bims-mikwok 2025-08-24 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2025–08–24
29 papers selected by
Gavin McStay, Liverpool John Moores University

Mitochondrial Quality Control in Health and Disease.
Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.
NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.
Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.
Mitophagy in Hypertensive Cardiac Hypertrophy: Mechanisms and Therapeutic Implications.
Lentinan rewrites extracellular matrix homeostasis by activating mitophagy via mTOR/PINK1/Parkin pathway in cartilage to alleviating osteoarthritis.
WSGC@FA@PEG/PEI-SPIONs Mitigate Chemoresistance in Gastric Adenocarcinoma by Modulating the Notch Signaling Pathway and Mitophagy.
[Effects of electroacupuncture on cognitive impairment and mitophagy mediated by KIF5A/Miro1 pathway in Parkinson's disease mice].
FUNDC1-dependent mitochondrial-ER membranes mediate mitochondrial dysfunction and melanocyte damage under oxidative stress.
ZEB1 stratifies the response to Sorafenib and Mdivi-1 combination therapy in hepatocellular carcinoma.
An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing.
Engineered RGD-Treg-Exos Targeted Delivery of miR-218-5p to Activate Mitophagy and Attenuate Podocyte Injury in Diabetic Kidney Disease.
SIRT3 promotes mitophagy to attenuate fumonisin B1-induced chicken hepatocyte senescence and antagonism of lycopene.
Mechanism of Lipi Jiangzhuo Decoction in Improving Metabolic Dysfunction-Associated Steatohepatitis Through the PERK/PINK1/GPx4 Pathway.
[Research progress on the mechanism of activating transcription factor 5 in regulating cellular inflammatory stress response].
Mitochondrial fission genes MTFP1/MTFP2 as predictive biomarkers in prostate cancer: a mendelian randomization study.
DRP1 downregulation impairs mitophagy, driving mitochondrial ROS and SASP production in rheumatoid arthritis CD4+PD-1+T cells.
Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.
Reasonable Design of Near-Infrared Boron Dipyrromethene with Cationic Pyridinium for Super-Resolution Imaging of Dynamic Voltages of Mitochondria in Living Cells.
Effect of sodium thiosulfate on preventing renal ischemia-reperfusion injury in high-fat diet-fed rats: the role of renal mitochondrial quality.
SeMet attenuates zearalenone-induced oxidative stress and mitochondrial autophagy in rabbit kidney through activation of Nrf2/Keap1 signaling pathway.
Sirtuin 3 in diabetic kidney disease: mechanisms and pharmacotherapy.
Macrophages and macrophage extracellular vesicles confer cancer ferroptosis resistance via PRDX6-mediated mitophagy inhibition.
Significance of Mitochondrial Dynamics in Reproductive Physiology: Current and Emerging Horizons in Mitochondrial Therapy for Assisted Reproductive Technologies.
Rapamycin coated selenium nanoparticles relieve oxidative senescence of vascular endothelium by mitophagy.
20S-O-Glc-DM regulates fatty acid metabolism and mitochondrial function in the treatment of diabetes mellitus-associated MAFLD.
Corrigendum to "Ginkgolide B effectively mitigates neuropathic pain by suppressing the activation of the NLRP3 inflammasome through the induction of mitophagy in rats" [Biomed. Pharmacother. 177 (2024) 117006].
Inhibition of inducible nitric oxide synthase (iNOS) alleviates thoracic aortic aneurysm by regulating mitochondrial dynamics.
Harnessing mitochondrial biogenesis to combat acute kidney injury: Current insights and futuredirections.

MedComm (2020). 2025 Aug;6(8): e70319

Mitochondrial Quality Control in Health and Disease.

Lin Ye, Xinzhi Fu, Qi Li.

  Mitochondria are central regulators of cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis. Mitochondrial quality control (MQC) encompasses a coordinated network of mitochondrial biogenesis, dynamics (fusion and fission), and selective autophagy (mitophagy), which together sustain mitochondrial structure and function. Under physiological conditions, MQC ensures the removal of dysfunctional mitochondria, restricts excessive reactive oxygen species production, and modulates apoptosis, thereby supporting the high energy demands of organs such as the heart and brain. Disruption of MQC contributes to the onset and progression of various diseases, including neurodegenerative disorders, cardiovascular pathologies, and metabolic syndromes, largely through accumulation of damaged mitochondria and impaired metabolic signaling. While the core components of MQC have been characterized, the mechanistic interplay among its modules and their disease-specific alterations remain incompletely defined. This review provides an integrated overview of the molecular pathways governing mitochondrial biogenesis, dynamics, and mitophagy, with a focus on their cross-talk in maintaining mitochondrial homeostasis. We further discuss how MQC dysfunction contributes to disease pathogenesis and examine emerging therapeutic approaches aimed at restoring mitochondrial quality. Understanding the regulatory logic of MQC not only elucidates fundamental principles of cellular stress adaptation but also informs novel strategies for disease intervention.

Keywords:  disease intervention; mitochondria; mitochondrial quality control; therapeutic strategies

DOI:  https://doi.org/10.1002/mco2.70319
Biochem Soc Trans. 2025 Aug 18. pii: BST20253050. [Epub ahead of print]

Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.

Nicoletta T Basilone, Viveka M Pimenta, Gary S Shaw.

  Parkin, a Ring-InBetweenRING-Rcat E3 ubiquitin ligase, plays a vital role in the clearance of damaged mitochondria (mitophagy) by ubiquitylating a broad spectrum of mitochondrial proteins. Mutations in the PRKN gene alter parkin ubiquitylation activity and are a leading cause of early-onset Parkinsonism, underlining its critical function in maintaining mitochondrial homeostasis. The structures, substrates, and ubiquitylation mechanisms used by parkin in mitophagy are well established. Yet, early studies as well as more recent proteomics studies identify alternative substrates that reside in the cytosol or other cellular compartments, suggesting potential roles for parkin beyond mitophagy. In addition to its well-documented activation via S65 phosphorylation, numerous other post-translational modifications (PTMs) have been identified in parkin. Some of these modifications have the potential to serve key regulatory mechanisms, perhaps fine-tuning parkin activity or potentially signaling the involvement in alternative cellular pathways beyond mitochondrial quality control. This review examines the canonical mechanism of parkin-mediated ubiquitylation while also exploring alternative regulatory influences that may modulate its enzyme activity. By analyzing emerging evidence on PTMs including phosphorylation, acetylation, ubiquitylation, oxidation, and interaction with alternative activating molecules, we highlight the broader functional landscape of parkin and its implications for cellular stress response.

Keywords:  Parkinson's disease; mitochondrial dysfunction; parkin; protein structure; ubiquitin ligases

DOI:  https://doi.org/10.1042/BST20253050
Transl Psychiatry. 2025 Aug 18. 15(1): 292

NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.

Ye Sun, Liya Li, Xianglong Yang, Shengming Yin, Zhaoyang Xiao.

Major depressive disorder (MDD) is characterized by persistent low mood and anhedonia. Mitochondrial dysfunction is linked to MDD, but the mechanisms are unclear. In this study, transcriptomic analysis of MDD patients' peripheral blood found three key genes: TFAM, SURF1, and NDUFB9. Single-cell transcriptomic analysis of the prefrontal cortex (PFC) in MDD patients identified seven cell types. Analysis showed strong interactions between excitatory and inhibitory neurons in the PFC, with the three genes mainly in inhibitory neurons and NDUFB9 having the highest expression. We then established a chronic unpredictable mild stress (CUMS) mouse model. CUMS exposure induced depressive-like behaviors in mice, as evidenced by decreased sucrose preference, increased immobility time in the forced swim, and reduced activity and frequency of entries into the central area in the open field. Moreover, CUMS-exposed mice exhibited mitochondrial dysfunction in the prefrontal cortex (PFC). Notably, the expressions of TFAM, SURF1, and NDUFB9 were decreased in the PFC of CUMS mice, with the most significant decrease observed in NDUFB9. Subsequently, the overexpression of NDUFB9 in CUMS-treated mice significantly alleviated depressive-like behaviors, restored mitochondrial function and reduced the death of inhibitory neurons. It also enhanced mitophagy by PINK1/Parkin pathway. Inhibiting autophagy and mitophagy confirmed mitophagy's pivotal role in NDUFB9-mediated restoration. Co-IP and protein half-life assays revealed that NDUFB9 stabilizes PINK1, thereby promoting mitophagy. In conclusion, our findings reveal a novel role of NDUFB9 on alleviating depression-like behavior by enhancing mitophagy, suggesting that targeting NDUFB9 could offer a promising therapeutic strategy for MDD.

DOI: https://doi.org/10.1038/s41398-025-03502-4
J Biomed Sci. 2025 Aug 19. 32(1): 77

Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.

Fasih A Rahman, Mackenzie Q Graham, Alex Truong, Joe Quadrilatero.

   BACKGROUND: Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
METHODS: We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7f/f:Acta1-Cre) mice.
RESULTS: Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
CONCLUSION: These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.

Keywords:  Apoptosis; Autophagy; BNIP3; Development; Mitochondria; Mitophagy; Skeletal muscle; UPS

DOI:  https://doi.org/10.1186/s12929-025-01153-7
J Clin Hypertens (Greenwich). 2025 Aug;27(8): e70127

Mitophagy in Hypertensive Cardiac Hypertrophy: Mechanisms and Therapeutic Implications.

Shijun Li, Xiaoying Li.

  Hypertensive cardiac hypertrophy (HCH) is a compensatory response to chronic pressure overload, ultimately progressing to heart failure if left unmanaged. Emerging evidence highlights the critical role of mitochondrial dysfunction in HCH pathogenesis, with impaired mitophagy-a selective autophagic process that removes damaged mitochondria-contributing to cardiomyocyte death, oxidative stress, and fibrosis. Protective mitophagy eliminates damaged mitochondria, averting reactive oxygen species (ROS)/calcium overload in HCH. Conversely, its dysregulation-either insufficient clearance or excessive removal-exacerbates mitochondrial dysfunction, driving pathological hypertrophy, fibrosis, and bioenergetic crisis. This dual nature presents a therapeutic paradox demanding contextual modulation. This review comprehensively examines the molecular mechanisms underlying mitophagy dysregulation in HCH, focusing on key pathways such as PINK1/Parkin, BNIP3/NIX, and FUNDC1. We also discuss the interplay between mitophagy and other cellular processes, including mitochondrial biogenesis, inflammasome activation, and metabolic remodeling. Furthermore, we explore potential therapeutic strategies targeting mitophagy to ameliorate HCH, including pharmacological agents, lifestyle interventions, and gene therapy approaches. Understanding the dual role of mitophagy in HCH-both protective and detrimental-may pave the way for novel precision medicine strategies in cardiovascular disease.

Keywords:  hypertensive cardiac hypertrophy; mitochondrial dysfunction; mitophagy; oxidative stress; therapeutic targets

DOI:  https://doi.org/10.1111/jch.70127
Int J Biol Macromol. 2025 Aug 15. pii: S0141-8130(25)07457-4. [Epub ahead of print]322(Pt 3): 146900

Lentinan rewrites extracellular matrix homeostasis by activating mitophagy via mTOR/PINK1/Parkin pathway in cartilage to alleviating osteoarthritis.

Qi Li, Hanwen Gu, Kangle Song, Xiangzhen Kong, Yanlin Li, Zhenchuan Liu, Qunbo Meng, Kaiwen Liu, Xiuqi Li, Qing Xie, Leixiang Han, Junhao Lin.

  Osteoarthritis (OA), an age-related joint disease characterized by cartilage degeneration, presents significant therapeutic challenges owing to its multifaceted pathogenesis. Lentinan (LNT), a β-(1,3)-glucan extracted from Lentinus edodes, has been demonstrated to possess multiple biological properties, including antioxidant and anti-inflammatory activities. Notably, the underlying mechanisms for its protective effects against OA remain unknown. The aim of this study was to investigate the therapeutic efficacy and mechanisms of LNT on OA. The effects of LNT on extracellular matrix (ECM), cellular senescence, apoptosis and inflammation were assessed in IL-1β induced chondrocytes. RNA sequencing analysis was subsequently performed to explore the mechanism of LNT, and the regulatory effects of LNT on mitophagy and the mTOR pathway were detected. The effects of LNT were further validated in a rat OA model with anterior cruciate ligament transection (ACLT). We found that LNT alleviated extracellular matrix degradation, chondrocyte senescence, apoptosis and inflammatory factors secretion induced by IL-1β. Mechanistically, LNT promoted mitophagy through activation of the PINK1/Parkin pathway, thereby maintaining mitochondrial homeostasis and protecting chondrocytes. Notably, this protective effect of LNT was suppressed upon treatment with an mTOR agonist. Moreover, LNT suppressed cartilage degeneration in ACLT-induced OA rats. In conclusion, LNT enhanced chondrocyte mitophagy through the mTOR/PINK1/Parkin pathway, thereby mitigating chondrocyte degeneration and delaying OA progression. Consequently, LNT may contribute to the development of new potential strategies for OA treatment.

Keywords:  Cartilage; Cellular senescence; Lentinan; Mitophagy; Osteoarthritis; mTOR

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146900
Adv Sci (Weinh). 2025 Aug 19. e15840

WSGC@FA@PEG/PEI-SPIONs Mitigate Chemoresistance in Gastric Adenocarcinoma by Modulating the Notch Signaling Pathway and Mitophagy.

Dongjian Song, Qiuliang Liu, Zechen Yan, Qi Wang, Meng Su, Hui Zhang, Longyan Shi, Yingzhong Fan, Qian Zhang, Heying Yang, Da Zhang.

  This study investigates the molecular mechanisms by which superparamagnetic iron oxide nanoparticles (SPIONs) loaded with the WSGC peptide (WSGC@FA@PEG/PEI-SPIONs)-a 40-amino acid polypeptide derived from apoC-III-modulate chemotherapy resistance in gastric adenocarcinoma (GA). Emphasis is placed on their role in regulating mitophagy and mitochondrial homeostasis via the Notch signaling pathway. The physicochemical properties of WSGC@FA@PEG/PEI-SPIONs are thoroughly characterized, demonstrating favorable biocompatibility, stable size distribution, and efficient peptide loading. In vitro experiments show that these nanoparticles significantly inhibit GA cell proliferation, migration, and invasion by downregulating mitophagy-associated proteins (LC3, PINK1, and Parkin), primarily through modulation of the Notch pathway. In vivo studies, using a GA nude mouse model, confirm the therapeutic potential of WSGC@FA@PEG/PEI-SPIONs, revealing marked tumor growth inhibition and increased apoptotic activity. Collectively, the findings highlight the WSGC peptide as a promising therapeutic agent for overcoming chemotherapy resistance in GA by targeting the Notch signaling pathway and suppressing mitophagy, thereby presenting a novel strategy for polypeptide-based cancer therapy.

Keywords:  Notch signaling pathway; WSGC Peptides; chemotherapy resistance; gastric adenocarcinoma; mitophagy; nanoparticles

DOI:  https://doi.org/10.1002/advs.202415840
Zhongguo Zhen Jiu. 2025 Aug 12. 45(8): 1111-1119

[Effects of electroacupuncture on cognitive impairment and mitophagy mediated by KIF5A/Miro1 pathway in Parkinson's disease mice].

Mengzhu Li, Jiafan Chen, Mengxuan Chen, Haiyan Li, Zhenyi Zhang, Da Gao, Weicong Zeng, Lijun Zhao, Meiling Zhu.

   Objective: To explore the improvement effect of electroacupuncture (EA) based on Xingnao Kaiqiao acupuncture (acupuncture for regaining consciousness and opening orifices) on cognitive impairment in mice with Parkinson's disease (PD), and to explore its regulatory mechanisms on the kinesin family member 5A (KIF5A)/mitochondrial Rho GTPase 1 (Miro1) pathway and mitophagy in prefrontal cortical neurons.
Methods: A total of 70 male C57BL/6J mice of clean grade were randomly divided into a normal group (12 mice), a sham operation group (12 mice), and a model pre-screening group (46 mice). Unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle was adopted to establish the PD model in the model pre-screening group. Twenty-four mice after successful modeling were randomly selected and divided into a model group and an EA group, 12 mice in each one. In the EA group, acupuncture was applied at "Shuigou" (GV26) and bilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6), ipsilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6) were connected to EA respectively, with disperse-dense wave, 5 Hz/20 Hz in frequency, 0.5 mA in current intensity, 20 min a time, 6 times a week for 30 days. Cognitive function was assessed by Y-maze and Morris water maze tests; morphology of prefrontal cortex was observed by H.E. staining; reactive oxygen species (ROS) level in prefrontal cortex was detected by fluorescence probe method; mitochondrial morphology and autophagosome ultrastructure were observed by transmission electron microscopy; the mRNA expression of tyrosine hydroxylase (TH) was detected by quantitative real-time PCR; the protein expression of TH, KIF5A, Miro1, p62, Parkin and PTEN induced kinase 1 (PINK1) was detected by Western blot.
Results: Compared with the sham operation group, both the model group and the EA group exhibited increased rotation number of per minute (P<0.001). Compared with the sham operation group, in the model group, the novel arm exploration time of Y-maze test was shortened (P<0.001), the escape latency of Morris water maze test was prolonged (P<0.05) and the platform crossing number of Morris water maze test was reduced (P<0.01); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was increased (P<0.001), and mitochondrial autophagosomes could be observed; in the prefrontal cortex, the relative expression of ROS was increased (P<0.001), the protein and mRNA expression of TH was decreased (P<0.001), the protein expression of Miro1, PINK1, Parkin was increased (P<0.001, P<0.01), the protein expression of KIF5A and p62 was decreased (P<0.001). Compared with the model group, in the EA group, the novel arm exploration time of Y-maze test was prolonged (P<0.01), the escape latency of Morris water maze test was shortened (P<0.05) and the platform crossing number of Morris water maze test was increased (P<0.05); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was decreased (P<0.001), and the number of mitochondrial autophagosomes reduced and the mitochondrial morphology was improved; in the prefrontal cortex, the relative expression of ROS was decreased (P<0.01), the protein and mRNA expression of TH was increased (P<0.001, P<0.01), the protein expression of Miro1, PINK1, Parkin was decreased (P<0.001, P<0.01, P<0.05), the protein expression of KIF5A and p62 was increased (P<0.01, P<0.05).
Conclusion: Xingnao Kaiqiao electroacupuncture effectively alleviates cognitive impairment and damage of neuronal function in PD mice, its mechanism may be related to the regulation of KIF5A/Miro1 pathway, hence reducing the mitophagy in prefrontal cortical neurons.

Keywords:  Parkinson's disease with cognitive impairment; Xingnao Kaiqiao acupuncture; electroacupuncture; kinesin family member 5A (KIF5A); mitochondrial Rho GTPcase1 (Miro1); mitophagy

DOI:  https://doi.org/10.13703/j.0255-2930.20250227-k0004
Free Radic Biol Med. 2025 Aug 15. pii: S0891-5849(25)00906-2. [Epub ahead of print]240 108-123

FUNDC1-dependent mitochondrial-ER membranes mediate mitochondrial dysfunction and melanocyte damage under oxidative stress.

Jingjing Ma, Mengsha Yuan, Sen Guo, Tianwen Gao, Chunying Li, Ling Liu.

   BACKGROUND: Mitochondria play a pivotal role in oxidative stress-induced melanocyte destruction in vitiligo. FUN14 domain containing 1 (FUNDC1), a mitochondrial outer-membrane protein, has an important role in mitochondrial function by regulating mitophagy and mitochondria-associated endoplasmic reticulum membranes (MAM). However, the role of FUNDC1 in melanocyte damage under oxidative remains unclear.
OBJECTIVES: To determine the contribution of FUNDC1 to oxidative stress-triggered melanocyte damage in vitiligo.
METHODS: We treated human melanocyte cell line PIG1 with H2O2 to establish an oxidative stress model. Cell viability, mitochondrial function and dynamics as well as mitophagy were detected. The transmission electron microscopy was used to assess MAM structure. FUNDC1 was then knocked down to examine its effects on MAM structure and mitochondrial function under H2O2 treatment. Additionally, we compared FUNDC1 expression, MAM structure and mitochondrial function between PIG1 cells and human vitiligo melanocyte cell line PIG3V. Finally, FUNDC1 expression and MAM structure were analyzed in vitiligo lesions and healthy control skin.
RESULTS: H2O2 treatment significantly increased intracellular H2O2 level, mitochondrial superoxide and lipid peroxide (LPO), while decreased glutathione (GSH) level in PIG1 cells. Impaired cell viability and mitochondrial function as well as excessive mitochondrial fission in PIG1 cells were observed after H2O2 incubation. However, H2O2 treatment didn't induce mitophagy but enhanced FUNDC1 expression and altered MAM structure. FUNDC1 knockdown inhibited H2O2-induced changes of MAM structure, mitochondrial calcium overloading, mitochondrial dysfunction, and recovered cell viability under oxidative stress. Interestingly, persistent H2O2 exposure reduced FUNDC1 expression, leading to MAM formation deficiency, excessive mitochondrial fusion and compromised mitochondrial function in the human vitiligo melanocyte cell line PIG3V. Finally, the decreased FUNDC1 expression and dysregulated MAM formation were confirmed in vitiligo lesions.
CONCLUSIONS: FUNDC1-dependent MAM structure mediates oxidative stress-induced mitochondrial dysfunction and melanocytes damage in vitiligo, suggesting that FUNDC1 and its associated MAM structure are potential targets for vitiligo treatment.

Keywords:  FUNDC1; MAM structure; Melanocytes; Mitochondria; Oxidative stress; Vitiligo

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.027
Sci Rep. 2025 Aug 19. 15(1): 30451

ZEB1 stratifies the response to Sorafenib and Mdivi-1 combination therapy in hepatocellular carcinoma.

H Freudenstein, M Strecker, S Gylstorff, W Shi, M Boettcher, S Medunjanin, C Catapano, C Siba, C Wex, T Wartmann, A Y Sanin, M Franz, J Arend, D Mougiakakos, M Pech, R S Croner, U D Kahlert, F Stelter.

  Primary liver cancer is one of the most frequently diagnosed and deadliest cancers. Zinc finger E-box binding homeobox 1 (ZEB1) is negative prognostic factor in liver cancer by promoting therapy resistance and tumorigenesis. Interfering in pathways of cellular metabolism emerges as a potent strategy to overcome tumor cells resistance to therapy. Our study aims to investigate the apoptotic potential of pharmacological inhibition of mitochondrial metabolism in primary liver cancer and whether this strategy can reduce ZEB1-associated resistance to standard of care chemotherapy Sorafenib. ZEB1 mRNA levels in patient samples and cancer cell lines were computationally screened using public datasets. Transcript and protein abundance of ZEB1 and regulators of mitochondrial fission and fusion were quantified in patient-matched tumor and non-tumor tissues of hepatocellular carcinoma (HCC) and cholangiocellular adenocarcinoma (CCA) from our clinic and common liver cancer cell lines. Functional assays on cell models with varying ZEB1 expression exposed to mitochondrial division inhibitor Mdivi-1 included mitochondrial mass quantification, mitochondrial membrane potential examination, apoptosis, extracellular flux, and cell growth analyses. Mdivi-1 treatment in human-physiological achievable concentration effectively induced apoptosis in all tested cell models. ZEB1 expression was heightened in younger patients, and dynamin-related protein 1 (Drp1) protein abundance was elevated in a subgroup of tumor tissue compared to healthy tissue. Cancer cell lines with high ZEB1 expression showed increased mitochondrial fission marker Drp1 and larger total mitochondrial mass, preserved membrane potential with reduced mitochondrial ATP production and respiration, resulting in an overall reduced mitochondrial fitness. Pharmacological inhibition of mitochondrial fission using Mdivi-1 reduced HCC resistance to Sorafenib in ZEB1-driven liver cancer. A subset of HCC cell lines with elevated ZEB1 levels exhibit increased mitochondrial mass and reduced metabolic activity. Targeting mitochondrial division in HCC by treatment with Mdivi-1 in combination with Sorafenib demonstrates a synergistic therapeutic effect in hepatocellular carcinoma (HCC) cell lines characterized by high ZEB1 expression. Further in vivo validation is needed to confirm these findings and evaluate this potential combined treatment option.

Keywords:  EMT; Hepatocellular carcinoma; Mdivi-1; Mitochondrial metabolism; Sorafenib; ZEB1

DOI:  https://doi.org/10.1038/s41598-025-16379-6
Nat Nanotechnol. 2025 Aug 19.

An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing.

Liyuan Chen, Yijie Fan, Nan Jiang, Xiaoshuai Huang, Min Yu, He Zhang, Zhengren Xu, Danqing He, Yu Wang, Chengye Ding, Xiaolan Wu, Chang Li, Shiying Zhang, Hangbo Liu, Xinmeng Shi, Fanghui Zhang, Ting Zhang, Dan Luo, Cunyu Wang, Yan Liu.

Energy restriction is closely related to cellular senescence and species longevity. Here, based on the structure and function of ATP synthase, a key enzyme for energy generation, we develop energy metabolism-engaged nanomedicines (EM-eNMs) to rejuvenate aged stromal/stem cells, and help to prevent skeletal ageing. We show that EM-eNMs infiltrate the mitochondria of aged bone marrow mesenchymal stromal/stem cells (BMMSCs), driving mitochondrial fission, mitophagy, glycolysis and maintaining BMMSC stemness and multifunction. The EM-eNMs directly bind to the ATP synthase and promote mitophagy through induction of the dynamin-related protein 1 (DRP1) gene. Remarkably, EM-eNMs selectively target bone tissues through systemic delivery and significantly reverse osteoporotic bone loss in aged mice by enhancing mitochondrial fission and mitophagy, while simultaneously restoring the stemness and osteogenic potential of aged BMMSCs in situ. Taken together, our findings highlight the potential of the EM-eNMs as a targeted therapy to alleviate cellular senescence and age-related diseases.

DOI: https://doi.org/10.1038/s41565-025-01972-7
Adv Sci (Weinh). 2025 Aug 19. e12034

Engineered RGD-Treg-Exos Targeted Delivery of miR-218-5p to Activate Mitophagy and Attenuate Podocyte Injury in Diabetic Kidney Disease.

Zhaochen Guo, Shaohui Gao, Ziyue Wang, Zige Chen, Jinglei Chen, Aiping Duan, Feng Xu, Qinger Wang, Weisong Qin, Caihong Zeng, Zhihong Liu, Hao Bao.

  Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease, and podocyte injury is an important factor in the development of DKD. Mitophagy is severely inhibited in the podocytes of patients. Damaged mitochondria aggregate in the cytoplasm and can not be removed effectively. Restoring mitophagy may be a novel strategy for the treatment of DKD. In this study, Regulatory T cells (Tregs) are found to reduce podocyte injury in DKD through exosomes. Sequencing and cross-sectional analysis revealed that exosomes from Tregs delivered miR-218-5p to increase mitophagy in podocytes by inhibiting the TNC/TLR4/SRC/FUNDC1 pathway. Treg-Exos are engineered to express RGD peptides on the membrane surface. RGD-Treg-Exos bind to integrins on the surface of podocytes and effectively target podocytes for the delivery of miR-218-5p, thus increasing mitophagy in podocytes, reducing cell apoptosis, and alleviating podocyte injury. In summary, this study revealed that engineered RGD-Treg-Exos effectively ameliorated podocyte injury in DKD, thus constituting a novel method for DKD treatment.

Keywords:  diabetic kidney disease; exosome; miRNA; mitophagy; treg

DOI:  https://doi.org/10.1002/advs.202412034
J Hazard Mater. 2025 Aug 13. pii: S0304-3894(25)02476-8. [Epub ahead of print]497 139557

SIRT3 promotes mitophagy to attenuate fumonisin B1-induced chicken hepatocyte senescence and antagonism of lycopene.

Yuan-Hang Chang, Ming-Shan Chen, Hong-Mei Zhu, Rui-Qi Liu, Zi-Yan Hu, Shang-Jia Yang, Xue-Qi Wang, Yue Cheng, Yi-Jia Song, Xin-Yue Mao, Jing Zheng, Yi-Bo Wang, Ming Lou, Yi Zhao, Jin-Long Li.

  Fumonisins are a class of mycotoxins produced by molds of the genus Fusarium, and fumonisin B1 (FB1) is the most toxic and common fumonisins. As a carotenoid with natural powerful antioxidant capacity found in plants, lycopene (LYC) can enhance immunity, modulate blood lipids, and prevent liver diseases. Sirtuin 3 (SIRT3) is a versatile molecule in modulating mitochondrial function with the significance in mitophagy and cellular senescence. Here, we aim to investigate the potential molecular mechanisms by which FB1 induces chicken hepatocyte damage and the antagonistic effects of LYC on it. In this study, we found that exposure to 25 μM FB1 for 24 h caused both functional and structural impairment of chicken hepatocyte. Next, FB1 exposure inhibited mitophagy and induced the accumulation of ROS. The result showed that FB1 exposure led to cell proliferation inhibition, cell cycle disorder and accelerated cellular senescence. Notably, LYC prevented FB1-induced cellular senescence by regulating chicken hepatocyte mitophagy. More importantly, SIRT3 knockdown eliminated the protective role of LYC against FB1-induced cellular senescence by inhibiting FOXO3-BNIP3L-mediated mitophagy in chicken hepatocyte. These findings suggest that regulating SIRT3-mediated FOXO3-BNIP3L pathway may be a potential therapeutic method for attenuating FB1-induced liver toxicity.

Keywords:  Fumonisin B1; Lycopene; Mitophagy; SIRT3; Senescence

DOI:  https://doi.org/10.1016/j.jhazmat.2025.139557
J Inflamm Res. 2025 ;18 10969-10994

Mechanism of Lipi Jiangzhuo Decoction in Improving Metabolic Dysfunction-Associated Steatohepatitis Through the PERK/PINK1/GPx4 Pathway.

Linlin Pan, Juhai Liu, Guowei Pang, Guirong Liu, Yuan Tian.

   Background: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized primarily by hepatocyte lipoapoptosis and hepatic inflammation, frequently developing from overweight/obesity. To date, no specific therapeutics exist to reverse MASH. Although resmetirom has been approved in some regions, patients in many Asian countries, including China, still lack access to approved pharmacotherapy for MASH. Lipi Jiangzhuo decoction (LPJZD) is a promising traditional Chinese medicine formula for MASH. However, to date, there have been no comprehensive studies clarifying its potential mechanism of action. This study aims to elucidate the underlying mechanism of action of LPJZD in the treatment of MASH.
Materials and Methods: A MASH mouse model was established by feeding a high-fat diet and subjecting them to fatigue protocols and cold stress for 12 weeks. After treating MASH mice with LPJZD, biochemical assays were conducted to assess the efficacy of LPJZD in alleviating the MASH symptoms. In addition, the in vitro effects of LPJZD on MASH were evaluated using L-02 cells. Specifically, we analyzed the effect of LPJZD on endoplasmic reticulum (ER) stress, mitophagy, and ferroptosis by Western blot analysis, flow cytometry, immunofluorescence staining, and enzyme-linked immunosorbent assay.
Results: In vivo, LPJZD effectively improved the inflammatory response, reduced body weight and blood lipid levels, improved liver function, reduced liver lipid droplet accumulation, and ameliorated the pathological status of MASH mice. In vitro, LPJZD effectively inhibited ferroptosis by reducing ferrous ions and reactive oxygen species levels, increasing GPx4 protein expression, elevating glutathione levels, and ameliorating mitochondrial swelling and matrix thinning. Simultaneously, LPJZD activated mitophagy by increasing PINK1 and Parkin protein expression, augmenting mitophagosome number, and restoring mitochondrial membrane potential. Additionally, LPJZD suppressed ER stress by decreasing PERK protein expression. Notably, activation of ER stress using a PERK activator attenuated LPJZD's effects on mitophagy activation and ferroptosis inhibition, inhibition of mitophagy via a PINK1 inhibitor diminished LPJZD's anti-ferroptotic effect, and administration of a GPx4 inhibitor reduced LPJZD's suppression of ferroptosis. Therefore, these results demonstrate that LPJZD ameliorates MASH by regulating the PERK/PINK1/GPx4 pathway.
Conclusion: LPJZD can improve MASH by regulating ER stress-mitophagy -ferroptosis axis in liver cells. The role of LPJZD in anti-inflammatory therapy provides new insights for the clinical prevention and treatment of MASH.

Keywords:  Lipi Jiangzhuo decoction; endoplasmic reticulum stress; ferroptosis; metabolic dysfunction-associated steatohepatitis; mitophagy

DOI:  https://doi.org/10.2147/JIR.S532630
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2025 May;37(5): 499-504

[Research progress on the mechanism of activating transcription factor 5 in regulating cellular inflammatory stress response].

Haiyun Lei, Bao Fu, Xiaoyun Fu.

Activating transcription factor 5 (ATF5) is a member of the activating transcription factor/cyclic adenosine monophosphate response element binding protein (ATF/CREB) family. As a stress-induced transcription factor, ATF5 plays a crucial role in cellular inflammatory stress responses. Under cellular inflammatory stress conditions, ATF5 maintains cell homeostasis and survival by regulating key genes in the mitochondrial unfolded protein response (UPRmt) and endoplasmic reticulum stress (ERS). As a key regulator in UPRmt, ATF5 senses mitochondrial stress and translocate to the nucleus to activate the transcription of UPRmt-related genes, thereby promoting mitochondrial function recovery. Meanwhile, in ERS, ATF5 maintains endoplasmic reticulum homeostasis by regulating the expression of genes related to protein folding, degradation, and apoptosis, determining cell survival or death. ATF5 plays a vital role in various cellular inflammatory stress responses. In infectious inflammation, ATF5 plays an important role in alleviating neuroinflammation and maintaining intestinal barrier function by regulating UPRmt. In inflammation related to degenerative diseases, ATF5 improves intervertebral disc degeneration and delays the progression of osteoarthritis by regulating UPRmt. In metabolic inflammation such as diabetes and obesity, ATF5 regulates UPRmt and ERS to maintain the function of pancreatic β-cells, controlling their survival or inducing apoptosis, thus influencing the progression of diabetes. ATF5 protects mitochondria in the kidneys, adipose tissue, and pancreas, slows the progression of diabetic nephropathy, and improves insulin sensitivity. Furthermore, in immune-related inflammation, ATF5 alleviates glomerulonephritis and promotes tissue repair by enhancing immune tolerance in dendritic cells. In summary, ATF5, as a key regulator in cellular inflammatory stress responses, maintains cell homeostasis through regulating UPRmt and ERS and determines cell fate. Its critical regulatory role in cellular inflammatory stress responses makes ATF5 a potential clinical therapeutic target. This article summarizes the structural features and translational regulatory mechanisms of ATF5, focusing on its role in cellular inflammatory stress responses, particularly its regulatory mechanisms in UPRmt and ERS, aiming to provide a theoretical basis for understanding ATF5's role in cell and organ protection and to offer new insights into the treatment of related inflammatory diseases.

DOI: https://doi.org/10.3760/cma.j.cn121430-20240729-00637
Discov Oncol. 2025 Aug 18. 16(1): 1579

Mitochondrial fission genes MTFP1/MTFP2 as predictive biomarkers in prostate cancer: a mendelian randomization study.

Xuejun Huangfu, Zhiqiang Fan, Jia Zheng, Jiabei Xie.

   BACKGROUND: Mitochondrial dynamics, particularly the balance between fission and fusion, play a crucial role in cancer progression, including prostate cancer, by influencing cellular metabolism and survival. MTFP1 and MTFP2 are key regulators of mitochondrial fission, and their roles in prostate cancer warrant further investigation.
METHODS: We conducted a comprehensive bioinformatics analysis using RNA-seq data from The Cancer Genome Atlas (TCGA) and SNP data from the UK Biobank (ukb-b-13348) GWAS dataset. Differential gene expression analysis was performed using the limma package, and pathway enrichment analysis was conducted using clusterProfiler. Hub genes were ranked using the CytoHubba algorithms. MCC was prioritized due to its robustness in identifying fully connected subgraphs. Mendelian Randomization (MR) analysis was performed using the TwoSampleMR package to assess the causal relationships between identified hub genes and prostate cancer.
RESULTS: The analysis revealed significant differential expression of MTFP1 and MTFP2 between tumor and adjacent normal tissues, with MTFP2 showing a highly significant upregulation (p-value = 7.06e-06) and an AUC of 0.698, suggesting its potential as a biomarker. In the MR analysis, several hub genes, including ANLN, CDC45, CDCA2, and KIF15, were identified as having a significant causal relationship with prostate cancer, with effect estimates ranging from - 0.03 to 0.15 and statistically significant p-values. These findings suggest that mitochondrial dynamics and related pathways play a critical role in prostate cancer pathogenesis.
CONCLUSION: The study highlights the potential diagnostic and prognostic value of mitochondrial fission-related genes, particularly MTFP2, in prostate cancer and underscores the importance of further investigating these pathways as therapeutic targets.

Keywords:  Cytoscape; GWAS; Hub genes; MTFP1; MTFP2; Mendelian randomization; Mitochondrial fission; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-03215-6
Redox Biol. 2025 Aug 09. pii: S2213-2317(25)00331-3. [Epub ahead of print]86 103818

DRP1 downregulation impairs mitophagy, driving mitochondrial ROS and SASP production in rheumatoid arthritis CD4+PD-1+T cells.

Ziran Bai, Jinyi Ren, Jiaqing Liu, Cheng Zhang, Huina Huang, Xiangge Zhao, Xianmei Chen, Jing Wei, Jingjing Qi, Siwen Yang, Weiping Li, Yawei Tang, Guan Wang, Xia Li.

  T cell senescence occurs in patients with rheumatoid arthritis (RA), but the specific phenotype and its contribution to tissue-destructive inflammation remain unclear. Here, we aim to investigate whether PD-1 marks pathogenic senescent CD4+T cells and to explore the role and mechanism of senescent CD4+PD-1+T cells in RA pathogenesis. Here, we identified an expanded population of CD4+PD-1+T cells in RA patients that exhibited hallmark senescence features, including elevated senescence-associated secretory phenotype (SASP) production. Adoptive transfer experiments demonstrated that CD4+PD-1+T cells significantly accelerated disease progression in collagen-induced arthritis (CIA) models. Mechanistically, we demonstrated that RA CD4+PD-1+T cells showed decreased expression of dynamin-related protein 1 (DRP1) and impaired mitophagy, leading to mitochondrial reactive oxygen species (MtROS) accumulation and subsequent SASP production. Importantly, PD-1 signaling transcriptionally suppressed DRP1 expression through hypoxia inducible factor 1 alpha subunit (HIF-1α) inhibition. Our findings establish CD4+PD-1+T cells as a pathogenic senescent subset that drives RA progression through a PD-1-DRP1-mitophagy-SASP axis.

Keywords:  CD4(+)PD-1(+)T cells; Dynamin-related protein 1; Mitochondrial reactive oxygen species; Rheumatoid arthritis; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.redox.2025.103818
FEBS J. 2025 Aug 17.

Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.

Maria Poles, Raffaella Pacchiana, Chiara Mortali, Barbara Cisterna, Nidula Mullappilly, Adriana Celesia, Federica Danzi, Martina Gaspari, Daniela Cecconi, Massimo Donadelli, Alessandra Fiore.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by poor prognosis and frequent gain-of-function mutations in the TP53 tumor suppressor gene. Given the crucial role of mutant p53 in the context of metabolic reprogramming and aggressive tumor behavior, we explored its role on mitochondria, which may present a valuable therapeutic target. In this study, we characterized the unique mitochondrial proteome observed in PDAC cells harboring the gain-of-function TP53R273H mutation and discovered a strong mutant p53-dependent upregulation of myosin heavy chain 14 (MYH14), a nonmuscle myosin, implicated in mitochondrial dynamics. We deeply investigated the role of mutant p53 in the regulation of mitochondrial architecture and functionality in PDAC cells. Our morphological and morphometric analyses with transmission electron microscopy and three-dimensional confocal imaging revealed that mutant p53 induced marked mitochondrial fragmentation, whereas wild-type p53 stimulated mitochondrial elongation. Interestingly, the fragmented mitochondrial morphology is associated with higher mitochondrial respiration levels and more efficient mitochondrial cristae. These findings support the role of oncogenic mutant p53 isoforms in inducing mitochondrial fragmentation through a mechanism involving MYH14, resulting in an increased oxidative phosphorylation level that may support PDAC cell growth and aggressiveness.

Keywords:  MYH14; mitochondrial dynamics; mutant p53; pancreatic ductal adenocarcinoma cancer metabolism

DOI:  https://doi.org/10.1111/febs.70223
ACS Sens. 2025 Aug 17.

Reasonable Design of Near-Infrared Boron Dipyrromethene with Cationic Pyridinium for Super-Resolution Imaging of Dynamic Voltages of Mitochondria in Living Cells.

Jiang-Lin Wang, Lu Zhang, Huan He, Pengfei Zhang, Feng-Lei Jiang.

  Mitochondrial membrane potential (ΔΨm) is a critical regulator of cellular homeostasis and an established biomarker in mitochondrial dysfunction. While super-resolution fluorescence imaging reveals intrinsic links between mitochondrial ultrastructure and function, prolonged monitoring of the dynamic ΔΨm remains constrained by the scarcity of photostable voltage-sensitive probes. Here, we designed and synthesized three water-soluble near-infrared boron dipyrromethene (BODIPY) probes (o/m/pMePy-BDP). These cationic pyridinium-functionalized probes exhibit specific mitochondria localization (Pearson's colocalization coefficient >0.93), high photostability (<15% intensity loss after 15 min laser irradiation), and exceptional biocompatibility. When integrated with structured illumination microscopy (SIM), they resolved mitochondrial cristae ultrastructure at 0.24 μm resolution and captured real-time ΔΨm fluctuations during fusion/fission (∼15 mV shifts) and mitochondria-lysosome contact (MLC). Semiquantitative submitochondrial models further revealed voltage gradients (150-170 mV) across cristae junctions, challenging the classical "homogeneous ΔΨm" paradigm. The probes' compatibility with multiplexed imaging enabled continuous ΔΨm tracking during mitophagy, uncovering transient bioenergetic hotspots. This work bridges nanoscale mitochondrial dynamics to disease mechanisms, providing tools to dissect pathologies from neurodegeneration to cancer.

Keywords:  BODIPY; SIM; fluorescent probes; organelle dynamics; voltage-sensitive imaging

DOI:  https://doi.org/10.1021/acssensors.5c01636
Biol Res. 2025 Aug 18. 58(1): 56

Effect of sodium thiosulfate on preventing renal ischemia-reperfusion injury in high-fat diet-fed rats: the role of renal mitochondrial quality.

Priyanka N Prem, Gino A Kurian.

   OBJECTIVE: Sodium Thiosulfate (STS), a clinically approved agent for cyanide poisoning and vascular calcification, possesses antioxidant, anti-inflammatory, mitochondrial preservation, and metal chelation capabilities, rendering it a promising candidate for managing ischemia-reperfusion (IR) injury. The detrimental impact of high-fat diets (HD) on the outcomes of IR during renal surgeries is well-documented. However, the potential of STS to ameliorate renal IR injury in rat fed with high fat diet is not known.
METHODS: Male Wistar rats were fed a standard diet (SD) or a high-fat diet (HD) for 16 weeks before undergoing an IR protocol (45 min of ischemia followed by 24 h of reperfusion). STS (10 mg/kg) was administered 30 min before IR.
RESULTS: STS effectively mitigated IR-induced physiological decline and tissue damage in SD rats but was less effective in HD rats. To explore this difference, we measured renal mitochondrial quality. STS improved mitochondrial bioenergetics, balanced mitochondrial dynamics, and increased mitochondrial copy number in SD-IR rats more than in HD-IR rats. Additionally, STS significantly reduced oxidative stress and upregulated Pgc-1α, Polg, and Tfam genes in SD-IR rats but had a lesser effect in HD-IR rats. The 16-week HD significantly reduced renal mitochondrial quality at the basal level, hindering STS-mediated protection.
CONCLUSION: These findings highlight the efficacy of STS in managing renal IR and emphasize the need for nutritional support to restore mitochondrial function in high-fat diet subjects.

Keywords:  High fat diet; Mitochondria; Oxidative stress; Renal ischemia reperfusion; Sodium thiosulfate

DOI:  https://doi.org/10.1186/s40659-025-00636-z
Int Immunopharmacol. 2025 Aug 18. pii: S1567-5769(25)01363-3. [Epub ahead of print]164 115372

SeMet attenuates zearalenone-induced oxidative stress and mitochondrial autophagy in rabbit kidney through activation of Nrf2/Keap1 signaling pathway.

Qiongxia Lv, Wenjing Xu, Fan Yang, Jiahui Li, Wenjuan Wei, Xiaoguang Chen, Yumei Liu, Ziqiang Zhang.

  Zearalenone (ZEA) is a secondary metabolite produced by Fusarium oxysporum with strong carcinogenicity, nephrotoxicity and immunotoxicity, etc. It is widely found in moldy cereal grains and their products, which poses a serious health hazard to humans and animals. Selenomethionine (SeMet) is the main form of selenium obtained by animals from plant-based feed ingredients, and has a variety of biological functions including antioxidant, anti-inflammatory, and antiviral. However, the mechanism of protective effect of SeMet against ZEA-induced kidney injury in rabbits is not clear. To explore this issue, we randomly divided fifty 90-day-old Ira rabbits into control (CON), ZEA, low-dose SeMet (L-Se), medium-dose SeMet (M-Se), and high-dose SeMet (H-Se) groups. The SeMet treatment groups were fed diets supplemented with 0.2 mg/kg, 0.35 mg/kg and 0.5 mg/kg SeMet, respectively, for a 21-d experimental period, and on the 15th d of the experiment, rabbits in the ZEA, L-Se, M-Se, and H-Se groups were gavaged with 1.2 mg/kg bw ZEA, and rabbits in the CON group were gavaged with 0.5 mL of olive oil for 7 d consecutively. Serum was collected for biochemical indexes, HE staining was used to observe the morphological changes in the kidney tissues of rabbits, and ELISA was used to detect the content of oxidative stress and inflammatory factor-related indexes in the kidney tissues. Immunohistochemistry, immunofluorescence staining and Western blot were used to detect the expression of relevant proteins in kidney tissues. The results showed that ZEA caused structural damage to the kidney, induced kidney fibrosis, inhibited antioxidant enzyme activity and the Nrf2/Keap1 antioxidant pathway to induce oxidative damage, and activated mitochondrial autophagy. SeMet pretreatment significantly attenuated ZEA-induced kidney injury, oxidative stress and mitochondrial autophagy. Thus, we demonstrate that SeMet alleviates ZEA-induced nephrotoxicity by activating the Nrf2/Keap1 antioxidant pathway. In addition, the protective effect of 0.35 mg/kg SeMet was more significant in this study.

Keywords:  Kidney; Rabbit; Selenomethionine; Zearalenone

DOI:  https://doi.org/10.1016/j.intimp.2025.115372
Ren Fail. 2025 Dec;47(1): 2543927

Sirtuin 3 in diabetic kidney disease: mechanisms and pharmacotherapy.

Yinfeng Chen, Ying Wang, Dongrong Yu, Hailing Zhao, Ping Li.

  Diabetic kidney disease (DKD) is a microvascular complication of diabetes and a major cause of kidney failure; current treatment methods still need improvement. Sirtuin 3 (SIRT3) is an NAD+-dependent protein deacetylase located in the mitochondria, where it regulates the activity and biological functions of diverse proteins and influences various mitochondrial functions via deacetylation. Increasing research indicates that SIRT3 holds promise as a therapeutic target for DKD. This review examines SIRT3's impact on mitochondrial functions, including mitochondrial biogenesis, autophagy, dynamics, oxidative homeostasis, and energy metabolism. We summarize that SIRT3 delays the progression of DKD by inhibiting oxidative stress, reducing inflammation, regulating cell death, and modulating energy metabolism. Finally, we categorize the applications of SIRT3 activators in renal diseases. In summary, this review provides a thorough understanding of SIRT3's functional role in DKD and proposes a potential therapeutic approach pending clinical validation.

Keywords:  Sirtuin 3; diabetic kidney disease; mitochondrion; molecular mechanisms; pharmacotherapy

DOI:  https://doi.org/10.1080/0886022X.2025.2543927
Redox Biol. 2025 Aug 16. pii: S2213-2317(25)00339-8. [Epub ahead of print]86 103826

Macrophages and macrophage extracellular vesicles confer cancer ferroptosis resistance via PRDX6-mediated mitophagy inhibition.

Naisheng Zheng, Fuli Li, Qing Huang, Xian Huang, Tomasz Maj.

  Ferroptosis has emerged as a promising therapeutic target in cancer therapy, with the tumor microenvironment (TME) playing a pivotal role in regulating ferroptosis. Although macrophages contribute to ferroptosis regulation within TME, the underlying mechanisms remain unclear. In this study, we demonstrate that macrophages consistently attenuate GPX4 inhibitor-induced lipid peroxidation and cell death in various tumor cell lines, whereas their resistance to cysteine transport inhibitor-triggered ferroptosis varies across cell types. This tumor protection from ferroptosis is mediated through macrophage-tumor cell contact and the delivery of macrophage-derived extracellular vesicles (Mφ-EV). Transcriptomic and proteomic analyses revealed that macrophages and Mφ-EV enhance glutathione metabolism in tumor cells. Notably, Mφ-EV are uniquely enriched with the glutathione metabolism-related protein PRDX6. Mechanistically, the glutathione peroxidase activity of PRDX6 elevates intracellular reduced glutathione, suppresses lipid peroxidation, and thereby mitigates ferroptosis. Furthermore, macrophage-derived PRDX6 reduces mitochondrial superoxide accumulation, alleviates ferroptosis-induced mitophagy, and enhances tumor cell viability, ultimately promoting tumor growth. Together, our findings provide a novel mechanism of ferroptosis resistance in TME, wherein macrophages confer tumor cell resilience by bypassing GPX4 inhibition.

Keywords:  Extracellular vesicles; Ferroptosis; Macrophages; Mitophagy; Peroxiredoxin 6

DOI:  https://doi.org/10.1016/j.redox.2025.103826
Reprod Med Biol. 2025 Jan-Dec;24(1):24(1): e12672

Significance of Mitochondrial Dynamics in Reproductive Physiology: Current and Emerging Horizons in Mitochondrial Therapy for Assisted Reproductive Technologies.

Sanath Udayanga Kankanam Gamage, Yoshiharu Morimoto.

   Background: Mitochondria play a critical role in cellular bioenergetics and signaling, with particular importance in the context of reproductive biology. This review summarizes their role in reproduction and explores current and emerging mitochondrial therapies for fertility treatment.
Methods: A comprehensive literature search using terms like mitochondria, infertility, reproduction, gametes, mitochondrial replacement, and mitochondrial transplantation identified relevant studies on mitochondria's role in gametogenesis, fertilization, and early embryonic development in relevant databases. Selected publications were reviewed and summarized to present current and future mitochondrial therapies for fertility.
Main Findings: Mitochondrial dynamics and functions are critical for meeting the energy requirements of essential reproductive processes, including gametogenesis, fertilization, and early embryonic development. Dysregulation of mitochondrial function has been associated with a range of reproductive disorders, such as infertility, recurrent pregnancy loss, and maternally inherited mitochondrial diseases. Emerging therapeutic strategies, such as mitochondrial replacement therapy, antioxidant supplementation, and mitochondrial transplantation, offer promising avenues for overcoming these challenges and improving reproductive outcomes.
Conclusions: Utilizing mitochondrial-based therapies represents a promising and innovative approach in the advancement of fertility treatments. Ongoing research and clinical development in this area hold significant potential to enhance reproductive outcomes and improve the quality of life for individuals and couples facing fertility challenges.

Keywords:  ascent; infertility; mitochondria; mitochondrial dysfunction; mitochondrial therapies for infertility; mitochondrial transplantation; reproductive aging

DOI:  https://doi.org/10.1002/rmb2.12672
Redox Biol. 2025 Aug 12. pii: S2213-2317(25)00335-0. [Epub ahead of print]86 103822

Rapamycin coated selenium nanoparticles relieve oxidative senescence of vascular endothelium by mitophagy.

Yutian Zhang, Jingru Wang, Hui Yang, Leting He, Miao Cui, Qinjie Ling, Jingjun He, Shan Gou, Fei Liu, Zhihui Cai, Zhi Huang.

  Rapamycin (RPM) extends longevity in various species and combats vascular senescence related diseases. Selenium nanoparticles (SeNPs) have attracted attention as a potential therapy for cardiovascular diseases due to their excellent antioxidant and drug-carrying capacity. However, RPM coated SeNPs (RPM-SeNPs) have not been reported and their potential for preventing endothelial oxidative senescence remains unclear. In the present study, RPM-SeNPs were generated by selenite and RPM with ascorbic acid reduction. Stability and dispersity of SeNPs were increased by coating with RPM, resulting in an average diameter of 67.51 ± 2.07 nm with a RPM:Se molar ratio of 1:120. Notably, RPM-SeNPs exhibited ameliorative effects on oxidative endothelial senescence in mouse aortas or MAECs induced by paraquat or hydrogen peroxide, respectively. There were evidenced by decreased SA-β-gal activity, lower SASP levels, and decreased endothelial dysfunction. Mechanically, RPM-SeNPs reduced oxidative stress in endothelial cells by upregulating GPX4, particularly mitochondrial GPX4 (mtGPX4) that mitigated of ROS and relieved mitochondria dysfunction. By downregulating the PI3K/Akt/mTOR pathway, RPM-SeNPs inhibited ULK1 phosphorylation at Ser757, subsequently leading to the activation of mitophagy and the reversal of mitochondrial dysfunction, including mitochondrial membrane potential collapse and ATP deficiency. Thus, these results suggest that RPM-SeNPs rescue endothelial cells from oxidative stress induced senescence by upregulating mtGPX4 and activating mitophagy. These results provide insight into the mechanisms of functionalizing SeNPs for potentially treating senescence-related diseases.

Keywords:  Endothelial senescence; Mitophagy; Oxidative stress; Rapamycin; Selenium nanoparticles

DOI:  https://doi.org/10.1016/j.redox.2025.103822
Phytomedicine. 2025 Aug 08. pii: S0944-7113(25)00775-5. [Epub ahead of print]146 157136

20S-O-Glc-DM regulates fatty acid metabolism and mitochondrial function in the treatment of diabetes mellitus-associated MAFLD.

Chen Gao, Lingzhi Zhang, Xinyi Guo, Xueman Lin, Jinling Yang, Zhe Wang, Hua Sun.

   BACKGROUND: The prevalence of diabetes mellitus-associated metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise, with over 90% of patients with Type 2 Diabetes Mellitus (T2DM) also suffering from MAFLD. Currently, there are no specific drugs available for the treatment of diabetes mellitus-associated MAFLD. Ginsenoside is commonly used to treat both MAFLD and diabetes. Previous studies have used biosynthesis to obtain the ginsenoside precursor compound 20S-O-Glc-DM (C20DM), which is suitable for industrial production, has high bioavailability, and is promising as a new treatment option for diabetes mellitus-associated MAFLD.
PURPOSE: This study is the first to reveal the protective effects of C20DM on diabetes mellitus-associated MAFLD and its potential pharmacological mechanisms.
METHODS: We used DB/DB mice fed a high-fat diet as an animal model of diabetes mellitus-associated MAFLD and HepG2 cells treated with high glucose medium combined with oleic acid as an in vitro model. In vivo, eukaryotic transcriptome sequencing and 16S rRNA analysis were used to explore the mechanism of action of C20DM. In vitro, further validation of the relationship between PGC-1α and C20DM in improving diabetes mellitus-associated MAFLD was conducted using the SR18292 inhibitor.
RESULTS: In both the in vitro and in vivo models of diabetes mellitus-associated MAFLD, C20DM improved hepatic lipid accumulation and mitochondrial function. 16S rRNA analysis revealed that C20DM ameliorated gut microbiota dysbiosis and increased the abundance of microbiota associated with mitochondrial function. Eukaryotic transcriptome analysis showed that differentially expressed genes were primarily involved in hepatic fatty acid metabolism and the PPAR pathway, with PGC-1α playing a key role.
CONCLUSIONS: In conclusion, our study demonstrates that C20DM improves diabetes mellitus-associated MAFLD by regulating fatty acid metabolism and mitochondrial function through the PGC-1α/PPARα/CPT1A pathway.

Keywords:  C20DM; Fatty acid metabolism; Gut microbiota; Mitochondrial biogenesis; PGC-1α

DOI:  https://doi.org/10.1016/j.phymed.2025.157136
Biomed Pharmacother. 2025 Aug 16. pii: S0753-3322(25)00672-9. [Epub ahead of print] 118478

Corrigendum to "Ginkgolide B effectively mitigates neuropathic pain by suppressing the activation of the NLRP3 inflammasome through the induction of mitophagy in rats" [Biomed. Pharmacother. 177 (2024) 117006].

Jing-Hao Liang, Heng Yu, Chuan-Peng Xia, Yue-Hui Zheng, Zhe Zhang, Yu Chen, Mazhar Ali Raza, Long Wu, Hede Yan.

DOI: https://doi.org/10.1016/j.biopha.2025.118478
Eur J Pharmacol. 2025 Aug 15. pii: S0014-2999(25)00825-8. [Epub ahead of print]1005 178071

Inhibition of inducible nitric oxide synthase (iNOS) alleviates thoracic aortic aneurysm by regulating mitochondrial dynamics.

Zhi-Fa Zheng, Jiao-Jiao Zhang, Li-Fei Wu, Xue-Ning Wang, Xing Zhang, Bin-Bin Zou, Xu-Yang Zhao, Jia-Yi Zheng, Kai-Fang Wang, Jia Guo, Wen-Jing Du, Ji-Min Cao.

  Thoracic aortic aneurysm (TAA) is life-threatening once developing to dissection (TAAD) or rupture and currently there is no effective pharmacological treatment. The abnormal activity of inducible nitric oxide synthase (iNOS) has been related with syndromic TAA, but its potential role in non-syndromic TAA is unknown. Here we identified elevations of inducible nitric oxide synthase (iNOS) and its downstream protein kinase G1 (PRKG1) in both human non-syndromic TAA and β-aminopropionitrile (BAPN)-induced mouse model of TAA. The iNOS-specific inhibitor 1400W effectively inhibited the formation of BAPN-induced TAA and TAAD in mice, improved aortic extracellular matrix (ECM) degradation, and reduced TAAD-associated death. The protective effect of 1400W on TAA was likely achieved by decreasing mitochondrial fusion and increasing mitochondrial fission, along with reduced reactive oxygen species (ROS) production and increased NAD+/NADH level, in human aortic vascular smooth muscle cells (HASMCs). In conclusion, here we confirm the protective effect of 1400W on non-syndromic TAA and suggest the value of regulating the iNOS-PRKG1-mitochondrial dynamics signaling in the treatment of non-syndromic TAA.

Keywords:  1400W; Mitochondria; Nitric oxide synthase; Thoracic aortic aneurysm

DOI:  https://doi.org/10.1016/j.ejphar.2025.178071
Genes Dis. 2025 Nov;12(6): 101645

Harnessing mitochondrial biogenesis to combat acute kidney injury: Current insights and futuredirections.

Yajie Hao, Fahui Chen, Xiya Ren, Xiu Huang, Xiaoshuang Zhou.

  Mitochondrial biogenesis (MB) is involved in the regulation of cellular energy metabolism, stress response, and survival. This review examines therapeutic approaches to acute kidney injury (AKI) that target MB, emphasizing clinical research findings and translational strategies in this field. AKI is a severe condition with high mortality and often leads to chronic kidney disease. AKI suppresses MB, resulting in mitochondrial dysfunction, oxidative stress, and further renal damage. Furthermore, studies have shown that ischemia-reperfusion-, sepsis-, and drug-induced AKI inhibit MB and subsequent kidney injury. Studies have shown that targeting MB through genetic and pharmacological interventions can alleviate AKI by restoring mitochondrial function and improving renal outcomes. Small molecule compounds, such as pyrroloquinoline quinone, ZLN005, and resveratrol, can enhance MB, offering potential therapeutic benefits. Nonetheless, further studies are needed to ensure efficacy across different models and mitigate related side effects. Future research should focus on optimizing drug design, understanding MB regulation, and conducting clinical trials to establish effective treatments for AKI.

Keywords:  Acute kidney injury; Mitochondrial biogenesis; Small compounds; Therapeutic interventions; Translational medicine

DOI:  https://doi.org/10.1016/j.gendis.2025.101645