor-Interacting Protein Kinase 3-Mediated Modulation of Endothelial Cell Necroptosis and Mitochondrial Dysfunction through AMPK/Drp1 Signaling Pathway: Insights into the Pathophysiological Mechanisms of Lipopolysaccharide-Induced Acute Lung Injury.

Zhaoning Zhao, Pingjun Zhu, Yue Lou, Ruoyu Hou, Heqiang Sun, Yingzhen Du, Guogang Xu.

  Receptor-interacting protein 3 (Ripk3) plays a crucial part in acute lung injury (ALI) by regulating inflammation-induced endothelial damage in the lung tissue. The precise mechanisms through which Ripk3 contributes to the endothelial injury in ALI still remain uncertain. In the current research, we employed Ripk3-deficient (Ripk3-/-) mice to examine the role of Ripk3 in ALI progression, focusing on its effects on endothelial cells (ECs), mitochondrial damage and necroptosis. Our study observed significant Ripk3 upregulation in lipopolysaccharide- (LPS-) treated lung tissues, as well as in murine pulmonary microvascular endothelial cells (PMVECs). Ripk3 deletion improved lung tissue morphology, reduced inflammation, oxidative stress and endothelial dysfunction under LPS challenge. It also mitigated LPS-induced necroptosis and mitochondrial damage in PMVECs. Ripk3 upregulation suppressed the AMP-activated protein kinase (AMPK) pathway and activated Drp1-mediated mitochondrial fission, increasing mitochondrial permeability transition pore (mPTP) opening and PMVEC necroptosis. Conversely, Ripk3 deletion activated the AMPK/Drp1-mitochondrial fission pathway, preventing mPTP opening and PMVEC necroptosis in ALI. These findings demonstrated that Ripk3 promotes necroptosis through the AMPK/Drp1/mPTP opening pathway, identifying a potential therapeutic target for ALI treatment.

Keywords:  Acute lung injury; Cell necroptosis; Mitochondrial damage; Ripk3

DOI:  https://doi.org/10.7150/ijms.104932
Nat Commun. 2024 Dec 30. 15(1): 10815

Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.

Marc A Morizono, Kelly L McGuire, Natalie I Birouty, Mark A Herzik.

Maintenance of protein homeostasis is necessary for cell viability and depends on a complex network of chaperones and co-chaperones, including the heat-shock protein 70 (Hsp70) system. In human mitochondria, mitochondrial Hsp70 (mortalin) and the nucleotide exchange factor (GrpEL1) work synergistically to stabilize proteins, assemble protein complexes, and facilitate protein import. However, our understanding of the molecular mechanisms guiding these processes is hampered by limited structural information. To elucidate these mechanistic details, we used cryoEM to determine structures of full-length human mortalin-GrpEL1 complexes in previously unobserved states. Our structures and molecular dynamics simulations allow us to delineate specific roles for mortalin-GrpEL1 interfaces and to identify steps in GrpEL1-mediated nucleotide and substrate release by mortalin. Subsequent analyses reveal conserved mechanisms across bacteria and mammals and facilitate a complete understanding of sequential nucleotide and substrate release for the Hsp70 chaperone system.

DOI: https://doi.org/10.1038/s41467-024-54499-1
Dev Cell. 2024 Dec 18. pii: S1534-5807(24)00733-0. [Epub ahead of print]

HMOX1-LDHB interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis.

Xiang Peng, Bin Sun, Chaohui Tang, Chengyu Shi, Xianwei Xie, Xueyu Wang, Dingsheng Jiang, Shuo Li, Ying Jia, Yani Wang, Huifang Tang, Shan Zhong, Minghui Piao, Xiuru Cui, Shenghao Zhang, Fan Wang, Yan Wang, Ruisi Na, Renping Huang, Yanan Jiang, Weihua Zhang, Juan Xu, Kaiyang Lin, Junli Guo, Zhenwei Pan, Kun Wang, Qiang Zhao, Huibin Liu, Bo Yu, Yong Ji, Jian Zhang, Shuijie Li, Jinwei Tian.

  Advanced atherosclerosis is the pathological basis for acute cardiovascular events, with significant residual risk of recurrent clinical events despite contemporary treatment. The death of foamy macrophages is a main contributor to plaque progression, but the underlying mechanisms remain unclear. Bulk and single-cell RNA sequencing demonstrated that massive iron accumulation in advanced atherosclerosis promoted foamy macrophage ferroptosis, particularly in low expression of triggering receptor expressed on myeloid cells 2 (TREM2low) foamy macrophages. This cluster exhibits metabolic characteristics with low oxidative phosphorylation (OXPHOS), increasing ferroptosis sensitivity. Mechanically, upregulated heme oxygenase 1 (HMOX1)-lactate dehydrogenase B (LDHB) interaction enables Lon peptidase 1 (LONP1) to degrade mitochondrial transcription factor A (TFAM), leading to mitochondrial dysfunction and ferroptosis. Administration of the mitochondria-targeted reactive oxygen species (ROS) scavenger MitoTEMPO (mitochondrial-targeted TEMPO) or LONP1 inhibitor bortezomib restored mitochondrial homeostasis in foamy macrophages and alleviated atherosclerosis. Collectively, our study elucidates the cellular and molecular mechanism of foamy macrophage ferroptosis, offering potential therapeutic strategies for advanced atherosclerosis.

Keywords:  LDHB; TREM2(low) foamy macrophages; advanced atherosclerosis; ferroptosis; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.devcel.2024.12.011
Nat Commun. 2025 Jan 02. 16(1): 276

Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice.

Akiyuki Nishimura, Seiryo Ogata, Xiaokang Tang, Kowit Hengphasatporn, Keitaro Umezawa, Makoto Sanbo, Masumi Hirabayashi, Yuri Kato, Yuko Ibuki, Yoshito Kumagai, Kenta Kobayashi, Yasunari Kanda, Yasuteru Urano, Yasuteru Shigeta, Takaaki Akaike, Motohiro Nishida.

The presence of redox-active molecules containing catenated sulfur atoms (supersulfides) in living organisms has led to a review of the concepts of redox biology and its translational strategy. Glutathione (GSH) is the body's primary detoxifier and antioxidant, and its oxidized form (GSSG) has been considered as a marker of oxidative status. However, we report that GSSG, but not reduced GSH, prevents ischemic supersulfide catabolism-associated heart failure in male mice by electrophilic modification of dynamin-related protein (Drp1). In healthy exercised hearts, the redox-sensitive Cys644 of Drp1 is highly S-glutathionylated. Nearly 40% of Cys644 is normally polysulfidated, which is a preferential target for GSSG-mediated S-glutathionylation. Cys644 S-glutathionylation is resistant to Drp1 depolysulfidation-dependent mitochondrial hyperfission and myocardial dysfunction caused by hypoxic stress. MD simulation of Drp1 structure and site-directed mutagenetic analysis reveal a functional interaction between Cys644 and a critical phosphorylation site Ser637, through Glu640. Bulky modification at Cys644 via polysulfidation or S-glutathionylation reduces Drp1 activity by disrupting Ser637-Glu640-Cys644 interaction. Disruption of Cys644 S-glutathionylation nullifies the cardioprotective effect of GSSG against heart failure after myocardial infarction. Our findings suggest a therapeutic potential of supersulfide-based Cys bulking on Drp1 for ischemic heart disease.

DOI: https://doi.org/10.1038/s41467-024-55661-5