bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–12–29
39 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
  2. Norepinephrine Attenuates Benzalkonium Chloride-Induced Dry Eye Disease by Regulating the PINK1/Parkin Mitophagy Pathway.
  3. Activated DRP1 promotes mitochondrial fission and induces glycolysis in ATII cells under hyperoxia.
  4. Mitochondrial quality control: the real dawn of intervertebral disc degeneration?
  5. [Parkin deletion affects PINK1/Parkin-mediated mitochondrial autophagy to exacerbate neuroinflammation and accelerate progression of Parkinson's disease in mice].
  6. Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.
  7. SPP1-ITGα5/β1 Accelerates Calcification of Nucleus Pulposus Cells by Inhibiting Mitophagy via Ubiquitin-Dependent PINK1/PARKIN Pathway Blockade.
  8. METTL3, m6A modification, and EGR1: interplay affecting myocardial I/R injury outcomes.
  9. Exercise training alleviates neuronal apoptosis and re-establishes mitochondrial quality control after cerebral ischemia by increasing SIRT3 expression.
  10. Cost-effective and simple flow cytometry quantification of receptor-mediated autophagy using fluorescent tagging.
  11. Inhibition of autophagy attenuates cognitive decline and mitochondrial dysfunction in an Alzheimer's disease mouse model with chronic cerebral hypoperfusion.
  12. Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1.
  13. Short-term effects of retinoic acid on the proliferation of SH-SY5Y cells via mitophagy and apoptosis.
  14. Trimethylamine-N-oxide accelerates osteoporosis by PERK activation of ATF5 unfolding.
  15. A New Perspective for Improving COPD: Ginsenoside Rg3 Links SIRT1 to Inhibit Mitochondrial Autophagy.
  16. Mitonuclear Communication in Stem Cell Function.
  17. Ailanthone blocks mitophagy to promote mtDNA leakage through BAX-BAK1 pores and suppress hepatocellular carcinoma cell proliferation.
  18. A transcription network underlies the dual genomic coordination of mitochondrial biogenesis.
  19. HMGB1 Promotes Accelerated Fracture Healing in Traumatic Brain Injury through PINK1/Parkin-Mediated Mitochondrial Autophagy.
  20. Attenuated NIX in impaired mitophagy contributes to exacerbating cellular senescence in experimental periodontitis under hyperglycemic conditions.
  21. Nrf2/NRF1 signaling activation and crosstalk amplify mitochondrial biogenesis in the treatment of triptolide-induced cardiotoxicity using calycosin.
  22. Microcystin-LR induces neuronal damage through mitophagy defects resulted from the downregulated transcription of Scd2 by directly targeting IGF-1R.
  23. Corrigendum to: HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells.
  24. Mitochondrial homeostatic imbalance-mediated developmental toxicity to H2S in embryonic zebrafish.
  25. Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
  26. Alternating Cellular Functions by Optogenetic Control of Organelles.
  27. JiangyaTongluo decoction ameliorates tubulointerstitial fibrosis via regulating the SIRT1/PGC-1α/mitophagy axis in hypertensive nephropathy.
  28. SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.
  29. Mitochondria-targeting materials and therapies for regenerative engineering.
  30. MDPAO1 Peptide from Human Milk Enhances Brown Adipose Tissue Thermogenesis and Mitigates Obesity.
  31. Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss.
  32. Sleep deprivation activated AMPK/FOXO3a signaling mediates pineal autophagy impairment to reduce melatonin secretion in CUMS + SD rats leading to depression combined with insomnia.
  33. NLRP3 Inflammasome Activation and Altered Mitophagy Are Key Pathways in Inclusion Body Myositis.
  34. Pressure to evade cell-autonomous innate sensing reveals interplay between mitophagy, IFN signaling, and SARS-CoV-2 evolution.
  35. Aerobic exercise timing affects mitochondrial dynamics and insulin resistance by regulating the circadian clock protein expression and NAD+-SIRT1-PPARα-MFN2 pathway in the skeletal muscle of high-fat-diet-induced diabetes mice.
  36. Knockdown of NDUFAF6 inhibits breast cancer progression via promoting mitophagy and apoptosis.
  37. Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.
  38. Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.
  39. Human umbilical mesenchymal stem cells ameliorate atrophic gastritis in aging mice by participating in mitochondrial autophagy through Ndufs8 signaling.
  1. J Cell Biol. 2025 Mar 03. pii: e202403140. [Epub ahead of print]224(3):
    Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
    Alia R Edington, Olivia M Connor, Abigail C Love, Madeleine Marlar-Pavey, Jonathan R Friedman.
      While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear whether internal mitochondrial proteins in metazoans play a direct role in the process. Previously, the yeast inner membrane protein Mdm33 was shown to be required for normal mitochondrial morphology and has been hypothesized to be involved in mitochondrial fission. However, it is unknown whether Mdm33 plays a direct role, and it is not thought to have a mammalian homolog. Here, we use a bioinformatic approach to identify a structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK), whose depletion phenocopies loss of Mdm33. We find that knockdown of CCDC51 also leads to reduced rates of mitochondrial fission. Further, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 overexpression promotes its spatial association with Drp1 and induces mitochondrial fragmentation, suggesting it is a positive effector of mitochondrial fission. Together, our data reveal that Mdm33 and CCDC51 are functionally conserved and suggest that internal mitochondrial proteins are directly involved in at least a subset of mitochondrial fission events in human cells.
    DOI:  https://doi.org/10.1083/jcb.202403140
  2. Ocul Immunol Inflamm. 2024 Dec 27. 1-15
    Norepinephrine Attenuates Benzalkonium Chloride-Induced Dry Eye Disease by Regulating the PINK1/Parkin Mitophagy Pathway.
    Han Zhao, Wushuang Wang, Yun Yang, Changming Feng, Tong Lin, Lan Gong.
       BACKGROUND: Increased reactive oxygen species (ROS) are involved in the pathological process of dry eye disease. Our previous results suggested that norepinephrine (NE) has a protective effect on dry eye.
    PURPOSE: This study explored the potential therapeutic role and underlying mechanisms of NE in benzalkonium chloride (BAC)-induced dry eye disease.
    METHODS: BAC-pretreated human corneal epithelial cells (HCEpiC) were cultured with various concentrations of NE. A BAC-induced dry eye mice model was established to explore the role of NE. Alterations in mice corneal tissues, ROS levels, mitochondrial function, and mitophagy levels were analyzed.
    RESULTS: In vitro, our results revealed that BAC-exposed HCEpiC led to mitochondrial malfunction, which involved excessive ROS production, decreased mitochondrial membrane potential (MMP), and promoted mitochondrial fragmentation through increased DRP1 and fission protein 1 (Fis1) expression and reduced mitofusin 2 (Mfn2) expression. Moreover, topical BAC application induced excessive mitophagy. These effects were reversed by NE. Additionally, the increased expression of LC3B, SQSTM1/p62, PINK1, and Parkin, which control mitophagy, in BAC-exposed HCEpiC was suppressed by NE. In BAC-induced C57BL/6J mice, NE resulted in lower fluorescein staining scores, decreased TUNEL-positive cells, and decreased mitochondrial fragmentation.
    CONCLUSIONS: In conclusion, our findings showed that NE therapy prevented HCEpiC following BAC application by regulating mitochondrial quality control, which is controlled by PINK1/Parkin-dependent mitophagy. Our research suggests a potential targeted treatment for dry eye disease.
    Keywords:  Benzalkonium chloride; dry eye disease; mitochondrial dysfunction; mitophagy; norepinephrine
    DOI:  https://doi.org/10.1080/09273948.2024.2447816
  3. Respir Res. 2024 Dec 26. 25(1): 443
    Activated DRP1 promotes mitochondrial fission and induces glycolysis in ATII cells under hyperoxia.
    Tong Sun, Haiyang Yu, Dingning Zhang, Danni Li, Jianhua Fu.
       BACKGROUD: Recent studies have reported mitochondrial damage and metabolic dysregulation in BPD, but the changes in mitochondrial dynamics and glucose metabolic reprogramming in ATII cells and their regulatory relationship have not been reported.
    METHODS: Neonatal rats in this study were divided into model (FIO2:85%) and control (FIO2: 21%) groups. Lung tissues were extracted at 3, 7, 10 and 14 postnatal days and then conducted HE staining for histopathological observation. We assessed the expression of mitochondria dynamic associated proteins and glycolysis associated enzymes in lung tissues, primary ATII cells and RLE-6TN cells. Double immunofluorescence staining was used to confirm the co-localization of DRP1 and ATII cells. Real-time analyses of ECAR and OCR were performed with primary ATII cells using Seahorse XF96. ATP concentration was measured using an ATP kit. We treated RLE-6TN cells at 85% hyperoxia for 48 h with mitochondrial fission inhibitor Mdivi-1 to verify the role of DRP1 in regulating glucose metabolic reprogramming.
    FINDINGS: We found that hyperoxia causes ATII cells' mitochondrial morphological change. The expression of DRP1 and p-DRP1 increased in lung tissue and primary ATII cells of neonatal rats exposed to hyperoxia. Glycolysis related enzymes including PFKM, HK2, and LDHA were also increased. Hyperoxia inhibited ATP production in ATII cells. In RLE-6TN cells, we verified that the administration of Mdivi-1 could alleviate the enhancement of aerobic glycolysis and fragmentation of mitochondria caused by hyperoxia.
    INTERPRETATIONS: Hyperoxia exposure leads to increased mitochondrial fission in ATII cells and mediates the reprogramming of glucose metabolism via the DRP1 signaling pathway. Inhibiting the activation of DRP1 signaling pathway may be a promising therapeutic target for BPD.
    Keywords:  ATII cells; Bronchopulmonary dysplasia; DRP1 signaling pathway; Metabolic reprogramming; Mitochondrial fission
    DOI:  https://doi.org/10.1186/s12931-024-03083-8
  4. J Transl Med. 2024 Dec 20. 22(1): 1126
    Mitochondrial quality control: the real dawn of intervertebral disc degeneration?
    Ba Qiu, Xiaoxing Xie, Yanhai Xi.
      Intervertebral disc degeneration is the most common disease in chronic musculoskeletal diseases and the main cause of low back pain, which seriously endangers social health level and increases people's economic burden. Disc degeneration is characterized by NP cell apoptosis, extracellular matrix degradation and disc structure changes. It progresses with age and under the influence of mechanical overload, oxidative stress and genetics. Mitochondria are not only the energy factories of cells, but also participate in a variety of cellular functions such as calcium homeostasis, regulation of cell proliferation, and control of apoptosis. The mitochondrial quality control system involves many mechanisms such as mitochondrial gene regulation, mitochondrial protein import, mitophagy, and mitochondrial dynamics. A large number of studies have confirmed that mitochondrial dysfunction is a key factor in the pathological mechanism of aging and intervertebral disc degeneration, and balancing mitochondrial quality control is extremely important for delaying and treating intervertebral disc degeneration. In this paper, we first demonstrate the molecular mechanism of mitochondrial quality control in detail by describing mitochondrial biogenesis and mitophagy. Then, we describe the ways in which mitochondrial dysfunction leads to disc degeneration, and review in detail the current research on targeting mitochondria for the treatment of disc degeneration, hoping to draw inspiration from the current research to provide innovative perspectives for the treatment of disc degeneration.
    Keywords:  Intervertebral disc degeneration; Mitochondrial dysfunction; Mitochondrial quality control; Mitochondrion
    DOI:  https://doi.org/10.1186/s12967-024-05943-9
  5. Nan Fang Yi Ke Da Xue Xue Bao. 2024 Dec 20. pii: 1673-4254(2024)12-2359-08. [Epub ahead of print]44(12): 2359-2366
    [Parkin deletion affects PINK1/Parkin-mediated mitochondrial autophagy to exacerbate neuroinflammation and accelerate progression of Parkinson's disease in mice].
    Chengcheng Jiang, Yangyang Li, Kexin Duan, Tingting Zhan, Zilong Chen, Yongxue Wang, Rui Zhao, Caiyun Ma, Yu Guo, Changqing Liu.
       OBJECTIVES: To investigate the role of mitochondrial autophagy disorder caused by deletion of E3 ubiquitin ligase Parkin in neuroinflammation in a mouse model of MPTP-induced Parkinson's disease (PD).
    METHODS: Wild-type (WT) male C57BL/6 mice and Parkin-/- mice were given intraperitoneal injections with MPTP or PBS for 5 consecutive days, and the changes in motor behaviors of the mice were observed using open field test. The effects of Parkin deletion on PD development and neuroinflammation were evaluated using immunofluorescence and Western blotting. The changes of the PINK 1/Parkin signaling pathway in the midbrain substantia nigra of the mice were examined to explore the molecular mechanism of Parkin-mediated regulation of mitochondrial autophagy and its effect on neuroinflammation in PD mice.
    RESULTS: Compared with their WT counterparts, the Parkin-/- mice with MPTP injections exhibited significant impairment of motor function with decreased TH+ neurons, increased α-synuclein (α-syn) accumulation, and increased numbers of GFAP+ and I-ba1+ cells in the midbrain substantia nigra. Parkin deletion obviously affected PINK1/Parkin-mediated mitochondrial autophagy to result in significantly increased mtDNA and upregulated expressions of STING and NLRP3 inflammatosomes in the midbrain substantia nigra of MPTP-treated transgenic mice.
    CONCLUSIONS: Parkin deletion causes mitochondrial autophagy disorder to accelerate PD progression and exacerbates neuroinflammation in mice by affecting the PINK1/Parkin signaling pathway, suggesting the important role of Parkin in early pathogenesis of PD.
    Keywords:  Parkin; Parkinson's disease; mitochondrial autophagy; neuroinflammation
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2024.12.11
  6. J Biol Chem. 2024 Dec 21. pii: S0021-9258(24)02626-7. [Epub ahead of print] 108124
    Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.
    Yunfan He, Zhining Tang, Gao Zhu, Luhang Cai, Chao Chen, Min-Xin Guan.
      Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS). However, the mechanisms by which mitochondrial dysfunctions induced by m.1555A>G mutation regulate intracellular signaling for mitochondrial and cellular integrity remain poorly understood. Here, we demonstrated that the m.1555A>G mutation downregulated the expression of nuclear-encoded subunits of complexes I and IV but upregulated the expression of assemble factors for OXPHOS complexes, using cybrids derived from one hearing-impaired Chinese subject bearing the m.1555A>G mutation and from one hearing normal control lacking the mutation. These alterations resulted in the aberrant assembly, instability and reduced activities of respiratory chain enzyme complexes I, IV and V, rate of oxygen consumption, and diminished ATP production. Furthermore, the mutant cell lines carrying the m.1555A>G mutation exhibited decreased membrane potential and increased the production of reactive oxygen species. The aberrant assembly and biogenesis of OXPHOS impacted mitochondrial quality controls, including the imbalance of mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology and impaired mitophagy. Strikingly, the cells bearing the m.1555A>G mutation revealed the upregulation of both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing the levels of Parkin, Pink, BNIP3L and NIX. The m.1555A>G mutation-induced deficiencies ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into pathophysiology of mitochondrial deafness arising from reshaping mitochondrial and cellular homeostasis due to 12S rRNA 1555A>G mutation.
    DOI:  https://doi.org/10.1016/j.jbc.2024.108124
  7. Adv Sci (Weinh). 2024 Dec 25. e2411162
    SPP1-ITGα5/β1 Accelerates Calcification of Nucleus Pulposus Cells by Inhibiting Mitophagy via Ubiquitin-Dependent PINK1/PARKIN Pathway Blockade.
    Hanwen Gu, Qi Li, Zhenchuan Liu, Yanlin Li, Kaiwen Liu, Xiangzhen Kong, Yuanqiang Zhang, Qunbo Meng, Kangle Song, Qing Xie, Yuan Gao, Lei Cheng.
      Low back pain (LBP) caused by nucleus pulposus degeneration and calcification leads to great economic and social burden worldwide. Unexpectedly, no previous studies have demonstrated the association and the underlying mechanism between nucleus pulposus tissue degeneration and calcification formation. Secreted Phosphoprotein 1 (SPP1) exerts crucial functions in bone matrix mineralization and calcium deposition. Here, a novel function of SPP1 is reported, namely that it can aggravate nucleus pulposus cells (NPs) degeneration by negatively regulating extracellular matrix homeostasis. The degenerated NPs have a higher mineralization potential, which is achieved by SPP1. Mechanistically, SPP1 can accelerate the degeneration of nucleus pulposus cells by activating integrin α5β1 (ITGα5/β1), aggravating mitochondrial damage and inhibiting mitophagy. SPP1-ITGα5/β1 axis inhibits mitophagy by PINK1/PARKIN pathway blockade. In conclusion, SPP1 activates ITGα5/β1 to inhibit mitophagy, accelerates NPs degeneration, and induces calcification, thereby leading to intervertebral disc degeneration (IVDD) and calcification, identifying the potentially unknown mechanism and relationship between IVDD and calcification. Important insights are provided into the role of SPP1 in nucleus pulposus calcification in IVDD by inducing nucleus pulposus cell senescence through inhibition of mitophagy and may help develop potential new strategies for IVDD treatment.
    Keywords:  calcification; integrin α5β1; intervertebral disc degeneration; mitophagy; nucleus pulposus cells; secreted phosphoprotein 1
    DOI:  https://doi.org/10.1002/advs.202411162
  8. Cell Biol Toxicol. 2024 Dec 21. 41(1): 7
    METTL3, m6A modification, and EGR1: interplay affecting myocardial I/R injury outcomes.
    Chen Huang, Xun Zhang, Shi-Xiong Wu, Qing Chang, Zhi-Kun Zheng, Jing Xu.
      The occurrence of severe myocardial ischemia/reperfusion (I/R) injury is associated with the clinical application of reestablishment technique for heart disease, and understanding its underlying mechanisms is currently an urgent issue. Prior investigations have demonstrated the potential enhancement of MIRI through EGR1 suppression, although the precise underlying regulatory pathways require further elucidation. The core focus of this investigation is to examine the molecular pathways through EGR1 regulates mitophagy-mediated myocardial cell pyroptosis and its impact on MIRI. Cardiomyocyte hypoxia/reoxygenation (H/R) injury models and mouse models of myocardial I/R injury were used to investigate the involvement of EGR1 in regulating mitophagy-mediated myocardial cell pyroptosis in myocardial I/R injury. The research outcomes demonstrated that under H/R conditions, EGR1 expression was upregulated and inhibited the JAK2/STAT3 pathway, leading to enhanced mitophagy and disrupted mitochondrial fusion/fission dynamics, ultimately resulting in myocardial cell pyroptosis. Further research revealed that the upregulation of EGR1 expression was mediated by methyltransferase like 3 (METTL3)-mediated m6A modification of EGR1 mRNA and depended on the binding of insulin like growth factor 2 mrna binding protein 2 (IGF2BP2) to the N6-methyladenosine (m6A) modification site to enhance mRNA stability. In vivo animal experiments confirmed that METTL3 upregulated EGR1 expression through IGF2BP2 and suppressed activation of the janus kinase 2 (JAK2) /signal transducer and activator of transcription 3 (STAT3) pathway, thereby inhibiting mitophagy, disrupting mitochondrial dynamics, promoting myocardial cell pyroptosis, and exacerbating I/R injury.
    Keywords:  EGR1; Janus Kinase 2/Signal Transducer and Activator of Transcription 3 Pathway; M6A Modification; Mitophagy; Myocardial Cell Pyroptosis; Myocardial Ischemia/Reperfusion Injury
    DOI:  https://doi.org/10.1007/s10565-024-09937-7
  9. Cell Biol Toxicol. 2024 Dec 21. 41(1): 10
    Exercise training alleviates neuronal apoptosis and re-establishes mitochondrial quality control after cerebral ischemia by increasing SIRT3 expression.
    Wenwen Wu, Zengyu Wei, Zhiyun Wu, Jianmin Chen, Ji Liu, Manli Chen, Jinjin Yuan, Zhijian Zheng, Zijun Zhao, Qiang Lin, Nan Liu, Hongbin Chen.
      Existing evidence indicates that exercise training can enhance neural function by regulating mitochondrial quality control (MQC), which can be impaired by cerebral ischemia, and that sirtuin-3 (SIRT3), a protein localized in mitochondria, is crucial in maintaining mitochondrial functions. However, the relationship among exercise training, SIRT3, and MQC after cerebral ischemia remains obscure. This study attempted to elucidate the relationship among exercise training, SIRT3 and MQC after cerebral ischemia in rats. Male adult SD rats received tMCAO after the transfection of adeno-associated virus encoding either sirtuin-3 (AAV-SIRT3) or SIRT3 knockdown (AAV-sh-SIRT3) into the ipsilateral striata and cortex. Subsequently, the animals were randomly selected for exercise training. The index changes were measured by transmission electron microscopy, Western blot analysis, nuclear magnetic resonance imaging, TUNEL staining, and immunofluorescence staining, etc. The results revealed that after cerebral ischemia, exercise training increased SIRT3 expression, significantly improved neural function, alleviated infarct volume and neuronal apoptosis, maintained the mitochondrial structural integrity, and re-established MQC. The latter promoted mitochondrial biogenesis, balanced mitochondrial fission/fusion, and enhanced mitophagy. These favorable benefits were reversed after SIRT3 interference. In addition, a cellular OGD/R model showed that the increased SIRT3 expression alleviates neuronal apoptosis and re-establishes mitochondrial quality control by activating the β-catenin pathway. These findings suggest that exercise training may optimize mitochondrial quality control by increasing the expression of SIRT3, thereby improving neural functions after cerebral ischemia, which illuminates the mechanism underlying the exercise training-conferred neural benefits and indicates SIRT3 as a therapeutic strategy for brain ischemia.
    Keywords:  Cerebral ischemia; Exercise training; Mitochondrial Quality Control (MQC); Neuronal apoptosis; SIRT3
    DOI:  https://doi.org/10.1007/s10565-024-09957-3
  10. FEBS Open Bio. 2024 Dec 23.
    Cost-effective and simple flow cytometry quantification of receptor-mediated autophagy using fluorescent tagging.
    Mija Marinković, Ana Rožić, Denis Polančec, Ivana Novak.
      Mitophagy, a selective clearance of damaged or superfluous mitochondria via autophagy machinery and lysosomal degradation, is an evolutionarily conserved process essential for various physiological functions, including cellular differentiation and immune responses. Defects in mitophagy are implicated in numerous human diseases, such as neurodegenerative disorders, cancer, and metabolic conditions. Despite significant advancements in mitophagy research over recent decades, novel and robust methodologies are necessary to elucidate its molecular mechanisms comprehensively. In this study, we present a detailed protocol for quantitatively assessing mitophagy through flow cytometry using a mitochondria-targeted fluorescent mitophagy receptor, GFP-BNIP3L/NIX. This method offers a rapid alternative to conventional microscopy or immunoblotting techniques for analyzing mitophagy activity. Additionally, this approach can theoretically be adapted to utilize any fluorescent-tagged selective autophagy receptor, enabling the direct and rapid analysis of various types of receptor-mediated selective autophagy.
    Keywords:  BNIP3L/NIX; flow cytometry; fluorescent tagging; receptor‐mediated mitophagy
    DOI:  https://doi.org/10.1002/2211-5463.13958
  11. Brain Res. 2024 Dec 20. pii: S0006-8993(24)00671-1. [Epub ahead of print]1850 149416
    Inhibition of autophagy attenuates cognitive decline and mitochondrial dysfunction in an Alzheimer's disease mouse model with chronic cerebral hypoperfusion.
    Qin Yang, Tingting Chen, Shaofa Li, Chengmin Yang, Xingwu Zheng, Sanying Mao, Ning Liu, Shenglong Mo, Dengxing Li, Meiling Yang, Zhicheng Lu, Lina Tang, Xiaorui Huang, Xia Liu, Chongdong Jian, Yixia Yin, Jingwei Shang.
      This study aimed to investigate the impact of chronic cerebral hypoperfusion (CCH) on cognitive function, amyloid-β (Aβ) deposition, cellular autophagy, and mitochondrial dynamics in an Alzheimer's disease (AD) mouse model, and to evaluate the intervention effects of autophagy modulation on these outcomes. Utilizing the APP/PS1 mouse model combined with CCH, we assessed cognitive function, Aβ deposition, and the expression levels of relevant proteins through behavioral tests and immunohistochemical analysis. Our findings revealed pronounced cognitive deficits and increased Aβ deposition in the AD + CCH group mice, along with upregulation of mitochondrial fission proteins (Drp1, Fis1) and downregulation of mitochondrial fusion proteins (Opa1, Mfn1), indicating a shift towards mitochondrial fission and promoting cell apoptosis. Additionally, alterations were observed in the expression levels of cellular autophagy-related proteins (LC3-II, P62), which were reversed by treatment with autophagic inhibitor 3-methyladenine (3-MA). Furthermore, the expression of mitochondrial autophagy-related proteins PINK1 and Parkin was affected, with 3-MA alleviating this effect. In summary, our study elucidates the complex interplay among cognitive decline, increased Aβ deposition, and mitochondrial dysfunction in the AD + CCH model, and suggests that modulating autophagy could be a potential therapeutic strategy for treating the AD + CCH model.
    Keywords:  3-methyladenine; Alzheimer’s disease; Chronic cerebral hypoperfusion; Mitochondrial fission; Mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.brainres.2024.149416
  12. Chem Biol Interact. 2024 Dec 24. pii: S0009-2797(24)00509-X. [Epub ahead of print] 111363
    Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1.
    Xiaoyan Wang, Chao Ma, Keying Mi, Xinran Cao, Yinghua Tan, Haitao Yuan, Jun Ren, Xinyue Liang.
      Doxorubicin (Dox) is a widely used antineoplastics although its clinical usage is greatly limited by its cardiotoxicity. Several studies have depicted an essential role for dampened mitophagy and mitochondrial injury in Dox cardiotoxicity. However, preventative measure to alleviate Dox-evoked cardiotoxicity via targeting mitophagy and mitochondrial integrity remains elusive. Urolithin A (UA) is a newly identified mitophagy inducer with antioxidant and anti-apoptotic properties although its effect on Dox-induced cardiotoxicity is unknown. This study was designed to explore the effect of UA on Dox cardiotoxicity and mechanisms involved. Our results indicated that UA alleviated Dox-induced cardiac dysfunction exhibited by echocardiographic parameters and histological analyses, and partially relieved Dox-induced apoptosis in vitro and in vivo, and mitochondrial dysfunction including ΔΨm dissipation and ROS production in vitro. The ability of UA to facilitate restoration of mitophagy in mice and H9C2s underscored its advantageous effects, manifested as upregulation of mitophagy-related proteins, including p62, LC3, PINK1 and Parkin, as well as the co-location between LC3 and mitochondria. Incubation with 3MA nearly reversed the UA-evoked rise of mitophagy-related proteins, and inhibition of apoptosis. Given that knockdown of Ambra1 almost abolished UA-induced protective effect, the enhanced expression of Ambra1 owing to UA increased PINK1 levels by inhibiting its degradation via LONP1. Collectively, our results suggest that the cardioprotective properties of UA depend on the stimulation of PINK1-dependent mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. This highlights UA's potential as a valuable treatment option and its importance in cardioprotective strategies against Dox-induced cardiotoxicity.
    Keywords:  Ambra1; cardiotoxicity; doxorubicin; mitophagy; urolithin A
    DOI:  https://doi.org/10.1016/j.cbi.2024.111363
  13. Cell Mol Biol (Noisy-le-grand). 2024 Nov 27. 70(11): 64-70
    Short-term effects of retinoic acid on the proliferation of SH-SY5Y cells via mitophagy and apoptosis.
    Dilara Aydin, Çağrı Öner, Senem Aslan Öztürk, Ertuğrul Çolak.
      Neuroblastoma shows the highest lethality in childhood and has poor prognosis at high grade. Our objectives included determining how retinoic acid affected the growth of neuroblastoma cells and the relationship between chemicals unique to neurons and cell death processes like apoptosis and mitophagy. The 50% inhibitory concentration of retinoic acid on SH-SY5Y neuroblastoma cells was determined at the 24th, 48th and 72nd hours. At the optimal concentration of retinoic acid on SH-SY5Y cells, Ki-67, cytochrome C, HIF-1α, Parkin, α-synuclein, DJ-1 and tyrosine β- hydroxylase gene expressions were determined by using RT-PCR. Tyrosine β-hydroxylase protein expression was assessed by ELISA. The optimal time and concentration for retinoic acid in SH-SY5Y cells was 10 μM at the 24th hour. The decreased gene expressions of Ki-67, α-synuclein, DJ-1 and tyrosine β-hydroxylase were observed while Cyt C, HIF-1α and Parkin gene expressions were upregulated (p<0.001). Tyrosine β-hydroxylase protein expression increased at the 24th and 72nd hours although it decreased at the 48th hour (p<0.001). Retinoic acid has short-term effect on the proliferation of SH-SY5Y neuroblastoma cells. It was observed that short-term retinoic acid treatment improved neurodegeneration parameters, but it decreased the proliferation by inducing mitophagy and apoptosis of SH-SY5Y neuroblastoma cells.
    DOI:  https://doi.org/10.14715/cmb/2024.70.11.9
  14. Cell Mol Life Sci. 2024 Dec 24. 82(1): 13
    Trimethylamine-N-oxide accelerates osteoporosis by PERK activation of ATF5 unfolding.
    Yu-Han Lin, Wei-Shiung Lian, Re-Wen Wu, Yu-Shan Chen, Shin-Long Wu, Jih-Yang Ko, Shao-Yu Wang, Holger Jahr, Feng-Sheng Wang.
      Imbalances in gut microbiota and their metabolites have been implicated in osteoporotic disorders. Trimethylamine-n-oxide (TMAO), a metabolite of L-carnitine produced by gut microorganisms and flavin-containing monooxygenase-3, is known to accelerate tissue metabolism and remodeling; however, its role in bone loss remained unexplored. This study investigates the relationship between gut microbiota dysbiosis, TMAO production, and osteoporosis development. We further demonstrate that the loss of beneficial gut microbiota is associated with the development of murine osteoporosis and alterations in the serum metabolome, particularly affecting L-carnitine metabolism. TMAO emerges as a functional metabolite detrimental to bone homeostasis. Notably, transplantation of mouse gut microbiota counteracts obesity- or estrogen deficiency-induced TMAO overproduction and mitigates key features of osteoporosis. Mechanistically, excessive TMAO intake augments bone mass loss by inhibiting bone mineral acquisition and osteogenic differentiation. TMAO activates the PERK and ATF4-dependent disruption of endoplasmic reticulum autophagy and suppresses the folding of ATF5, hindering mitochondrial unfolding protein response (UPRmt) in osteoblasts. Importantly, UPRmt activation by nicotinamide riboside mitigates TMAO-induced inhibition of mineralized matrix biosynthesis by preserving mitochondrial oxidative phosphorylation and mitophagy. Collectively, our findings revealed that gut microbiota dysbiosis leads to TMAO overproduction, impairing ER homeostasis and UPRmt, thereby aggravating osteoblast dysfunction and development of osteoporosis. Our study elucidates the catabolic role of gut microflora-derived TMAO in bone integrity and highlights the therapeutic potential of healthy donor gut microbiota transplantation to alter the progression of osteoporosis.
    Keywords:  ER-phagy; Gut microecosystem; Misfolding; OXPHOS; Parkin; Trimethylamine-n-oxide
    DOI:  https://doi.org/10.1007/s00018-024-05501-y
  15. Discov Med. 2024 Dec;36(191): 2386-2398
    A New Perspective for Improving COPD: Ginsenoside Rg3 Links SIRT1 to Inhibit Mitochondrial Autophagy.
    Yuanyuan Wang, Nianzhi Zhang, Feng Liu, Jing Zhou, Gang Teng, He Huang.
       BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a prevalent yet manageable respiratory condition. However, treatments presently used normally have side effects and cannot cure COPD, making it urgent to explore effective medications. The ginsenoside Rg3 (Rg3) has been shown to have anti-inflammatory and anti-tumor properties and can improve COPD. The primary objectives of this investigation were to explore the impact of Rg3 on COPD and delve into the associated mechanisms.
    METHODS: In vitro models exposed human bronchial epithelial cells (BEAS-2B) to cigarette smoke extract (CSE), and in vivo models induced COPD in mice through chronic inhalation of cigarette smoke (CS). Sirtuin 1 (SIRT1) expression was regulated via cell transfection or mice infection with recombinant lentiviruses. SIRT1 mRNA levels were quantified using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and SIRT protein levels were assessed by western blot or enzyme-linked immunosorbent assays (ELISA). Mitophagy was evaluated by light chain 3 (LC3) II/I and phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) levels, and apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Lung function was measured with the Buxco system, and inflammation was assessed via interleukin 6 (IL-6) and keratinocyte-derived cytokine (KC) levels in bronchial alveolar lavage fluid. Lung morphological impairments were determined through Hematoxylin and Eosin (H&E) staining and mean linear intercept (MLI) measurement.
    RESULTS: In BEAS-2B cells, CSE treatment caused a decrease in SIRT1 expression (p < 0.01) and an increase in LC3 II/I (p < 0.01) and PINK1 (p < 0.01), which were all reversed by Rg3 (p < 0.01), with 20 μM Rg3 performing the best and being used subsequently. CSE increased apoptosis of BEAS-2B cells (p < 0.01), which was reversed by Rg3 (p < 0.01). Upregulated SIRT1 further decreased levels of LC3 II/I (p < 0.001), PINK1 (p < 0.001), and cell apoptosis (p < 0.001) for CSE- and Rg3-treated cells, whereas downregulated SIRT1 reversely increased levels of LC3 II/I (p < 0.001), PINK1 (p < 0.001), and cell apoptosis (p < 0.001). The establishment of COPD caused a decrease in SIRT1 mRNA (p < 0.001), SIRT1 protein (p < 0.001), and lung functions (p < 0.001) whereas IL-6 (p < 0.001), KC (p < 0.001), lung impairment, and MLI (p < 0.001) were increased; all of these effects were reversed by Rg3 (p < 0.001). Moreover, the Rg3-induced reversion was furthered by SIRT1 upregulation (p < 0.001) and was disrupted by SIRT1 downregulation (p < 0.001).
    CONCLUSION: Rg3, through activation of SIRT1, suppresses mitophagy and apoptosis, ameliorates COPD, and improves lung functions.
    Keywords:  SIRT1; apoptosis; chronic obstructive pulmonary disease; ginsenoside Rg3; mitochondrial autophagy
    DOI:  https://doi.org/10.24976/Discov.Med.202436191.220
  16. Cell Prolif. 2024 Dec 26. e13796
    Mitonuclear Communication in Stem Cell Function.
    Baozhou Peng, Yaning Wang, Hongbo Zhang.
      Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.
    Keywords:  aging; fate determination; metabolism; mitochondria; mitochondrial stress; mitonuclear communication; stem cell
    DOI:  https://doi.org/10.1111/cpr.13796
  17. Front Pharmacol. 2024 ;15 1509482
    Ailanthone blocks mitophagy to promote mtDNA leakage through BAX-BAK1 pores and suppress hepatocellular carcinoma cell proliferation.
    Yan Qin, Ying Gao, Dan Wu, Qing-Qing Liu, Chang Su, Guan Liu, Le Yang, Ming-Gao Zhao, Jing-Yue Yao.
       Introduction: Hepatocellular carcinoma (HCC), the third leading cancer mortality worldwide, shows rising incidence. The mitochondria in HCC cells are prone to damage from metabolic stress and oxidative stress, necessitating heightened mitophagy for mitochondrial homeostasis and cell survival. Thus, mitophagy inhibition is a promising HCC therapy. The traditional Chinese medicinal herb ailanthone have proved promote mitochondrial dysfunction and inhibits HCC. However, the underlying mechanism remains unclear.
    Methods: CCK8 assay was applied to detect the proliferation. JC-1, MitoTracker Red/Green and MitoSOX staining were applied to detect the mitochondrial homeostasis. Inflammatory factors were analysed via ELISA and WB assay. Mitochondria and cytoplasm separation, genome extraction and qPCR were used to detect mitochondrial DNA (mtDNA) leakage. Mitochondria ultrastructure was detected by transmission electron microscopy. WB and IHC experiments were applied to detect protein expression. Protein-protein interactions detected by immunoprecipitation and immunofluorescence imaging. The in vivo antitumor effect was validated by the xenograft mouse model.
    Results: In this study, we demonstrated the potent anti-HCC properties of ailanthone and revealed its molecular mechanism. In vitro studies demonstrated that ailanthone effectively inhibited PINK1-PRKN mediated mitophagy and promoted BAX-BAK1 mitochondrial pores formation through PRKN inhibition. This process led to the mitochondrial mtDNA leakage into the cytoplasm, which subsequently triggered the induction of inflammatory factors. The inhibition of mitophagy and the activation of inflammatory response ultimately led to HCC proliferation inhibition. In vivo studies demonstrated that ailanthone exhibited stronger anti-HCC activity than 5-Fluorouracil (5-FU), with no significant adverse effects on animal body weight or the physiological functions of vital organs.
    Conclusion: This study highlighted the efficacy of ailanthone against HCC and elucidated its underlying molecular mechanisms, suggesting the promising therapeutic potential of ailanthone for HCC.
    Keywords:  BAX-BAK1; PINK1-PRKN; ailanthone; hepatocellular carcinoma; inflammation; mtDNA
    DOI:  https://doi.org/10.3389/fphar.2024.1509482
  18. Elife. 2024 Dec 27. pii: RP96536. [Epub ahead of print]13
    A transcription network underlies the dual genomic coordination of mitochondrial biogenesis.
    Fan Zhang, Annie Lee, Anna V Freitas, Jake T Herb, Zong-Heng Wang, Snigdha Gupta, Zhe Chen, Hong Xu.
      Mitochondrial biogenesis requires the expression of genes encoded by both the nuclear and mitochondrial genomes. However, aside from a handful transcription factors regulating specific subsets of mitochondrial genes, the overall architecture of the transcriptional control of mitochondrial biogenesis remains to be elucidated. The mechanisms coordinating these two genomes are largely unknown. We performed a targeted RNAi screen in developing eyes with reduced mitochondrial DNA content, anticipating a synergistic disruption of tissue development due to impaired mitochondrial biogenesis and mitochondrial DNA (mtDNA) deficiency. Among 638 transcription factors annotated in the Drosophila genome, 77 were identified as potential regulators of mitochondrial biogenesis. Utilizing published ChIP-seq data of positive hits, we constructed a regulatory network revealing the logic of the transcription regulation of mitochondrial biogenesis. Multiple transcription factors in core layers had extensive connections, collectively governing the expression of nearly all mitochondrial genes, whereas factors sitting on the top layer may respond to cellular cues to modulate mitochondrial biogenesis through the underlying network. CG1603, a core component of the network, was found to be indispensable for the expression of most nuclear mitochondrial genes, including those required for mtDNA maintenance and gene expression, thus coordinating nuclear genome and mtDNA activities in mitochondrial biogenesis. Additional genetic analyses validated YL-1, a transcription factor upstream of CG1603 in the network, as a regulator controlling CG1603 expression and mitochondrial biogenesis.
    Keywords:  ChIP-seq; D. melanogaster; RNA-seq; SDHA; TFAM; genetics; genomics; mitochondrial biogenesis; transcription factors
    DOI:  https://doi.org/10.7554/eLife.96536
  19. Biol Pharm Bull. 2024 ;47(12): 2143-2153
    HMGB1 Promotes Accelerated Fracture Healing in Traumatic Brain Injury through PINK1/Parkin-Mediated Mitochondrial Autophagy.
    Shiyang Chen, Aiguo Zhou, Wenlong Yan.
      We aimed to investigate the mechanism of high mobility group box 1 (HMGB1) in the accelerated fracture healing process during Traumatic brain injury (TBI). The lateral ventricles of mice in the TBI model group were injected with adenovirus-packaged short hairpin RNA (shRNA)-HMGB1 or overexpressing (ov)-HMGB1 vector. We found HMGB1 levels were higher in bone tissue at the fracture end of TBI combined with fracture model mice. Compared with the TBI combined with fracture model mice, the mice in the ov-HMGB1 group healed faster and the expression levels of mitochondrial autophagy-related proteins were higher. Compared to the ov-HMGB1 group, mice in the ov-HMGB1 + autophagy inhibitor cyclosporin A (CsA) and ov-HMGB1 + shRNA-phosphatase and tensin homolog-induced kinase 1 (PINK1) groups showed slower healing and lower expression of mitochondrial autophagy-associated proteins. The expression of osteocalcin (OCN), SOX9, and bone morphogenetic protein (BMP)-2 in bone tissue at the fracture end of the ov-HMGB1 + shRNA-PINK1 group was lower than that in the ov-HMGB1 group. The mRNA expression levels of chondrogenic differentiation markers in bone tissue at the fracture end of the ov-HMGB1 + shRNA-PINK1 group were lower than those in the ov-HMGB1 group. Fracture healing was accelerated during TBI, especially when HMGB1 was highly expressed, and HMGB1 promote accelerated fracture healing during TBI through PINK1/Parkin-mediated mitochondrial autophagy.
    Keywords:  Parkin RBR E3 ubiquitin-protein ligase pathway; high mobility group box 1 (HMGB1); mitochondrial autophagy; phosphatase and tensin homolog-induced kinase 1; traumatic brain injury combined with fracture
    DOI:  https://doi.org/10.1248/bpb.b24-00203
  20. FEBS J. 2024 Dec 24.
    Attenuated NIX in impaired mitophagy contributes to exacerbating cellular senescence in experimental periodontitis under hyperglycemic conditions.
    Danni Song, Beibei Chen, Tianfan Cheng, Lijian Jin, Jiangfeng He, Yongming Li, Chongshan Liao.
      Premature accumulation of senescent cells results in tissue destruction, and it is one of the potential primary mechanisms underlying the accelerated progression of diabetes and periodontitis. However, whether this characterized phenomenon could account for periodontal pathogenesis under hyperglycemic conditions remains unclear. In this study, we assessed the senescent phenotypic changes in experimental periodontitis under hyperglycemic conditions. Next, we investigated the mitochondrial function and the potential mitophagy pathways in cellular senescence in vitro and in vivo. Our findings showed that significant senescence occurred in the gingival tissues of diabetic periodontitis mice with increased expression of senescence-related protein p21Cip1 and the senescence-associated secretory phenotype response as well as the decreased expression of NIP3-like protein X (NIX), a mitochondrial receptor. Likewise, we showed that mitochondrial dysfunction (e.g., reduction of mitochondrial membrane potential and accumulation of reactive oxygen species) was attributed to cellular senescence in: human periodontal ligament cells (hPDLCs) through hyperglycemia-induced and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS)-induced oxidative stresses. Notably, the resulting reduced NIX expression was reversed by the use of the mitochondrial reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC), thus correcting the mitochondrial dysfunction. We further verified the expression of inflammatory mediators and senescence-related factors in mice gingival tissues and identified the possible regulatory pathways. Taken together, our work demonstrates the critical role of cellular senescence and mitochondrial dysfunction in periodontal pathogenesis under hyperglycemic conditions. Hence, restoration of mitochondrial function may be a potential novel therapeutic approach to tackling periodontitis in diabetic patients.
    Keywords:  NIX; hyperglycemia; mitophagy; periodontitis; senescence
    DOI:  https://doi.org/10.1111/febs.17352
  21. Cell Biol Toxicol. 2024 Dec 20. 41(1): 2
    Nrf2/NRF1 signaling activation and crosstalk amplify mitochondrial biogenesis in the treatment of triptolide-induced cardiotoxicity using calycosin.
    Xiao-Ming Qi, Wei-Zheng Zhang, Yu-Qin Zuo, Yuan-Biao Qiao, Yuan-Lin Zhang, Jin-Hong Ren, Qing-Shan Li.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates both oxidative stress and mitochondrial biogenesis. Our previous study reported the cardioprotection of calycosin against triptolide toxicity through promoting mitochondrial biogenesis by activating nuclear respiratory factor 1 (NRF1), a coregulatory effect contributed by Nrf2 was not fully elucidated. This work aimed at investigating the involvement of Nrf2 in mitochondrial protection and elucidating Nrf2/NRF1 signaling crosstalk on amplifying the detoxification of calycosin. Results indicated that calycosin inhibited cardiomyocytes apoptosis and F-actin depolymerization following triptolide exposure. Cardiac contraction was improved by calycosin through increasing both fractional shortening (FS%) and ejection fraction (EF%). This enhanced contractile capacity of heart was benefited from mitochondrial protection reflected by ultrastructure improvement, augment in mitochondrial mass and ATP production. NRF1 overexpression in cardiomyocytes increased mitochondrial mass and DNA copy number, whereas NRF1 knockdown mitigated calycosin-mediated enhancement in mitochondrial mass. For nuclear Nrf2, it was upregulated by calycosin in a way of disrupting Nrf2-Keap1 (Kelch-like ECH associated protein 1) interaction, followed by inhibiting ubiquitination and degradation. The involvement of Nrf2 in mitochondrial protection was validated by the results that both Nrf2 knockdown and Nrf2 inhibitor blocked the calycosin effects on mitochondrial biogenesis and respiration. In the case of calycosin treatment, its effect on NRF1 and Nrf2 upregulations were respectively blocked by PGCα/Nrf2 and NRF1 knockdown, indicative of the mutual regulation between Nrf2 and NRF1. Accordingly, calycosin activated Nrf2/NRF1 and the signaling crosstalk, leading to mitochondrial biogenesis amplification, which would become a novel mechanism of calycosin against triptolide-induced cardiotoxicity.
    Keywords:  Calycosin; Mitochondrial biogenesis; NRF1; Nrf2; Triptolide
    DOI:  https://doi.org/10.1007/s10565-024-09969-z
  22. Environ Pollut. 2024 Dec 24. pii: S0269-7491(24)02306-6. [Epub ahead of print] 125589
    Microcystin-LR induces neuronal damage through mitophagy defects resulted from the downregulated transcription of Scd2 by directly targeting IGF-1R.
    Yao Tan, Yujing Huang, Weiyan Chen, Tingyuan Lang, Lingqiao Wang, Xiaoling Chen, Haili Yu, Zhiqun Qiu, Ke Cui, Chengwei Guo, Yiqi Wang, Ziyuan Zhou.
      Microcystin-LR (MC-LR), a prevalent cyanotoxin present in hazardous cyanobacterial blooms, is recognized as a neurotoxic environmental pollutant that induces brain damage and neurobehavioral deficits. However, the mechanisms underlying MC-LR-induced neurotoxicity remain unclear. This study aims to elucidate the role of mitophagy in MC-LR-induced neurotoxicity both in vitro and in vivo. We found that administration of 10 μg/kg body weight (intraperitoneally) MC-LR impaired learning and memory abilities and induced neuronal damage and apoptosis in the CA1 region of the hippocampus in rats. Exposure to MC-LR (1 μM to 10 μM) resulted in cellular damage and apoptosis in PC-12 and HT22 cells. MC-LR induced mitophagy through the PINK1/Parkin pathway but hindered mitophagy progression by repressing Scd2 transcription in neurons. These inhibitory effects were reversed by Scd2 overexpression. Furthermore, MC-LR was found to repress Scd2 transcription by directly binding to type 1 insulin-like growth factor receptor (IGF-1R) and competitively inhibiting its activation by Insulin-like growth factor 1 (IGF-1). Overexpression of IGF-1R and administration of exogenous IGF-1 mitigated the MC-LR-induced inhibition of Scd2 and the associated mitophagy defects. These findings indicate that IGF-1R is the direct target of MC-LR in neurons. MC-LR initiates mitophagy defects and apoptosis by inhibiting Scd2 transcription through binding to IGF-1R.
    Keywords:  IGF-1R; Microcystin-LR; Neurotoxicity; Scd2; mitophagy
    DOI:  https://doi.org/10.1016/j.envpol.2024.125589
  23. Acta Biochim Biophys Sin (Shanghai). 2025 Jan 25.
    Corrigendum to: HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells.
    Xinxin Kou, Xiaoxia Yang, Zheng Zhao, Lei Li.
      
    DOI:  https://doi.org/10.3724/abbs.2024243
  24. Environ Pollut. 2024 Dec 25. pii: S0269-7491(24)02305-4. [Epub ahead of print]367 125588
    Mitochondrial homeostatic imbalance-mediated developmental toxicity to H2S in embryonic zebrafish.
    Yinai Liu, Yu Cao, Huiqi Li, Huanpeng Liu, Ting Chen, Qizhuan Lin, Changyong Gong, Fan Yu, Helei Cai, Libo Jin, Renyi Peng.
      Hydrogen sulfide (H2S) is a pervasive environmental and industrial pollutant that poses a substantial threat to human health. Even short-term exposure to H2S can result in severe respiratory and neurological damage. However, the underlying mechanisms of its biotoxicity remain unclear. Our study demonstrated that continuous exposure to 30 μM (1.02 ppm), whin environmentally H2S concentration range, results in notable developmental toxicity, including high mortality rates, morphological deformities, and behavioral abnormalities, in zebrafish larvae. Through transcriptomic analysis, examination of mitochondrial structure and function, and tissue and cellular staining, we found that H2S exposure disrupted mitochondrial dynamics, autophagy, and biogenesis, leading to an imbalance in mitochondrial homeostasis. This disruption induced oxidative stress and extensive apoptosis. Nitric oxide (NO) is a multifunctional signaling molecule known to target and regulate mitochondrial regeneration. In our study, we discovered that sodium nitroprusside (SNP), an NO donor, can activate the NO-sGC-cGMP signaling pathway. This activation improves the homeostatic regulation of mitochondrial dynamics, autophagy, and biogenesis, thereby enhancing mitochondrial function and effectively mitigating H2S-induced biotoxicity. Our research not only elucidates the biotoxicity mechanisms of H2S exposure but also provides valuable insights into potential therapeutic strategies that alleviate or eliminate its toxic effects.
    Keywords:  Hydrogen sulfide; Mitochondrial homeostatic; Nitric oxide; Zebrafish
    DOI:  https://doi.org/10.1016/j.envpol.2024.125588
  25. Neurotherapeutics. 2024 Dec 26. pii: S1878-7479(24)00200-9. [Epub ahead of print] e00513
    Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
    Matteo Massaro, Gherardo Baudo, Hyunho Lee, Haoran Liu, Elvin Blanco.
      Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β1-42 (Aβ1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.
    Keywords:  Alzheimer's disease; Amyloid beta; Mitochondrial biogenesis; Mitochondrial dysfunction; Nuclear respiratory factor-1 (NRF1)
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00513
  26. Methods Mol Biol. 2025 ;2840 175-183
    Alternating Cellular Functions by Optogenetic Control of Organelles.
    Kangqiang Qiu, Xiuqiong Xu, Kai Zhang, Jiajie Diao.
      Organelles play essential roles in cellular homeostasis and various cellular functions in eukaryotic cells. The current experimental strategy to modulate organelle functions is limited due to the dynamic nature and subcellular distribution of organelles in live cells. Optogenetics utilizes photoactivatable proteins to enable dynamic control of molecular activities through visible light. This modality has been rapidly expanded for the dynamic regulation of organelle functions. This chapter describes a method by optical modulation of the mitochondria-lysosome contacts (MLCs). Detailed procedures of transfection, optogenetic MLCs, mitochondrial morphology, and functional analysis are described. Optogenetic control of organelles in live cells offers an innovative paradigm for cell engineering and synthetic biology.
    Keywords:  Mitochondria-lysosome contacts; Mitochondrial fission; Optogenetics; Regulation of cellular functions; Subcellular manipulation
    DOI:  https://doi.org/10.1007/978-1-0716-4047-0_13
  27. Front Pharmacol. 2024 ;15 1491315
    JiangyaTongluo decoction ameliorates tubulointerstitial fibrosis via regulating the SIRT1/PGC-1α/mitophagy axis in hypertensive nephropathy.
    Yun Zhao, Qi Jia, Gaimei Hao, Lin Han, Yushan Gao, Xiaoyu Zhang, Ziming Yan, Boyang Li, Yiping Wu, Boya Zhang, Yubo Li, Jianguo Qin.
       Introduction: With the increasing prevalence of hypertension, the incidence of kidney diseases is also increasing, resulting in a serious public burden. Jiangya Tongluo decoction (JYTL), a recognized prescription in traditional Chinese medicine (TCM), is commonly used to calm an overactive liver and reduce excess yang, while also promoting blood flow to alleviate obstructions in the meridians. Previous research has indicated that JYTL may help mitigate kidney damage caused by hypertension; however, the underlying mechanisms have not been thoroughly assessed.
    Methods: First, an amalgamation of UPLC-QE/MS and network pharmacology techniques was employed to pinpoint potential active components, primary targets, and crucial action mechanisms of JYTL in treating hypertensive nephropathy (HN). Then, we used spontaneous hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) to evaluate the efficacy of JYTL on HN with valsartan as a positive reference. We also conducted DCFH-DA fluorescence staining in rat renal tissues to detect the level of ROS. Western blotting and immunohistochemistry were performed to investigate further the effect of JYTL decoction on key targets and signaling pathways.
    Results: Through UPLC-QE/MS and network analysis, 189 active ingredients and 5 hub targets were identified from JYTL. GSEA in the MitoCarta3.0 database and PPI network analysis revealed that JYTL predominantly engages in the Sirt1-mitophagy signaling pathway. Tanshinone iia, quercetin, and adenosine in JYTL are the main active ingredients for treating HN. In vivo validation showed that JYTL decoction could improve kidney function, ameliorate tubulointerstitial fibrosis (TIF), and improve mitochondrial function by inhibiting ROS production and regulating mitochondrial dynamics in SHRs. JYTL treatment could also increase the expression of SIRT1, PGC-1α, Nrf1, and TFAM, and activate PINK1/Parkin-mediated mitophagy.
    Conclusion: JYTL decoction may exert renal function protective and anti-fibrosis effects in HN by ameliorating mitochondrial function and regulating the SIRT1/PGC-1α-mitophagy pathway.
    Keywords:  Chinese medicine; SIRT1; hypertensive nephropathy; mitochondrial dysfunction; mitophagy; tubulointerstitial fibrosis
    DOI:  https://doi.org/10.3389/fphar.2024.1491315
  28. iScience. 2024 Dec 20. 27(12): 111467
    SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.
    Ritam Naha, Rebecca Strohm, Yulia Schaumkessel, Jennifer Urbach, Ilka Wittig, Andreas S Reichert, Arun Kumar Kondadi, Ruchika Anand.
      The MICOS complex, essential for cristae organization, comprises MIC10 and MIC60 subcomplexes, with MIC13 as a crucial subunit. MIC13 mutations cause severe mitochondrial hepato-encephalopathy, cristae defects, and MIC10-subcomplex loss. We demonstrate that depletion of the mitochondrial protease YME1L in MIC13 KO stabilizes MIC10-subcomplex, restoring MIC60-MIC10 interaction and crista junction (CJ) defects, indicating MIC13 is crucial for MIC10-subcomplex stabilization rather than MIC60-MIC10 bridging. We identified stomatin-like protein 2 (SLP2) as a key MIC13 interaction partner, essential for cristae morphology and CJ formation. SLP2 serves as an interaction hub for MICOS subunits and stabilizes MIC26 by protecting it from YME1L-mediated degradation. Deleting both SLP2 and MIC13 impairs MIC60-subcomplex assembly and its nanoscale organization. Restoring the MIC10-subcomplex in MIC13-SLP2 double KO cells through YME1L depletion reinstates MIC60-subcomplex assembly and cristae morphology. Overall, we propose SLP2 and the MIC10-subcomplex act as a proteolytically controlled 'seeder' complex, facilitating MICOS-MIB complex assembly and maintaining mitochondrial integrity.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111467
  29. Biomaterials. 2024 Dec 15. pii: S0142-9612(24)00559-3. [Epub ahead of print]316 123023
    Mitochondria-targeting materials and therapies for regenerative engineering.
    Hongying Fu, Jingrong Cheng, Le Hu, Boon Chin Heng, Xuehui Zhang, Xuliang Deng, Yang Liu.
      The hemostatic, inflammatory, proliferative, and remodeling phases of healing require precise spatiotemporal coordination and orchestration of numerous biological processes. As the primary energy generators in the cell, mitochondria play multifunctional roles in regulating metabolism, stress reactions, immunity, and cell density during the process of tissue regeneration. Mitochondrial dynamics involves numerous crucial processes, fusion, fission, autophagy, and translocation, which are all necessary for preserving mitochondrial function, distributing energy throughout cells, and facilitating cellular signaling. Tissue regeneration is specifically associated with mitochondrial dynamics due to perturbations of Ca2+, H2O2 and ROS levels, which can result in mitochondrial malfunction. Increasing evidence from multiple models suggests that clinical interventions or medicinal drugs targeting mitochondrial dynamics could be a promising approach. This review highlights significant advances in the understanding of mitochondrial dynamics in tissue regeneration, with specific attention on mitochondria-targeting biomaterials that accelerate multiple tissues' regeneration by regulating mitochondrial metabolism. The innovations in nanomaterials and nanosystems enhance mitochondrial-targeting therapies are critically examined with the prospects of modulating mitochondrial dynamics for new therapies in regenerative engineering.
    Keywords:  Mitochondria-targeting materials; Mitochondrial dynamics; Mitochondrial transfer; Regenerative engineering
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.123023
  30. Mol Cell Endocrinol. 2024 Dec 20. pii: S0303-7207(24)00299-5. [Epub ahead of print] 112443
    MDPAO1 Peptide from Human Milk Enhances Brown Adipose Tissue Thermogenesis and Mitigates Obesity.
    Yao Gao, Jiahui Zhang, Mengda Cao, Yiting Zhang, Minkai Cao, Wei Gu, Mingxin Wang.
      The regulatory effect of breastfeeding on offspring metabolism has garnered significant attention as an effective strategy in combating childhood obesity. However, the underlying mechanism remains largely unknown. Through integrated analysis of multiple human milk peptide databases and functional screening, MDPAO1 (milk-derived peptide associated with obesity 1) was identified as having potential activity in promoting the expression of thermogenic genes. In lactating mice, intervention with MDPAO1 enhanced the thermogenic phenotype of brown adipose tissue (BAT) and overall metabolic activity. Moreover, MDPAO1 intervention led to reduced body weight gain, increased brown fat mass, and improved glucose tolerance and insulin sensitivity in a mouse model of high-fat diet (HFD)-induced obesity. RNA-seq analysis of BAT post-MDPAO1 intervention revealed close association with mitochondrial oxidative respiratory chain and mitophagy. Subsequent in vitro experiments conducted on primary brown adipocytes confirmed that MDPAO1 inhibited mitophagy, increased mitochondrial mass, and elevated levels of mitochondrial respiratory chain complexes. In conclusion, this study underscores the potential of MDPAO1, a peptide enriched in breast milk, in activating the thermogenic phenotype of brown adipose tissue and mitigating obesity, thus offering novel insights into the mechanisms underlying breastfeeding's role in preventing childhood obesity.
    Keywords:  human milk; mitophagy; obesity; peptide; thermogenesis
    DOI:  https://doi.org/10.1016/j.mce.2024.112443
  31. J Adv Res. 2024 Dec 24. pii: S2090-1232(24)00611-8. [Epub ahead of print]
    Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss.
    Wentao Wang, Qing Wang, Wenming Li, Hao Xu, Xiaolong Liang, Wei Wang, Ning Li, Huilin Yang, Yaozeng Xu, Jiaxiang Bai, Shuli Yang, Dechun Geng.
       INTRODUCTION: Inflammatory diseases, such as diabetes mellitus, rheumatoid arthritis, and inflammatory bowel disease, lead to systemic immune microenvironment disturbances, contributing to bone loss, yet the mechanisms by which specific receptors regulate this process in inflammatory bone loss remain poorly understood. As a G-protein-coupled receptor, the Apelin receptor plays a crucial role in the regulation of inflammation and immune microenvironment. However, the precise mechanisms governing its role in inflammatory bone loss remain incompletely understood.
    OBJECTIVE: This study aims to investigate how APJ regulates macrophage polarization to mitigate inflammatory bone loss.
    METHODS: Lipopolysaccharide induced systemic inflammatory bone loss model in mice was used to explore the relationship between bone loss and osteoclast activation, macrophage polarization and APJ. In vitro studies, Bone marrow derived macrophages and siRNA were used to elucidate the regulatory influence of APJ on the immune microenvironment and osteoclast differentiation, while high-throughput sequencing is leveraged to uncover the underlying mechanisms through which APJ modulates macrophage polarization.
    RESULTS: Our study established a link between APJ and macrophage M1 polarization in systemic inflammatory bone loss mice. The activation of APJ effectively mitigated M1 polarization in macrophages, suppressed excessive osteoclast activation, and alleviated systemic inflammatory bone loss. In vitro high-throughput sequencing analysis revealed that APJ modulates macrophage polarization, linking to mitochondrial autophagy and the NOD-like receptor signaling pathway and the involvement of the AMPK and MAPK signaling pathways in signal transduction after APJ activation was also suggested. Subsequent experiments substantiated that APJ predominantly enhances mitophagy and diminishes the accumulation of reactive oxygen species by regulating the AMPK/BNIP3/PINK1/PARKIN axis, thereby suppressing the activation of macrophage M1 polarization and osteoclastogenesis.
    CONCLUSION: This study elucidated the underlying mechanism by which APJ modulates macrophage polarization, thereby proposing a new therapeutic target for addressing inflammatory bone loss.
    Keywords:  APJ; Bone immune microenvironment; Macrophage polarization; Mitophagy
    DOI:  https://doi.org/10.1016/j.jare.2024.12.033
  32. Neurosci Lett. 2024 Dec 20. pii: S0304-3940(24)00470-1. [Epub ahead of print] 138091
    Sleep deprivation activated AMPK/FOXO3a signaling mediates pineal autophagy impairment to reduce melatonin secretion in CUMS + SD rats leading to depression combined with insomnia.
    Zirong Li, Yi Shu, Qian Liu, Deguo Liu, Sheng Xie, Mingjun Wei, Lidan Lan, Xinyi Yang.
      This study established an animal model of comorbid depression and insomnia by combining chronic unpredictable mild stress (CUMS) with sleep deprivation (SD). The pathogenesis of comorbid depression and insomnia may be associated with impaired AMPK/FOXO3a signaling, which mediates autophagy inhibition, leading to decreased pineal melatonin secretion. The findings revealed that CUMS + SD rats exhibited more pronounced depression-like behaviors, sleep disorders, increased central oxidative stress, and exacerbated neuroinflammation, accompanied by reduced levels of 5-hydroxytryptophan (5-HT) and melatonin in the pineal gland. Notably, further investigations revealed that impaired mitochondrial autophagy in the pineal gland is closely linked to the significant suppression of AMPK/FOXO3a signaling. The combined intervention of venlafaxine and melatonin effectively ameliorated the impaired mitochondrial autophagy in the pineal gland of CUMS + SD rats and stimulated melatonin secretion. Consequently, the study proposes that dysfunctional mitochondrial autophagy regulated by the AMPK/FOXO3a pathway can influence melatonin secretion, thereby playing a pivotal role in the pathogenesis of depression combined with insomnia.
    Keywords:  Chronic mild unpredictable stress; Depressive insomnia comorbidity; Melatonin; Mitochondrial autophagy; Pineal gland; Sleep deprivation
    DOI:  https://doi.org/10.1016/j.neulet.2024.138091
  33. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13672
    NLRP3 Inflammasome Activation and Altered Mitophagy Are Key Pathways in Inclusion Body Myositis.
    Elie Naddaf, Thi Kim Oanh Nguyen, Jens O Watzlawik, Huanyao Gao, Xu Hou, Fabienne C Fiesel, Jay Mandrekar, Eileen Kokesh, William S Harmsen, Ian R Lanza, Wolfdieter Springer, Eugenia Trushina.
       BACKGROUND: Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM.
    METHODS: The study population consisted of 38 IBM patients and 22 age- and sex-matched controls without a myopathy. Mean age was 62.9 years (SD = 9) in IBM group and 59.7 (10) in controls. Bulk RNA sequencing, Meso Scale Discovery electrochemiluminescence (ECL), western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.
    RESULTS: We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome being the most upregulated pathway on RNA sequencing, along with increased expression of NLRP3 and ASC proteins in IBM group. NLRP3 RNA levels most strongly correlated with TLR7 (correlation coefficient ρ = 0.91) and complement activation-related genes, and inversely correlated with several mitochondria-related genes among others. On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibres. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction-NLRP3 inflammasome activation. Herein, we showed altered mitophagy, as witnessed by the elevated levels of p-S65-Ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls (median of 114.3 vs. 81.25 ECL units, p = 0.005). The p-S65-Ubiquitin levels were most significantly elevated in IBM males compared to male controls (136 vs. 83.5 ECL units; p = 0.013), whereas IBM females had milder nonsignificant elevation compared to female controls (97.25 vs. 69 ECL units, p = 0.31). On muscle histopathology, p-S65-Ubiquitin aggregates accumulated in muscle fibres that were mostly Type 2 and devoid of cytochrome-c-oxidase reactivity. NLRP3 RNA levels correlated with p-S65-Ubiquitin levels in both sexes (males: ρ = 0.48, females: ρ = 0.54) but with loss of muscle strength, as reflected by the manual motor test score, only in males (males: ρ = 0.62, females: ρ = -0.14). Lastly, we identified sex-specific molecular pathways in IBM. Females had upregulation of pathways related to response to stress, which could conceivably offset some of the pathomechanisms of IBM, while males had upregulation of pathways related to cell adhesion and migration.
    CONCLUSIONS: There is activation of the NLRP3 inflammasome in IBM, along with altered mitophagy, particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.
    Keywords:  autophagy; inclusion body myositis; inflammasome; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1002/jcsm.13672
  34. Cell Rep. 2024 Dec 20. pii: S2211-1247(24)01466-9. [Epub ahead of print]44(1): 115115
    Pressure to evade cell-autonomous innate sensing reveals interplay between mitophagy, IFN signaling, and SARS-CoV-2 evolution.
    Jae Seung Lee, Mark Dittmar, Jesse Miller, Minghua Li, Kasirajan Ayyanathan, Max Ferretti, Jesse Hulahan, Kanupriya Whig, Zienab Etwebi, Trevor Griesman, David C Schultz, Sara Cherry.
      SARS-CoV-2 emerged, and continues to evolve, to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling occurring only in bystander cells. How the virus continues to evolve in the face of innate responses has important consequences, but the pathways involved are incompletely understood. Here, we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons and, thus, permissivity to infection. Mechanistically, autophagy (mitophagy) genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, loss of autophagy increased MAVS and overcomes ORF9b-mediated antagonism. This has driven the evolution of SARS-CoV-2 to express more ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of mitophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.
    Keywords:  CP: Immunology; CP: Microbiology; ORF9b; SARS-CoV-2; autophagy; cell-autonomous interferon response; coronavirus; innate immune signaling; mitophagy; viral evolution
    DOI:  https://doi.org/10.1016/j.celrep.2024.115115
  35. J Physiol Biochem. 2024 Dec 24.
    Aerobic exercise timing affects mitochondrial dynamics and insulin resistance by regulating the circadian clock protein expression and NAD+-SIRT1-PPARα-MFN2 pathway in the skeletal muscle of high-fat-diet-induced diabetes mice.
    Raha Pourabdi, Fereshteh Shahidi, Mohammad Reza Tabandeh, Mojtaba Salehpour.
      The circadian clock regulates mitochondrial function and affects time-dependent metabolic responses to exercise. The present study aimed to determine the effects of aerobic exercise timing at the light-dark phase on the proteins expression of the circadian clock, mitochondrial dynamics, and, NAD+-SIRT1-PPARα axis in skeletal muscle of high-fat diet-induced diabetic mice. In this experimental study, thirty male mice were randomly assigned into two groups based on time: the early light phase, ZT3, and the early dark phase, ZT15, and three groups at each time: (1) Healthy Control (HC), (2) Diabetic Control (DC), and (3) Diabetic + Exercise (DE). Diabetes was induced by 5 weeks of feeding with a high-fat diet and Streptozotocin injection. Following confirmation of diabetes, animals underwent treadmill running at ZT3 and ZT15 for eight-weeks (5 days, 60-80 min, 50-60%Vmax). The expression of proteins of muscle aryl-hydrocarbon receptor nuclear translocator-like-1 (BMAL1), period-2 (PER2), mitofusin-2 (MFN2), dynamin-related proteins-1 (DRP-1), glucose transporter (GLUT4), sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-alpha (PPARα), and nicotinamide adenine dinucleotide (NAD+) level were analyzed in gastrocnemius muscle at both exercise times. The results showed that aerobic exercise at both times reversed the dysregulation of the diabetes-induced skeletal muscle clock by increasing the BMAL1 and PER2 protein levels. Aerobic exercise, especially at ZT15 compared to ZT3, increased GLUT4-mediated glucose uptake, and improved the diabetes-induced imbalance of mitochondrial fusion-fission by a significant increase in MFN2 protein level. Moreover, time-dependent aerobic exercise only at ZT15 increased the SIRT1 and PPARα protein levels and reduced diabetes-induced hyperglycemia. However, the aerobic exercise timing could not restore the attenuation of diabetes-induced NAD+ levels and DRP-1 protein. Our findings demonstrated that the synchronization of aerobic exercise with the circadian rhythm of NAD+-SIRT1 may boost MFN2-mediated mitochondrial fusion by activating the BMAL1-PER2-SIRT1-PPARα axis in the skeletal muscle of diabetic mice and be more effective in facilitating glycemic control and insulin resistance.
    Keywords:  Aerobic exercise timing; Circadian molecular clock; Diabetes; Insulin resistance; Mitochondrial dynamics; NAD+/SIRT1; Skeletal muscle
    DOI:  https://doi.org/10.1007/s13105-024-01066-3
  36. Cancer Biol Ther. 2025 Dec;26(1): 2445220
    Knockdown of NDUFAF6 inhibits breast cancer progression via promoting mitophagy and apoptosis.
    Shang Wu, Xindi Ma, Xiangmei Zhang, Kaiye Du, Chao Shi, Ahmed Ali Almaamari, Boye Han, Suwen Su, Yunjiang Liu.
       BACKGROUND: While NDUFAF6 is implicated in breast cancer, its specific role remains unclear.
    METHODS: The expression levels and prognostic significance of NDUFAF6 in breast cancer were assessed using The Cancer Genome Atlas, Gene Expression Omnibus, Kaplan-Meier plotter and cBio-Portal databases. We knocked down NDUFAF6 in breast cancer cells using small interfering RNA and investigated its effects on cell proliferation and migration ability. We performed gene expression analysis and validated key findings using protein analysis. We also assessed mitochondrial activity and cellular metabolism.
    RESULTS: NDUFAF6 was highly expressed in breast cancer, which was associated with a poorer prognosis. Knockdown of NDUFAF6 reduced the proliferation and migration ability of breast cancer cells. Transcriptome analysis revealed 2,101 differentially expressed genes enriched in apoptosis and mitochondrial signaling pathways. Western blot results showed NDUFAF6 knockdown enhanced apoptosis. In addition, differential gene enrichment analysis was related to mitochondrial signaling pathways, and western blot results verified that mitophagy was enhanced in NDUFAF6 knockdown breast cancer cells. JC-1 assay also showed that mitochondrial dysfunction and reactive oxygen species content were increased after knocking down NDUFAF6. In addition, basal and maximal mitochondrial oxygen consumption decreased, and intracellular glycogen content increased.
    CONCLUSIONS: Knockdown of NDUFAF6 resulted in apoptosis and mitophagy in breast cancer cells and NDUFAF6 may be a potential molecular target for breast cancer therapy.
    Keywords:  Breast cancer; NDUFAF6; apoptosis; mitophagy; prognosis
    DOI:  https://doi.org/10.1080/15384047.2024.2445220
  37. Res Sq. 2024 Dec 13. pii: rs.3.rs-5494402. [Epub ahead of print]
    Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.
    Jiangbin Ye, Haowen Jiang, Sarah Tiche, Clifford He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert Li, Anh Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin Svensson, Daniel Cuthbertson, Florette Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu.
      Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
    DOI:  https://doi.org/10.21203/rs.3.rs-5494402/v1
  38. Adv Sci (Weinh). 2024 Dec 23. e2404620
    Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.
    Leisi Zhang, Honghai Zhang, Ting-Yu Wang, Mingli Li, Anthony K N Chan, Hyunjun Kang, Lai C Foong, Qiao Liu, Sheela Pangeni Pokharel, Nicole M Mattson, Priyanka Singh, Zeinab Elsayed, Benjamin Kuang, Xueer Wang, Steven T Rosen, Jianjun Chen, Lu Yang, Tsui-Fen Chou, Rui Su, Chun-Wei David Chen.
      Cell signaling pathways are enriched for biological processes crucial for cellular communication, response to external stimuli, and metabolism. Here, a cell signaling-focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 depletion or pharmacological inhibition of Complex IV (using chlorpromazine) synergized with venetoclax, providing a promising avenue for improved leukemia therapy. This study highlights COX4I1, a nuclear encoded mitochondrial protein, as a critical mitochondrial checkpoint, offering insights into its functional significance and potential clinical implications in AML.
    Keywords:  COX4I1; chlorpromazine; leukemia; mitochondria; venetoclax
    DOI:  https://doi.org/10.1002/advs.202404620
  39. Stem Cell Res Ther. 2024 Dec 20. 15(1): 491
    Human umbilical mesenchymal stem cells ameliorate atrophic gastritis in aging mice by participating in mitochondrial autophagy through Ndufs8 signaling.
    Qiang Rui, Chuyu Li, Yiqi Rui, Chuanzhuo Zhang, Cunbing Xia, Qing Wang, Yuanyuan Liu, Peng Wang.
       BACKGROUND: Chronic atrophic gastritis (CAG) is a chronic disease of the gastric mucosa characterized by a reduction or an absolute disappearance of the original gastric glands, possibly replaced by pseudopyloric fibrosis, intestinal metaplasia, or fibrosis. CAG develops progressively into intestinal epithelial metaplasia, dysplasia, and ultimately, gastric cancer. Epidemiological statistics have revealed a positive correlation between the incidence of CAG and age. Mesenchymal stem cells (MSCs) are a type of adult stem cells derived from mesoderm, with strong tissue repair capabilities. Therefore, the restoration of the gastric mucosa may serve as an efficacious strategy to ameliorate CAG and avert gastric cancer. However, the mechanisms by which MSCs inhibit the relentless progression of aging atrophic gastritis remain to be elucidated. This study endeavored to assess a novel approach utilizing MSCs to treat CAG and forestall carcinogenics.
    METHODS: In this study, we selected mice with atrophic gastritis from naturally aging mice and administered human umbilical cord-derived mesenchymal stem cells (hUMSCs) via tail vein injection to evaluate the therapeutic effects of hUMSCs on age-related chronic atrophic gastritis. Initially, we employed methods such as ELISA, immunohistochemical analysis, and TUNEL assays to detect changes in the mice post-hUMSC injection. Proteomic and bioinformatics analyses were conducted to identify differentially expressed proteins, focusing on NADH: ubiquinone oxidoreductase core subunit S8 (Ndufs8). Co-culturing hUMSCs with Ndufs8 knockout gastric mucosal epithelial cells (GMECs), we utilized flow cytometry, Western blotting, real-time quantitative PCR, and immunofluorescence to investigate the mechanisms of action of hUMSCs.
    RESULTS: We observed that hUMSCs are capable of migrating to and repairing damaged gastric mucosa. Initially, hUMSCs significantly enhanced the secretion of gastric proteins PG-1 and G17, while concurrently reducing inflammatory cytokines. Furthermore, hUMSCs mitigated gastric fibrosis and apoptosis in mucosal cells. Proteomic and bioinformatic analyses revealed alterations in the protein network involved in mitochondrial autophagy, with Ndufs8 playing a pivotal role. Upon knocking out Ndufs8 in GMECs, we noted mitochondrial damage and reduced autophagy, leading to an aged phenotype in GMECs. Co-culturing Ndufs8-knockout GMECs with hUMSCs demonstrated that hUMSCs could ameliorate mitochondrial dysfunction and restore the cell cycle in GMECs.
    DOI:  https://doi.org/10.1186/s13287-024-04094-4
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