bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–12–22
forty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. Overproduction of Mitochondrial Fission Proteins and Mitochondrial Fission in Podocytes of Lupus Nephritis Patients.
  2. Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.
  3. Crosstalk between mitochondrial homeostasis and AMPK pathway mediate the receptor-mediated cardioprotective effects of estradiol in ovariectomized female rats.
  4. Acute treadmill exercise induces mitochondrial unfolded protein response in skeletal muscle of male rats.
  5. A molecular glue for Prkn/parkin.
  6. Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.
  7. Mitophagosomes induced during EV-D68 infection promote viral nonlytic release.
  8. Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias.
  9. Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.
  10. New insights into the role of mitophagy related gene affecting the metastasis of osteosarcoma through scRNA-seq and CRISPR-Cas9 genome editing.
  11. Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.
  12. Dynamic mitophagy trajectories hallmark brain aging.
  13. Mitochondrial Dynamics in Brain Cells During Normal and Pathological Aging.
  14. Correction: NL-1 Promotes PINK1-Parkin-Mediated Mitophagy Through MitoNEET Inhibition in Subarachnoid Hemorrhage.
  15. ABALON regulates mitophagy and 5-FU sensitivity in colorectal cancer via PINK1-Parkin pathway.
  16. EGCG Alleviates Skeletal Muscle Oxidative Damage in Heat-Stressed Pigs via Keap1/PGAM5 Complex-Mediated Mitophagy.
  17. CoCrMo nanoparticle induces neurotoxicity mediated via mitochondrial dysfunction: a study model for implant derived nanoparticle effects.
  18. Association between mitophagy and NLRP3 inflammasome in uric acid nephropathy.
  19. SLMO transfers phosphatidylserine between the outer and inner mitochondrial membrane in Drosophila.
  20. Exosomes derived from cardiac fibroblasts with Ang-II stimulation provoke myocardial hypertrophy via miR-15b-5p/PTEN-L axis.
  21. Advances in Osteoblast and Mitochondrial Dynamics and Their Transfer in Osteoporosis.
  22. Zinc Mitigates the Combined Neurotoxicity of Binary Metal Mixtures via Mitophagy and Mitochondrial Fusion.
  23. Differential effects of EPA and DHA on aging-related sarcopenia in mice and possible mechanisms involved.
  24. Adipose mesenchymal stem cell-derived extracellular vesicles regulate PINK1/parkin-mediated mitophagy to repair high glucose-induced dermal fibroblast senescence and promote wound healing in rats with diabetic foot ulcer.
  25. Quercetin preserves mitochondria-endoplasmic reticulum contact sites improving mitochondrial dynamics in aged myocardial cells.
  26. Paeoniflorin ameliorates reperfusion injury in H9C2 cells through SIRT1-PINK1/parkin-mediated mitochondrial autophagy.
  27. Proteolytic regulation of mitochondrial magnesium channel MRS2 by m-AAA protease and prohibitin complex.
  28. Mitochondria-targeted antioxidant mitoquinone mitigates vitrification-induced damage in mouse ovarian tissue by maintaining mitochondrial homeostasis via the p38 MAPK pathway.
  29. Panax Quinquefolium Saponins protects neuronal activity by promoting mitophagy in both in vitro and in vivo models of Alzheimer's disease.
  30. Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.
  31. Senolysis by GLS1 Inhibition Ameliorates Kidney Aging by Inducing Excessive mPTP Opening through MFN1.
  32. Dipeptidyl Peptidase 4 (DPP4) Exacerbates Osteoarthritis Progression in an Enzyme-Independent Manner.
  33. Empagliflozin promotes skin flap survival by activating AMPK signaling pathway.
  34. A Reduction in Mitophagy Is Associated with Glaucomatous Neurodegeneration in Rodent Models of Glaucoma.
  35. Trehalose Alleviates D-Galactose-Induced Aging-Related Granulosa Cell Death in Ovaries.
  36. Hesperetin Increases Lifespan and Antioxidant Ability Correlating with IIS, HSP, mtUPR, and JNK Pathways of Chronic Oxidative Stress in Caenorhabditis elegans.
  37. Ginsenoside Rd-Loaded Antioxidant Polymersomes to Regulate Mitochondrial Homeostasis for Bone Defect Healing in Periodontitis.
  38. A role for lysosomal calcium channels in mitigating mitochondrial damage and oxidative stress.
  39. Aging promotes an increase in mitochondrial fragmentation in astrocytes.
  40. Age-associated accumulation of RAB9 disrupts oocyte meiosis.
  41. Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma.
  42. Susceptibility of Mitophagy-Deficient Tumors to Ferroptosis Induction by Relieving the Suppression of Lipid Peroxidation.
  43. Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.
  44. Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
  45. Exploring Co-expression Modules-Traits Correlation through Weighted Gene Co-expression Network Analysis: A Promising Approach in Wound Healing Research.
  46. The Role of Calorie Restriction in Modifying the Ageing Process through the Regulation of SIRT1 Expression.
  47. Assessing the role of mitonuclear interactions on mitochondrial function and organismal fitness in natural Drosophila populations.
  48. Maternal Low-Protein Diet Leads to Mitochondrial Dysfunction and Impaired Energy Metabolism in the Skeletal Muscle of Male Rats.
  49. Eugenol Nanoparticles Ameliorate Doxorubicin-Induced Spermatogenic Dysfunction by Inhibiting the PINK1/Parkin and BNIP3/NIX Signaling Pathways.
  1. J Inflamm Res. 2024 ;17 10807-10818
    Overproduction of Mitochondrial Fission Proteins and Mitochondrial Fission in Podocytes of Lupus Nephritis Patients.
    Qijiao Wei, Xinchen Wu, Zhihan Chen, He Lin, Lei Xiong, Na Wang.
       Background: The glomerular injury is associated with different pathogeneses, and podocyte damage is common in various ISN/RPS class lupus nephritis (LN). In podocyte, mitochondrial morphological changes are observed in lupus nephritis (LN) in our previous study. This study aimed to explore mitochondrial fission proteins expression in podocytes using bioinformatics analysis and further to investigate the associations between mitochondrial fission proteins and laboratory features in LN.
    Methods: To determine the differentially expressed genes (DEGs) between LN and normal controls, we downloaded and analyzed microarray datasets. Then download the mitochondrial genes list from the MitoMiner 4.0 database, then take the genes that are common with the DEGs. Functional enrichment analyses were then performed. Then mitochondrial fission was observed through electron microscope. We performed immunofluorescence staining to explore the expression of mitochondrial fission proteins in LN patients.
    Results: Among these 658 DEGs, 5 DEGs related to mitochondrial dynamics were identified. Mitochondrial dynamics proteins were involved in mitophagy. Mitochondrial fission proteins Drp1 and Fis1 staining were significantly enhanced compared to that in the controls. 24h-UTP are positively correlated with mitochondrial fission proteins expression.
    Conclusion: Mitochondrial fission was observed in LN patients' podocytes. Mitochondrial fission proteins Drp1 and Fis1 were overproduced in podocytes, and then they can lead to mitochondrial fission, which may aggravate podocyte damage and proteinuria. While the mechanism still needs to be explored.
    Keywords:  Drp1; Fis1; lupus nephritis; mitochondria fission; podocyte injury
    DOI:  https://doi.org/10.2147/JIR.S497813
  2. Front Mol Neurosci. 2024 ;17 1504802
    Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.
    Michael Aschner, Anatoly V Skalny, Rongzhu Lu, Airton C Martins, Yousef Tizabi, Sergey V Nekhoroshev, Abel Santamaria, Anton I Sinitskiy, Alexey A Tinkov.
      Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.
    Keywords:  copper; cuproptosis; fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.3389/fnmol.2024.1504802
  3. PLoS One. 2024 ;19(12): e0312397
    Crosstalk between mitochondrial homeostasis and AMPK pathway mediate the receptor-mediated cardioprotective effects of estradiol in ovariectomized female rats.
    Mennatallah A Gowayed, Zainab Zaki Zakaraya, Nehal Abu-Samra, Reem H Elhamammy, Lobna M Abdel Moneim, Hala A Hafez, Ihab A Moneam, Ghaleb A Oriquat, Maher A Kamel.
      Estrogen (E2) deficiency is a risk factor for cardiovascular disease (CVD), however, the exact mechanism for the E2 protective effect on CVD remains unclear. This study aimed to investigate the estrogen receptor (ER) and non-receptor mediated effects of E2 treatment on the cardiac expression of adenosine monophosphate-dependent protein kinase (AMPK), autophagic, mitophagy and mitochondrial homeostasis-regulating genes in ovariectomized (OVX) rats. Female rats were divided into two main groups; sham and bilaterally OVX rats, then each group was subdivided into four subgroups according to treatment; untreated, subcutaneously treated with E2 (30 μg/kg), or Fulvestrant (F) (5 mg/Kg), or a combination of both drugs for 28 days. The OVX rats or F-treated sham rats showed dyslipidemia, and marked disturbances in parameters of AMPK signaling, autophagy, mitophagy, mitochondrial fission, fusion and biogenesis. E2 administration to OVX or F-treated sham rats has corrected the disturbed lipid and cardiac profiles, increased AMPK, and restored the balance of cardiac autophagy, mitophagy, and mitochondrial dynamics and homeostasis. Most of these effects in OVX rats were blocked by the ER antagonist (F). Estrogen treatment has cardioprotective effects in OVX females through modulating cardiac mitochondrial homeostasis, mitophagy and autophagy and restoring the AMPK signaling pathway. As witnessed by Fulvestrant, these effects suggest the main role of ER-mediated signaling in regulating mitophagy and plasma and cardiac lipids along with the existence of a post-translational control mechanism or the involvement of estrogenic non-receptor pathway controlling the postmenopausal cardiac mitochondrial energy production machinery that needs further investigation.
    DOI:  https://doi.org/10.1371/journal.pone.0312397
  4. Biochim Biophys Acta Bioenerg. 2024 Dec 13. pii: S0005-2728(24)00502-4. [Epub ahead of print]1866(2): 149532
    Acute treadmill exercise induces mitochondrial unfolded protein response in skeletal muscle of male rats.
    Ibrahim Turkel, Gokhan Burcin Kubat, Tugba Fatsa, Ozgu Acet, Berkay Ozerklig, Burak Yazgan, Gulcin Simsek, Keshav K Singh, Sukran Nazan Kosar.
      Mitochondria are often referred to as the energy centers of the cell and are recognized as key players in signal transduction, sensing, and responding to internal and external stimuli. Under stress conditions, the mitochondrial unfolded protein response (UPRmt), a conserved mitochondrial quality control mechanism, is activated to maintain mitochondrial and cellular homeostasis. As a physiological stimulus, exercise-induced mitochondrial perturbations trigger UPRmt, coordinating mitochondria-to-nucleus communication and initiating a transcriptional program to restore mitochondrial function. The aim of this study was to evaluate the UPRmt signaling response to acute exercise in skeletal muscle. Male rats were subjected to acute treadmill exercise at 25 m/min for 60 min on a 0 % grade. Plantaris muscles were collected from both sedentary and exercise groups at various times: immediately (0), and at 1, 3, 6, 12, and 24 h post-exercise. Reactive oxygen species (ROS) production was assessed using hydrogen peroxide assay and dihydroethidium staining. Additionally, the mRNA and protein expression of UPRmt markers were measured using ELISA and real-time PCR. Mitochondrial activity was assessed using succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) staining. Our results demonstrated that acute exercise increased ROS production and upregulated UPRmt markers at both gene and protein levels. Moreover, skeletal muscle exhibited an increase in mitochondrial activity in response to exercise, as indicated by SDH and COX staining. These findings suggest that acute treadmill exercise is sufficient to induce ROS production, activate UPRmt signaling, and enhance mitochondrial activity in skeletal muscle, expanding our understanding of mitochondrial adaptations to exercise.
    Keywords:  Exercise; Mitochondria; Mitochondrial proteostasis; Mitochondrial unfolded protein response; Skeletal muscle; UPR(mt)
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149532
  5. Autophagy. 2024 Dec 19.
    A molecular glue for Prkn/parkin.
    Véronique Sauvé, Kalle Gehring.
      Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra, primarily due to mitochondria dysfunction. PRKN (parkin RBR E3 ubiquitin protein ligase) and PINK1 (PTEN induced kinase 1) are linked to early-onset cases of PD and essential for the clearance of damaged mitochondria via selective mitochondrial autophagy (mitophagy). In a recent publication, we detail how a small molecule can activate PRKN mutants that are unable to be phosphorylated, restoring mitophagy in cellular assays. These findings offer hope for the design of therapeutic drugs for some forms of PD.
    Keywords:  Activator; PARK2; mitochondria; neurodegeneration; parkinson disease; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2024.2443232
  6. J Cell Sci. 2024 Dec 20. pii: jcs.263459. [Epub ahead of print]
    Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.
    Yuli Buckley, Maria S K Stoll, Charles L Hoppel, Jason A Mears.
      In response to external stress, mitochondrial dynamics is often disrupted, but the associated physiologic changes are often uncharacterized. In many cancers, including glioblastoma (GBM), mitochondrial dysfunction has been observed. Understanding how mitochondrial dynamics and physiology contribute to treatment resistance will lead to more targeted and effective therapeutics. This study aims to uncover how mitochondria in GBM cells adapt to and resist ionizing radiation (IR), a component of the standard of care for GBM. Using several approaches, we investigated how mitochondrial dynamics and physiology adapt to radiation stress and uncover a novel role for Fis1, a pro-fission protein, in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics. Importantly, our data demonstrate that increased fission in response to IR leads to removal of mtDNA damage and more efficient oxygen consumption through altered ETC activities in intact mitochondria. These findings demonstrate a key role for Fis1 in targeting damaged mtDNA for degradation and regulating mitochondrial bioenergetics through altered dynamics.
    Keywords:  Bioenergetics; Fis1; Ionizing radiation; Mitochondrial fission; MtDNA
    DOI:  https://doi.org/10.1242/jcs.263459
  7. bioRxiv. 2024 Dec 06. pii: 2024.12.05.627125. [Epub ahead of print]
    Mitophagosomes induced during EV-D68 infection promote viral nonlytic release.
    Alagie Jassey, Bimal Paudel, Michael A Wagner, Noah Pollack, I-Ting Cheng, Raquel Godoy-Ruiz, David J Weber, William T Jackson.
      Enterovirus-D68 (EV-D68) is a plus-strand RNA virus that primarily causes infant respiratory infections. In rare pediatric cases, infection with EV-D68 has been associated with acute flaccid myelitis, a polio-like paralytic disease. We have previously demonstrated that EV-D68 induces nonselective autophagy for its benefit. Here, we demonstrate that EV-D68 induces mitophagy, the specific autophagic degradation of mitochondria. EV-D68 infection induces mitophagosome formation and several hallmarks of mitophagy, including mitochondrial fragmentation, mitochondrial membrane potential loss, and Parkin translocation to the mitochondria were observed in EV-D68 infected cells. The 3C protease of EV-D68 cleaves the mitochondrial fusion protein, mitofusin-2, near the C-terminal HR2 domain to induce mitochondrial fragmentation, and these fragmented mitochondria colocalized with double-stranded RNA (dsRNA), which labels viral RNA replication sites after peak viral RNA replication. Depleting components of mitophagy signaling specifically reduced EV-D68 release without impacting viral intracellular titers. Our results suggest that whereas the machinery of macroautophagy supports various stages of enterovirus replication, including viral genomic RNA replication and capsid maturation, mitophagy is the specific form of autophagy that regulates the nonlytic release of enteroviruses from cells.
    Keywords:  BCL2L13; EV-D68; Mitofusin-2; Mitophagy; PINK1; Parkin
    DOI:  https://doi.org/10.1101/2024.12.05.627125
  8. Sci Rep. 2024 12 16. 14(1): 30478
    Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias.
    Anke Schumann, Ainhoa Martinez-Pizarro, Eva Richard, Christoph Schell, Anna Laura Kössinger, Karina A Zeyer, Stefan Tholen, Oliver Schilling, Michael Barry, Björn Neubauer, Michael Köttgen, Luciana Hannibal, Lourdes R Desviat, Ute Spiekerkötter.
      Mutations in the mitochondrial enzyme propionyl-CoA carboxylase (PCC) cause propionic aciduria (PA). Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD. The pathophysiological mechanisms of CKD are unclear. We investigated the renal phenotype of a hypomorphic murine PA model (Pcca-/-(A138T)) to identify CKD-driving mechanisms. Pcca-/-(A138T) mice show elevated retention parameters and express markers of kidney damage progressing with time. Morphological assessment of the Pcca-/-(A138T) mouse kidneys indicated partial flattening of tubular epithelial cells and focal tubular-cystic dilation. We observed altered renal mitochondrial ultrastructure and mechanisms acting against oxidative stress were active. LC-MS/MS analysis confirmed disease-specific metabolic signatures and revealed disturbances in mitochondrial energy generation via the TCA cycle. Our investigations revealed altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy. We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission. Our results suggest that impairment of mitochondrial homeostasis and quality control are involved in CKD development in PA. Therapeutic targeting of the identified pathways might help to ameliorate CKD in addition to the current treatment strategies.
    Keywords:  Chronic kidney disease; Mitochondrial dysfunction; Mitochondrial energy metabolism; Mitochondrial fission; Mitochondrial homeostasis; Mitochondrial quality control; Propionic aciduria
    DOI:  https://doi.org/10.1038/s41598-024-79572-z
  9. Oncogene. 2024 Dec 17.
    Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.
    Jordan Alyse Woytash, Rahul Kumar, Ajay K Chaudhary, Cullan Donnelly, Adam Wojtulski, Murali Bethu, Jianmin Wang, Joseph Spernyak, Peter Bross, Neelu Yadav, Joseph R Inigo, Dhyan Chandra.
      The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPRmt in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPRmt in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPRmt heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPRmt. We discovered that UPRmt promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPRmt resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPRmt promotes mitochondrial health via upregulating β-catenin signaling and UPRmt represents viable therapeutic target for NEPC.
    DOI:  https://doi.org/10.1038/s41388-024-03261-4
  10. Cell Commun Signal. 2024 Dec 18. 22(1): 592
    New insights into the role of mitophagy related gene affecting the metastasis of osteosarcoma through scRNA-seq and CRISPR-Cas9 genome editing.
    Sikuan Zheng, Mengliang Luo, Hong Huang, Xuanxuan Huang, Zhidong Peng, Shaowei Zheng, Jianye Tan.
       BACKGROUND: Osteosarcoma (OSA), the most common primary bone malignancy, poses significant challenges due to its aggressive nature and propensity for metastasis, especially in adolescents. Mitophagy analysis can help identify new therapeutic targets and combined treatment strategies.
    METHODS: This study integrates single-cell sequencing (scRNA-seq) data and bulk-seq to identify mitophagy-related genes (MRGs) associated with the progression of OSA metastasis and analyze their clinical significance. scRNA-seq data elucidates the relationship between mitophagy and OSA metastasis, employing "CellChat" R package to explore intercellular communications and report on hundreds of ligand-receptor interactions. Subsequently, the combination of bulk-seq and CRISPR-Cas9 gene editing identifies mitophagy-related biomarker associated with metastatic prognosis. Finally, validation of the relationship between mitophagy and OSA metastasis is achieved through cellular biology experiments and animal studies.
    RESULTS: The distinct mitophagy activity of various mitochondria manifests in diverse spatial localization, cellular developmental trajectories, and intercellular interactions. OSA tissue exhibits notable heterogeneity in mitophagy within osteoblastic OSA cells. However, high mitophagy activity correlates consistently with high metastatic potential. Subsequently, we identified three critical genes associated with mitophagy in OSA, namely RPS27A, TOMM20 and UBB. According to the aforementioned queue of genes, we have constructed a mitophagy_score (MIP_score). We observed that it consistently predicts patient prognosis in both internal and external datasets, demonstrating strong robustness and stability. Furthermore, we have found that MIP_score can also guide chemotherapy, with varying sensitivities to chemotherapeutic agents based on different MIP_score. It is noteworthy that, through the integration of CRISPR-Cas9 genome-wide screening and validation via cellular and animal experiments, we have identified RPS27A as a potential novel biomarker for OSA.
    CONCLUSIONS: Our comprehensive analysis elucidated the profile of mitophagy throughout the OSA metastasis process, forming the basis for a mitophagy-related prognostic model that addresses clinical outcomes and drug sensitivity following OSA metastasis. Additionally, an online interactive platform was established to assist clinicians in decision-making ( https://mip-score.shinyapps.io/labtan/ ). These findings lay the groundwork for developing targeted therapies aimed at improving the prognosis of OSA patients.
    DOI:  https://doi.org/10.1186/s12964-024-01989-w
  11. Life Sci. 2024 Dec 12. pii: S0024-3205(24)00907-X. [Epub ahead of print] 123317
    Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.
    Mengnan Liu, Binru Li, Zhixue Yin, Lu Yin, Ye Luo, Qi Zeng, Dechou Zhang, Anguo Wu, Li Chen.
      Intracerebral hemorrhage (ICH) is a major global health issue with high mortality and disability rates. Following ICH, the hematoma exerts direct pressure on brain tissue, and blood entering the brain directly damages neurons and the blood-brain barrier. Subsequently, oxidative stress, inflammatory responses, apoptosis, brain edema, excitotoxicity, iron toxicity, and metabolic dysfunction around the hematoma further exacerbate brain tissue damage, leading to secondary brain injury (SBI). Mitochondria, essential for energy production and the regulation of oxidative stress, are damaged after ICH, resulting in impaired ATP production, excessive reactive oxygen species (ROS) generation, and disrupted calcium homeostasis, all of which contribute to SBI. Therefore, a central factor in SBI is mitochondrial dysfunction. Mitochondrial dynamics regulate the shape, size, distribution, and quantity of mitochondria through fusion and fission, both of which are crucial for maintaining their function. Fusion repairs damaged mitochondria and preserves their health, while fission helps mitochondria adapt to cellular stress and removes damaged mitochondria through mitophagy. When this balance is disrupted following ICH, mitochondrial dysfunction worsens, oxidative stress and metabolic failure are exacerbated, ultimately contributing to SBI. Targeting mitochondrial dynamics offers a promising therapeutic approach to restoring mitochondrial function, reducing cellular damage, and improving recovery. This review explores the latest research on modulating mitochondrial dynamics and highlights its potential to enhance outcomes in ICH patients.
    Keywords:  Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Neuroprotection strategies; Secondary brain injury
    DOI:  https://doi.org/10.1016/j.lfs.2024.123317
  12. Autophagy. 2024 Dec 19. 1-3
    Dynamic mitophagy trajectories hallmark brain aging.
    Anna Rappe, Thomas G McWilliams.
      Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping in vivo autophagy dynamics at the single cell level within projection neurons, interneurons and microglia, to astrocytes and secretory cells, we provide a new framework for understanding brain aging and offer potential targets and timepoints for further study and intervention in neurodegenerative diseases.
    Keywords:  Aging; autophagy; brain; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2426115
  13. Int J Mol Sci. 2024 Nov 29. pii: 12855. [Epub ahead of print]25(23):
    Mitochondrial Dynamics in Brain Cells During Normal and Pathological Aging.
    Vladimir S Sukhorukov, Tatiana I Baranich, Anna V Egorova, Anastasia V Akateva, Kseniia M Okulova, Maria S Ryabova, Krisitina A Skvortsova, Oscar V Dmitriev, Natalia M Mudzhiri, Dmitry N Voronkov, Sergey N Illarioshkin.
      Mitochondrial dynamics significantly play a major role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. The dysregulation of mitochondrial biogenesis and function, characterized by impaired fission and fusion processes mediated by a number of proteins, in particular, Drp1, Mfn1, Mfn2, Opa1, and PGC-1α, contributes to neuronal vulnerability and degeneration. Insufficient mitophagy and disrupted mitochondrial transport exacerbate oxidative stress and neurotoxicity. Emerging therapeutic strategies that target mitochondrial dynamics, including various pharmacological agents, demonstrate potential for restoring mitochondrial balance and enhancing neuroprotection. This growing body of research underscores the importance of mitochondrial health in developing effective interventions for neurodegenerative conditions. This review highlights well-established links between the disruption of mitochondrial dynamics and the development of neurodegenerative processes. We also discuss different therapeutic strategies that target mitochondrial function in neurons that have been proposed as perspective neuroprotective treatments.
    Keywords:  mitochondrial dynamics; mitophagy; neurodegeneration; neuroprotection
    DOI:  https://doi.org/10.3390/ijms252312855
  14. Neurochem Res. 2024 Dec 16. 50(1): 62
    Correction: NL-1 Promotes PINK1-Parkin-Mediated Mitophagy Through MitoNEET Inhibition in Subarachnoid Hemorrhage.
    Tongyu Zhang, Minghai Zhang.
      
    DOI:  https://doi.org/10.1007/s11064-024-04303-9
  15. Transl Cancer Res. 2024 Nov 30. 13(11): 6201-6218
    ABALON regulates mitophagy and 5-FU sensitivity in colorectal cancer via PINK1-Parkin pathway.
    Huimin Liu, Ying Huang, Chunmei Zhao, Guihua Wang, Xudong Wang.
       Background: Growing evidence demonstrated that long non-coding RNAs (lncRNAs) are closely related with chemoresistance in colorectal cancer (CRC). Mitophagy serves as an essential factor to maintain the quality of tumor cells. However, it is unclear whether lncRNAs are involved in mitophagy regulation in CRC. The aim of this study is to evaluate whether lncRNAs are involved in regulating mitophagy and chemoresistance in CRC.
    Methods: In this study, gain/loss of function was used to analyze the biological function influenced by apoptotic BCL2L1-antisense long non-coding RNA (ABALON). Western blot and JC-1 probe were carried out for detecting mitophagy. Chemosensitivity of CRC cells to 5-fluorouracil (5-FU) was determined using cell counting kit-8 (CCK-8), flow cytometry, colony formation and trans well assays.
    Results: We found that ABALON expression was increased in CRC, especially in consensus molecular subtype 1 (CMS1) and highly expressed ABALON was related with tumor differentiation, tumor node metastasis (TNM) staging, and lymph node metastasis (P<0.05). ABALON knockdown led to impaired proliferation and enhanced apoptosis in CRC. Mitophagy variations primed by ABALON enhanced mitochondrial homeostasis. The half maximal inhibitory concentration (IC50) of 5-FU in ABALON interference groups declined, while ABALON overexpression elevated IC50. Furthermore, defective mitophagy not only rescued the proliferation, metastasis, and apoptosis induced by ABALON overexpression, but also, enhanced the anti-tumor effect of 5-FU in vivo.
    Conclusions: Collectively, our study proposed that ABALON potentiates CRC progression via PINK1/Parkin mediated mitophagy, and ABALON is a promising therapeutic target in reversing 5-FU resistance.
    Keywords:  5-fluorouracil (5-FU); Colorectal cancer (CRC); long non-coding RNA (lncRNA); mitophagy; sensitivity
    DOI:  https://doi.org/10.21037/tcr-24-933
  16. J Agric Food Chem. 2024 Dec 18.
    EGCG Alleviates Skeletal Muscle Oxidative Damage in Heat-Stressed Pigs via Keap1/PGAM5 Complex-Mediated Mitophagy.
    Bao Yang, Qian Wang, Chongwan Wei, Yanjie Sun, Yin Li, Yangyang Wei, Qinyang Jiang, Yanna Huang.
      The heat stress (HS) induced by high temperatures can result in oxidative damage to muscles, thereby compromising both muscle growth and immune function within the organism. Mitophagy serves as a pivotal pathway in alleviating excessive ROS production and subsequent oxidative damage. However, the potential role of epigallocatechin-3-gallate (EGCG), a natural antioxidant found in tea, in mitophagy under HS remains unexplored. Here, we present evidence of EGCG mitigating the oxidative-redox imbalance in porcine skeletal muscles induced by HS involving the antioxidant enzyme system mediated by the Keap1/Nrf2 pathway and mitophagy mediated by the PINK1/Parkin pathway. Importantly, we identified phosphate mutase 5 (PGAM5) for the first time as a key protein modulated by EGCG under HS conditions, regulating mitophagy. Inhibition of PGAM5 significantly attenuated the activation of mitophagy by EGCG. Molecular docking and dynamics simulations further suggested that EGCG directly binds to Keap1, disrupting the Keap1-PGAM5 protein interaction and thus promoting the release of PGAM5 and subsequently activating mitophagy. In summary, this study represents the first discovery of EGCG directly targeting Keap1/PGAM5-mediated mitophagy, which serves as a potential functional supplement for regulating the antioxidant capacity in pigs.
    Keywords:  epigallocatechin-3-gallate; heat stress; mitophagy; oxidative damage; phosphoglycerate mutase 5; porcine skeletal muscle
    DOI:  https://doi.org/10.1021/acs.jafc.4c06573
  17. Nanotoxicology. 2024 Dec;18(8): 707-723
    CoCrMo nanoparticle induces neurotoxicity mediated via mitochondrial dysfunction: a study model for implant derived nanoparticle effects.
    Priyadarshini Vijayakumar, Yongchao Mou, Xuejun Li, Jahnavi Anil, Neeraja Revi, Kai-Yuan Cheng, Mathew T Mathew, Divya Bijukumar.
      Toxicity associated with elevated levels of cobalt-chromium-molybdenum (CoCrMo) nanoparticles in total hip replacement (THR) patients has been a rising concern. Recent investigations demonstrated that these particles can induce polyneuropathy in THR patients. The current study aims to address a detailed molecular investigation of CoCrMo nanoparticle-mediated mitochondrial dynamics using induced pluripotent stem cell-derived neurons (iPSC neurons). Telencephalic neurons from iPSCs were used in this study. A statistically significant dose-dependent reduction in membrane potential and mitochondrial superoxide generation was observed after CoCrMo nanoparticle treatment. The gene expression analysis confirmed that the oxidative-specific genes were significantly upregulated in particle-treated cells compared to untreated cells. When iPSCs were exposed to CoCrMo nanoparticles, there was a significant reduction in the area, perimeter, and length of mitochondria. Live cell imaging (mitochondrial tracking) revealed a significant reduction in mitochondrial movements in the presence of CoCrMo nanoparticles. Further protein expression confirmed increased mitochondrial fission in CoCrMo particle-treated cells by significantly upregulating Drp-1 protein and downregulating Mfn-2. In conclusion, the results show that CoCrMo nanoparticles can significantly alter neuronal mitochondrial dynamics. The disturbance in balance restricts mitochondrial movement, reduces energy production, increases oxidative stress, and can cause subsequent neurodegeneration.
    Keywords:  CoCrMo; THR; iPSC neurons; mitochondrial dynamics; nanoparticles
    DOI:  https://doi.org/10.1080/17435390.2024.2438118
  18. Ren Fail. 2024 Dec;46(2): 2438847
    Association between mitophagy and NLRP3 inflammasome in uric acid nephropathy.
    Xiao-Qian Li, Yong-Qing Gu, Yuan-Yuan Ling, Mei Wang, Jin Miao, Li Xue, Wei Ji, Jun Liu.
       OBJECTIVE: This study was recruited to investigate the role of mitophagy in activating NLRP3 inflammasome in the kidney of uric acid (UA) nephropathy (UAN) rats.
    METHODS: This study developed a uric acid nephropathy (UAN) rat model divided into five groups: Negative control (NC), UAN model (M), UAN + autophagy inhibitor (3-MA), UAN + lysosome inhibitor (CQ), and ROS scavenger (N-acetylcysteine, N). H&E staining assessed renal structure, ROS levels were measured with 2, 7-dichlorofluorescin diacetate, and ELISA measured serum markers (creatinine, UA, cystatin C, NGAL, IL-1β, IL-18). Western blot and qRT-PCR evaluated autophagy and inflammation-related protein (LC3 II/I, p62, Pink1, Parkin, NLRP3, Caspase1, IL-1β) expression. NRK-52E cells treated with uric acid and shRNA were analyzed by western blot.
    RESULTS: Renal injury in UAN rats was aggravated by ROS accumulation, which promoted mitophagy and activated the NLRP3 inflammasome. Eliminating ROS reduced mitophagy, inhibited NLRP3 activation, lowered IL-1β and IL-18 levels, and alleviated renal injury. Notably, inhibiting mitophagy increased ROS accumulation, up-regulated NLRP3, Caspase1, and IL-1β expression, further worsening renal injury. In vitro, uric acid treatment of NRK-52E cells altered autophagy-related protein and pro-inflammatory cytokine levels, highlighting the interplay between mitophagy and inflammation in uric acid nephropathy.
    CONCLUSION: Mitophagy influences renal injury in uric acid nephropathy (UAN) by regulating ROS accumulation and NLRP3 inflammasome activation, suggesting that mitophagy may serve as a potential therapeutic target for UAN.
    Keywords:  NLRP3 inflammasome; Uric acid nephropathy; hyperuricemia; inflammation; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.1080/0886022X.2024.2438847
  19. PLoS Biol. 2024 Dec;22(12): e3002941
    SLMO transfers phosphatidylserine between the outer and inner mitochondrial membrane in Drosophila.
    Siwen Zhao, Xuguang Jiang, Ning Li, Tao Wang.
      Phospholipids are critical building blocks of mitochondria, and proper mitochondrial function and architecture rely on phospholipids that are primarily transported from the endoplasmic reticulum (ER). Here, we show that mitochondrial form and function rely on synthesis of phosphatidylserine (PS) in the ER through phosphatidylserine synthase (PSS), trafficking of PS from ER to mitochondria (and within mitochondria), and the conversion of PS to phosphatidylethanolamine (PE) by phosphatidylserine decarboxylase (PISD) in the inner mitochondrial membrane (IMM). Using a forward genetic screen in Drosophila, we found that Slowmo (SLMO) specifically transfers PS from the outer mitochondrial membrane (OMM) to the IMM within the inner boundary membrane (IBM) domain. Thus, SLMO is required for shaping mitochondrial morphology, but its putative conserved binding partner, dTRIAP, is not. Importantly, SLMO's role in maintaining mitochondrial morphology is conserved in humans via the SLMO2 protein and is independent of mitochondrial dynamics. Our results highlight the importance of a conserved PSS-SLMO-PISD pathway in maintaining the structure and function of mitochondria.
    DOI:  https://doi.org/10.1371/journal.pbio.3002941
  20. Exp Cell Res. 2024 Dec 12. pii: S0014-4827(24)00471-3. [Epub ahead of print]444(2): 114380
    Exosomes derived from cardiac fibroblasts with Ang-II stimulation provoke myocardial hypertrophy via miR-15b-5p/PTEN-L axis.
    Zhiwen Hu, Dijiu Xiao, Liang Wang, Jiaxiang You, Tao Long, Jinping Wang, Yibiao Shang, Dasong Yi, Lu Ding, Xiang Wang, Xiaoping Peng, Junyi Zeng.
      This study aimed to examine the impact of exosomes derived from Ang II-stimulated cardiac fibroblasts (CFs) on myocardial hypertrophy. Neonatal rat CFs were isolated and identified using Vimentin immunofluorescence. Following Ang II stimulation, exosomes were collected, characterized, and subjected to miRNA sequencing. Myocardial hypertrophy models were induced both in vitro and in vivo using Ang II. CFs were transfected with miR-15b-5p mimics or inhibitors, and their exosomes were co-cultured with rat cardiomyocytes (H9C2). Changes in cell viability, myocardial hypertrophy, and the expression levels of PTEN-L, PINK1, and Parkin proteins were assessed using the CCK-8 assay, cell surface area evaluation, and Western blot analysis. Cardiac tissue pathology and myocardial hypertrophy were evaluated through HE and WAG staining, respectively, while PTEN-L expression was detected by immunohistochemistry. The results demonstrated successful isolation of CFs and their exosomes, with miR-15b-5p significantly enriched in the exosomes derived from Ang II-stimulated CFs (Ang II-CFs-Exos). Ang II-CFs-Exos inhibited cell viability, exacerbated myocardial hypertrophy, and activated mitophagy via miR-15b-5p in the in vitro myocardial hypertrophy model. PTEN-L was identified as a downstream target of miR-15b-5p, with its overexpression reversed the effects of miR-15b-5p mimic on myocardial hypertrophy and mitophagy. Additionally, mitochondrial inhibitors also countered the effects of the miR-15b-5p mimic on myocardial hypertrophy. Furthermore, Ang II-CFs-Exos exacerbated myocardial hypertrophy in rats, while knockout of miR-15b-5p in Ang II-CFs-Exos mitigated this effect. To sum up, Ang II-CFs-Exos promote myocardial hypertrophy by modulating PINK1/Parkin signaling -mediated mitophagy through the miR-15b-5p/PTEN-L axis.
    Keywords:  Cardiac fibroblasts; Exosomes; Mitophagy; Myocardial hypertrophy; miR-15b-5p
    DOI:  https://doi.org/10.1016/j.yexcr.2024.114380
  21. J Cell Mol Med. 2024 Dec;28(24): e70299
    Advances in Osteoblast and Mitochondrial Dynamics and Their Transfer in Osteoporosis.
    Jiaxuan Liu, Xuequan Zhang, Honghao Hou, Jun Ouyang, Jingxing Dai.
      Mitochondria are important organelles in the human body and play a major role in providing cellular energy, maintaining tissue homeostasis and apoptosis. Osteoporosis, characterised by a decrease in the amount of bone tissue per unit volume, is a metabolic bone pathology with multiple causes. Under pathological conditions, mitochondrial dysfunction leads to an imbalance in mitochondrial homeostasis, resulting in a disruption of osteoblast-osteoclast homeostasis, which in turn disrupts bone homeostasis, and this disruption of homeostasis is an important pathogenetic mechanism underlying chronic metabolic bone disease in osteoporosis. Numerous studies have shown that bone homeostasis is closely related to mitochondrial dynamics and mitochondrial translocation in the mitochondrial quality control system, and the balance between osteoblasts and osteoclasts is closely related to osteoporosis. In this review, we describe the progress of osteoblast and osteoclast research and mitochondrial dynamics in osteoporosis, and the role of mitochondrial translocation in bone homeostasis, in the hope that it can stimulate new research in osteoporotic metabolic bone disease and the development of novel therapeutic strategies.
    Keywords:  mitochondrial dynamics; mitochondrial transfer; osteoblasts; osteoclasts; osteoporosis
    DOI:  https://doi.org/10.1111/jcmm.70299
  22. Mol Neurobiol. 2024 Dec 14.
    Zinc Mitigates the Combined Neurotoxicity of Binary Metal Mixtures via Mitophagy and Mitochondrial Fusion.
    Haiqing Cai, Junxiu He, Wanting Zheng, Hong Cheng, Xiaoting Ge, Yu Bao, Yue Wei, Yanfeng Zhou, Xiaolin Liang, Xing Chen, Chaoqun Liu, Fei Wang, Xiaobo Yang.
      Environmental metal mixtures can cause combined neurotoxicity, but the underlying mechanism remains unclear. Mitochondria are crucial for energy metabolism in the nervous system, and their dysfunction leads to neurodegeneration. Zinc (Zn) is a coenzyme of many mitochondrial enzymes that controls mitochondrial function. This study investigated the role of Zn in the neurotoxicity induced by Mn + Pb and Pb + As mixtures. Zn supplementation improved the survival rate and learning ability of Caenorhabditis elegans following their exposure to mixtures of Mn + Pb and Pb + As by enhancing their mitochondrial morphology, membrane potential, and respiratory chain. Similarly, in HT22 cells, Zn mitigated the decrease in cellular activity and increase in apoptosis induced by the Mn + Pb and Pb + As mixtures by improving mitochondrial morphology and function. Mechanistically, Zn activated the PINK1 and MFN-2/OPA-1 pathways, promoting mitophagy and mitochondrial fusion. However, inhibition of mitophagy reversed the protective effect of Zn, indicating its reliance on mitophagy for neuroprotection. Our study demonstrated that Zn alleviates the combined neurotoxicity of Mn + Pb and Pb + As mixtures by enhancing mitophagy and mitochondrial fusion, suggesting that Zn supplementation is a potential treatment for metal-induced neurotoxicity.
    Keywords:  Combined neurotoxicity; Metal mixtures; Mitophagy and mitochondrial fusion; Zinc
    DOI:  https://doi.org/10.1007/s12035-024-04648-w
  23. Food Funct. 2024 Dec 20.
    Differential effects of EPA and DHA on aging-related sarcopenia in mice and possible mechanisms involved.
    Zi-Jian Wu, Ying-Chao Li, Yan Zheng, Meng-Qing Zhou, Hui Li, Shi-Xiang Wu, Xin-Yue Zhao, Yu-Hong Yang, Lei Du.
      Sarcopenia frequently occurs with aging and leads to major adverse impacts in elderly individuals. The protective effects of omega-3 polyunsaturated fatty acids against aging-related sarcopenia have been demonstrated; however, the effect and underlying mechanism of EPA or DHA alone remain inconclusive. Hence, the present study was aimed to clarify the differential effects and possible mechanisms of EPA and DHA on aging-related sarcopenia. In this study, two-month-old and eighteen-month-old male C57BL/6J mice were fed with an AIN-93M diet and an AIN-93M diet containing 1% EPA or 1% DHA for 24 weeks, respectively. The results revealed that EPA and DHA supplementation effectively alleviated the decline in grip strength, skeletal muscle mass, and myofiber cross-sectional areas in aged mice, with EPA exhibiting a better effect against aging-related sarcopenia than DHA. The ROS scavenging role of EPA in aged skeletal muscle was also superior to that of DHA. Additionally, EPA showed a stronger role in improving protein turnover and myogenesis in aged skeletal muscle, as evidenced by suppressing the activation of FoxO3a and NF-κB, blunting the expression levels of muscle atrophy markers MAFbx and MuRF1, activating the PI3K/Akt/mTOR signaling pathway, and elevating MyoD expression. Moreover, EPA also revealed a better effect on inhibiting mitochondria- and endoplasmic reticulum stress-mediated apoptosis in aged skeletal muscle. Furthermore, EPA manifested a more pronounced effect on improving mitochondrial damage of aged skeletal muscle than DHA, and the reason might be due to its superior capability of regulating mitochondrial quality control, as clearly shown by enhancing mitochondrial biogenesis through the AMPK/PGC-1α-dependent pathway, restraining the loss of mitochondrial fusion and fission proteins including Opa1, Mfn2, and Fis1, and promoting mitophagy via the PINK1/Parkin-dependent pathway.
    DOI:  https://doi.org/10.1039/d4fo04341c
  24. Acta Diabetol. 2024 Dec 16.
    Adipose mesenchymal stem cell-derived extracellular vesicles regulate PINK1/parkin-mediated mitophagy to repair high glucose-induced dermal fibroblast senescence and promote wound healing in rats with diabetic foot ulcer.
    Yinji Luo, Qijie Guo, Chang Liu, Yuxuan Zheng, Yichong Wang, Bin Wang.
       AIMS: Diabetic foot ulcers (DFUs) cause prominent morbidity and mortality. Adipose mesenchymal stem cell (ASC)-derived extracellular vesicles (EVs) show property in facilitating diabetic wound healing, and we explored their role in DFU rats.
    METHODS: ASCs were cultured in vitro, passaged and then identified by flow cytometry and induction of osteogenic/adipogenic differentiation. ASC-EVs were extracted and identified. DFU rat model was treated with ASC-EVs. High glucose (HG)-induced rat dermal fibroblasts were treated with ASC-EVs or 3-MA and sh-PINK1 plasmid in vitro. Wound healing was observed. Histological changes, inflammatory cytokines (TNF-α, IL-1β), and α-SMA and p21 double-positive cell level were assessed by HE staining, ELISA, and immunofluorescence. Mitochondrial membrane potential (MMP), cell viability and senescence, and ROS production in cells were assessed by fluorescence dye JC-1, CCK-8, SA-β-gal staining, and ROS kit. p21, LC3II/I, p62, PINK1 and parkin protein levels were determined by Western blot.
    RESULTS: DFU rats had slow wound healing and elevated levels of IL-1β, TNF-α, α-SMA and p21 double-positive cells, and SA-β-gal, while HG-induced cells had weakened viability, elevated ROS, SA-β-gal, p21 and p62 protein levels, and decreased LC3II/I, PINK1 and parkin protein levels and MMP, which were reversed by ASC-EVs. HG inhibited mitophagy by suppressing the PINK1/parkin pathway to accelerate dermal fibroblast senescence. The PINK1/parkin pathway inhibition partly mitigated the effect of ASC-EVs. ASC-EVs promoted mitophagy by activating the PINK1/parkin pathway in vivo.
    CONCLUSIONS: ASC-EVs mediated mitophagy by activating the PINK1/parkin pathway, thereby impeding HG-induced rat dermal fibroblast senescence and promoting wound healing in DFU rats.
    Keywords:  Adipose mesenchymal stem cell-derived extracellular vesicles; Cellular senescence; Dermal fibroblasts; Diabetic foot ulcer; Mitophagy; Wound healing
    DOI:  https://doi.org/10.1007/s00592-024-02422-x
  25. Biogerontology. 2024 Dec 20. 26(1): 29
    Quercetin preserves mitochondria-endoplasmic reticulum contact sites improving mitochondrial dynamics in aged myocardial cells.
    Ray Jiménez, Alejandra Zúñiga-Muñoz, Edith Álvarez-León, Wylly Ramsés García-Niño, Gabriela Navarrete-Anastasio, Elizabeth Soria-Castro, Israel Pérez-Torres, Elizabeth Lira-Silva, Natalia Pavón, Alfredo Cruz-Gregorio, Rebeca López-Marure, Cecilia Zazueta, Alejandro Silva-Palacios.
      Cardiomyocyte senescence plays a crucial role in the pathophysiology of age-related cardiovascular disease. Senescent cells with impaired contractility, mitochondrial dysfunction, and hypertrophic growth accumulate in the heart during aging, contributing to cardiac dysfunction and remodeling. Mitochondrial dynamics is altered in aging cells, leading to changes in their function and morphology. Such rearrangements can affect the spatially restricted region of the mitochondrial membrane that interacts with reticulum membrane fragments, termed mitochondria-endoplasmic reticulum (ER) contact sites (MERCs). Besides, oxidative stress associated with inefficient organelle turnover can drive cellular senescence. Therefore, in this study, we evaluated the possible association between the senolytic effect of the antioxidant quercetin (Q) and MERCs preservation in a D-galactose-induced cellular senescence model. We found that Q ameliorates the senescent phenotype of H9c2 cells in association with increased mitochondria-ER colocalization, reduced distance between both organelles, and lower ROS production. Moreover, regulation of fusion and fission processes was related with increased mitochondrial ATP production and enhanced transmembrane potential. Overall, our data provide evidence that the inhibitory effect of Q on cellular senescence is associated with preserved MERCs and improved mitochondrial function and morphology, which might contribute to the attenuation of cardiac dysfunction.
    Keywords:  Cardiac senescence; Mitochondria-endoplasmic reticulum contact sites; Mitochondrial dynamic; Quercetin; Senolysis
    DOI:  https://doi.org/10.1007/s10522-024-10174-y
  26. Mol Immunol. 2024 Dec 17. pii: S0161-5890(24)00215-3. [Epub ahead of print]177 32-43
    Paeoniflorin ameliorates reperfusion injury in H9C2 cells through SIRT1-PINK1/parkin-mediated mitochondrial autophagy.
    Xingcan Chen, Tong Sun, Yuxiang Qi, Bingqi Zhu, Lan Li, Jie Yu, Zhishan Ding, Fangmei Zhou.
      Myocardial ischemia-reperfusion injury (MIRI) injury is a serious health problem, which can seriously affect the recovery of patients with myocardial infarction and even lead to death. Paeoniflorin (PF) is a potential therapeutic drug to prevent reperfusion injury. However, the mechanism of PF in MIRI is not clear. Compared with other cells, cardiomyocytes have the largest number of mitochondria. Therefore, this study researched the protective mechanism of paeoniflorin pretreatment on myocardial ischemia-reperfusion injury (AMI) from the perspective of mitochondrial autophagy. Paeoniflorin was given or not given to H9C2 cells 12 h before reperfusion. Pretreatment of paeoniflorin can significantly increase the viability of H9C2 cells and inhibit the increase of ROS secretion induced by OGD/R. The increase of MDC autophagy fluorescence and mitochondrial membrane potential (MMP) suggested that the myocardial protective effect of paeoniflorin may also be related to mitochondrial autophagy. Next, we detected the related signals in the classical mitochondrial autophagy pathway of PINK1/parkin by Q-PCR and Western blots. The results showed that the pretreatment of paeoniflorin could promote the levels of SIRT1, Beclin1, PINK1, parkin and LC3, inhibit the level of P62. In order to further clarify whether paeoniflorin-induced SIRT1 activation is necessary for autophagy and its potential mechanism, we detected the autophagy level of H9C2 cells with SIRT1 inhibitor (EX527). The results showed that after pretreatment of EX527, the protective effect of paeoniflorin on oxidative damage and autophagy pathway was significantly decreased. The mechanism may relate to SIRT1-PINK1/parkin mitochondrial autophagy pathway. In summary, these results suggested that paeoniflorin may protect H9C2 cells from OGD/R damage by activating SIRT1-PINK1/parkin pathway. This provides new experimental basis for paeoniflorin in the treatment of MIRI.
    Keywords:  Mitochondrial autophagy; PINK1/parkin; Paeoniflorin; Reperfusion injury; SIRT1
    DOI:  https://doi.org/10.1016/j.molimm.2024.12.003
  27. Genetics. 2024 Dec 05. pii: iyae203. [Epub ahead of print]
    Proteolytic regulation of mitochondrial magnesium channel MRS2 by m-AAA protease and prohibitin complex.
    Alaumy Joshi, Rachel A Stanfield, Andrew T Spletter, Vishal M Gohil.
      Mitochondrial membrane phospholipid cardiolipin is essential for the stability of several inner mitochondrial membrane protein complexes. We recently showed that the abundance of mitochondrial magnesium channel MRS2 is reduced in models of Barth syndrome, an X-linked genetic disorder caused by a remodeling defect in cardiolipin. However, the mechanism underlying the reduced abundance of MRS2 in cardiolipin-depleted mitochondria remained unknown. In this study, we utilized yeast mutants of mitochondrial proteases to identify an evolutionarily conserved m-AAA protease, Yta10/Yta12, responsible for degrading Mrs2. The activity of m-AAA protease is regulated by the inner mitochondrial membrane scaffolding complex prohibitin, and consistent with this role, we find that Mrs2 turnover is increased in yeast prohibitin mutants. Importantly, we find that deleting Yta10 in cardiolipin-deficient yeast cells restores the steady-state levels of Mrs2 to the wild-type cells, and the knockdown of AFG3L2, a mammalian homolog of Yta12, increases the abundance of MRS2 in a murine muscle cell line. Thus, our work has identified the m-AAA protease/prohibitin complex as an evolutionarily conserved regulator of Mrs2 that can be targeted to restore Mrs2 abundance in cardiolipin-depleted cells.
    Keywords:   m-AAA protease; MRS2; Mitochondria; cardiolipin; prohibitin
    DOI:  https://doi.org/10.1093/genetics/iyae203
  28. Eur J Med Res. 2024 Dec 18. 29(1): 593
    Mitochondria-targeted antioxidant mitoquinone mitigates vitrification-induced damage in mouse ovarian tissue by maintaining mitochondrial homeostasis via the p38 MAPK pathway.
    Tianqi Du, Han Su, Dan Cao, Qingxia Meng, Ming Zhang, Zhenxing Liu, Hong Li.
       OBJECTIVE: Ovarian tissue cryopreservation has become a promising alternative for fertility preservation in cancer patients, allowing ovarian tissue to be stored for future autotransplantation. Oxidative stress damage occurring during the cryopreservation process may impact tissue quality and function. This study aims to investigate the protective effects and potential mechanisms of Mitoquinone (MitoQ), a mitochondria-targeted derivative of the antioxidant ubiquinone, during the vitrification of ovarian tissue in mice.
    METHODS: KGN cells were treated with various concentrations (0.1, 1, 10, and 50 μM) of MitoQ to determine the optimal concentration. Female ICR mice were divided into three groups: control, conventional vitrification, and MitoQ-supplemented vitrification. Ovarian samples were cryopreserved, thawed, and assessed for tissue morphology using Hematoxylin and Eosin (H&E) staining, and mitochondrial changes using immunofluorescence, transmission electron microscopy, and Western blot analysis. RNA sequencing (RNA-seq) was employed to explore potential protective mechanisms. Autotransplantation experiments were conducted, and the long-term effects of MitoQ on ovarian function were evaluated by counting follicle numbers through H&E staining and measuring serum estradiol and AMH levels using ELISA.
    RESULTS: MitoQ at 1 μM was found to be the optimal concentration for maintaining follicular morphology after vitrification. It effectively reduced mitochondrial oxidative damage, preserved mitochondrial morphology, and regulated the expression of mitochondrial dynamics proteins (Drp1 and Mfn2). RNA-seq and Western blot analyses revealed that MitoQ inhibited the p38 MAPK pathway, thereby reducing apoptosis. Additionally, autotransplantation experiments showed that MitoQ treatment significantly increased follicle counts, estradiol (E2), and anti-Müllerian hormone (AMH) levels compared to conventional vitrification.
    CONCLUSIONS: MitoQ effectively mitigates vitrification-induced oxidative damage, maintains mitochondrial homeostasis, and preserves both follicular reserve and endocrine function. These findings suggest that MitoQ is a valuable adjunct in ovarian tissue cryopreservation and could significantly improve fertility preservation outcomes for cancer patients.
    Keywords:  Fertility preservation; Mitochondrial homeostasis; Mitoquinone; Ovarian tissue cryopreservation; Oxidative stress; p38 MAPK pathway
    DOI:  https://doi.org/10.1186/s40001-024-02181-z
  29. J Ethnopharmacol. 2024 Dec 14. pii: S0378-8741(24)01549-6. [Epub ahead of print] 119250
    Panax Quinquefolium Saponins protects neuronal activity by promoting mitophagy in both in vitro and in vivo models of Alzheimer's disease.
    Wei Zhao, Rui Yang, Xin Meng, Shi-Qi Xu, Meng-Meng Li, Zhi-Chao Hao, Si-Yi Wang, Yi-Kai Jiang, Anam Naseem, Qing-Shan Chen, Li-Li Zhang, Hai-Xue Kuang, Bing-You Yang, Yan Liu.
       ETHNOPHARMACOLOGICAL RELEVANCE: In the realm of traditional Chinese medicine, Panax quinquefolius L. has garnered significant attention for its potential to treat various ailments associated with deficiencies, including qi, blood, and kidneys. As its primary bioactive constituent, Panax quinquefolius saponins (PQS) have the potential therapeutic role of Alzheimer's disease (AD) treatment, but with unclear mechanisms of action. Meanwhile, AD is considered as a common dementia disease with kidney insufficiency and deficiency by traditional medicine, and often accompanied by autophagy in modern medical research.
    AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of PQS on AD through the regulation of mitophagy.
    MATERIALS AND METHODS: The chemical constituents of PQS were characterised using the UPLC-QTOF-MS technique. After that, the HT22 cell line was used to establish the D-galactose-induced cell model, and the SAMP8 mice model of AD was also employed. Cell viability was assessed using the CCK-8 assay, ROS detection, JC-1 staining, Mito-tracker Red and LC3 staining, and Mito-tracker Green and Lyso-tracker Red staining were used to assess levels of mitophagy. The Morris Water Maze (MWM) was used for the experimental evaluation of learning and memory abilities in mice. Subsequently, the mechanism was studied by pathological staining and western blotting.
    RESULTS: Fifty-eight triterpenoid saponins were identified from PQS, and PQS alleviated D-galactose-induced HT22 cell death and increased intracellular levels of mitochondrial autophagy-related factors. In vivo, PQS significantly improved cognitive deficits and mitigated AD-like pathological features by activating the mitophagy mechanism. Furthermore, PQS may promote Pink1/Parkin-mediated mitophagy by activating the AMPK/mTOR/ULK1/DRP1 and SIRT1/PGC-1α pathways.
    CONCLUSION: In conclusion, PQS have demonstrated the potential to mitigate mitochondrial dysfunction and enhance cognitive function in AD through the activation of mitophagy. This promising strategy holds great promise for the treatment of AD.
    Keywords:  Alzheimer’s disease; Mitophagy; PINK1/Parkin; Panax Quinquefolium Saponins
    DOI:  https://doi.org/10.1016/j.jep.2024.119250
  30. J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02578-X. [Epub ahead of print] 108076
    Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.
    Tadato Ban, Kimiya Kuroda, Mitsuhiro Nishigori, Keisuke Yamashita, Keisuke Ohta, Takumi Koshiba.
      Prohibitins (PHBs) are ubiquitously expressed proteins in the mitochondrial inner membrane (MIM) that provide membrane scaffolds for both mitochondrial proteins and phospholipids. Eukaryotic PHB complexes contain two highly homologous PHB subunits, PHB1 and PHB2, which are involved in various cellular processes, including metabolic control through the regulation of mitochondrial dynamics and integrity. Their mechanistic actions at the molecular level, however, particularly those of PHB1, remain poorly understood. To gain insight into the mechanistic actions of PHB1, we established an overexpression system for the full-length recombinant protein using silkworm larvae and characterized its biophysical properties in vitro. Using recombinant PHB1 proteoliposomes reconstituted into MIM-mimicking phospholipids, we found that PHB1 forms an oligomer via its carboxy-terminal coiled-coil region. A proline substitution into the PHB1 coiled-coil collapsed its well-ordered oligomeric state, and its destabilization correlated with mitochondrial morphologic defects. Negative-staining electron microscopy revealed that homotypic PHB1-PHB1 interactions via the coiled-coil also induced liposome tethering with remodeling of the lipid membrane structure. We clarified that PHB1 promotes membrane fusion mediated by optic atrophy 1 (OPA1), a key regulator of MIM fusion. Additionally, the presence of PHB1 reduces the dependency of lipids and OPA1 for completing the fusion process. Our in vitro study provides structural insight into how the mitochondrial scaffold plays a crucial role in regulating mitochondrial dynamics. Modulating the structure and/or function of PHB1 may offer new therapeutic potential, not only for mitochondrial dysfunction but also for other cell-related disorders.
    Keywords:  Coiled-coil; Prohibitin 1; membrane fusion; mitochondria; proteoliposomes
    DOI:  https://doi.org/10.1016/j.jbc.2024.108076
  31. J Gerontol A Biol Sci Med Sci. 2024 Dec 19. pii: glae294. [Epub ahead of print]
    Senolysis by GLS1 Inhibition Ameliorates Kidney Aging by Inducing Excessive mPTP Opening through MFN1.
    Yuting Chen, Nan Zhao, Yu Zhang, Xueqi Chen, Yi Chen, Yifan Wang, Jianqing Wu, Weihong Zhao.
      Cellular senescence is a pivotal contributor to aging and age-related diseases. The targeted elimination of senescent cells, known as senolysis, has emerged as a promising therapeutic strategy for mitigating these conditions. Glutaminase 1 (GLS1), a key enzyme in the glutaminolysis pathway, has been implicated in various cellular senescence processes. However, its specific role in senescent renal tubular epithelial cells (TECs) remains unclear. This study investigates the role and underlying mechanisms of GLS1 in senescent TECs. Using D-galactose (D-gal)-induced senescence of HK-2 cells, we found that GLS1 inhibition eliminated senescent TECs by promoting excessive mitochondrial permeability transition pore (mPTP) opening. Mechanistically, the excessive mPTP opening is associated with upregulation of mitofusin 1 (MFN1). Inhibition of GLS1 in D-gal-treated HK-2 cells induced a shift in mitochondrial dynamics from fission to fusion, accompanied by a significant increase in MFN1 expression. Knocking down MFN1 reduced the mPTP opening and the expression of mPTP-related genes (PPIF, VDAC and BAX) in cells co-treated with D-gal and the GLS1 inhibitor BPTES. Moreover, treatment of aged mice with BPTES specifically eliminated senescent TECs and ameliorated age-associated kidney disease. These findings reveal that GLS1 inhibition eliminate senescent TECs by promoting excessive mPTP opening, suggesting that targeting GLS1 may be a novel senolytic strategy for alleviating aging-related kidney diseases.
    Keywords:  GLS1; MFN1; kidney aging; mPTP; senolysis
    DOI:  https://doi.org/10.1093/gerona/glae294
  32. Adv Sci (Weinh). 2024 Dec 16. e2410525
    Dipeptidyl Peptidase 4 (DPP4) Exacerbates Osteoarthritis Progression in an Enzyme-Independent Manner.
    Xinyu Li, Zhao Zhang, Wenyu Jiang, Yucan Ju, Weihua Guo, Zeyu Huang.
      Chondrocyte senescence is a key driver of osteoarthritis (OA). Mitochondrial dysfunction and oxidative stress can induce chondrocyte senescence. However, the specific mechanisms by which senescence contributes to OA progression are not fully understood. Here, it is attested that Dipeptidyl peptidase 4 (DPP4) is significantly upregulated in osteoarthritic chondrocytes in both humans and mice. DPP4 promotes oxidative stress and cellular senescence in chondrocytes through excessive mitochondrial fission in an enzyme-independent manner. Intra-articular injection of adeno-associated virus 2 to upregulate DPP4 in chondrocytes promotes post-traumatic and aging-induced OA in mice in an enzyme-independent manner. Mechanistically, DPP4 competitively binds to Myosin heavy chain 9 (MYH9), interfering with its E3 ubiquitin ligase Carboxyl terminus of Hsc70-interacting protein (CHIP), and thereby upregulates MYH9 expression. Finally, a small molecule, 4,5-Dicaffeoylquinic acid is identified, which disrupts the interaction between DPP4 and MYH9, thereby ameliorating post-traumatic and aging-induced OA in mice caused by DPP4 upregulation. The study indicates that the non-enzymatic activity of DPP4 is a promising target for OA treatment.
    Keywords:  DPP4; MYH9; mitochondrial dynamics; osteoarthritis; senescence
    DOI:  https://doi.org/10.1002/advs.202410525
  33. Eur J Pharmacol. 2024 Dec 16. pii: S0014-2999(24)00897-5. [Epub ahead of print] 177207
    Empagliflozin promotes skin flap survival by activating AMPK signaling pathway.
    Jialong Yang, Weijian Ye, Kaitao Wang, An Wang, Jiapeng Deng, Guodong Chen, Yizhen Cai, Zijie Li, Yiqi Chen, Dingsheng Lin.
      Flaps are widely used in surgical wound repair, yet distal necrosis poses a significant postoperative challenge, stemming from potential factors such as inadequate blood perfusion, inflammation, ischemia/reperfusion (I/R1) injury, mitochondrial impairment, and subsequent ferroptosis. Empagliflozin (EMPA2), a sodium-glucose cotransporter 2 inhibitor, has pharmacological activities that promote angiogenesis, mitophagy, and inhibit inflammation, I/R injury, and ferroptosis. However, it is unclear whether EMPA can enhance flap survival. Here, we established a modified McFarlane flap model and applied EMPA to demonstrate its mechanism of action. 24 rats were evenly divided into four groups: the control, low-dose EMPA (10mg/kg), high-dose EMPA (30mg/kg), and inhibitor groups. Molecular biology experiments demonstrated that EMPA promoted the expression of angiogenesis-related factors vascular endothelial growth factor (VEGF3) and CD34. Additionally, it also increased superoxide dismutase (SOD4) activity and reduced malondialdehyde (MDA5) levels, thus suppressing oxidative stress. EMPA further alleviated inflammation by downregulating the expression of tumor necrosis factor-α (TNF-α6) and interleukin-6 (IL-67). In vitro experiments showed that EMPA promoted the proliferation of human umbilical vein endothelial cells (HUVECs8) and reduce their reactive oxygen species (ROS9) production. Further investigation demonstrated that EMPA improves flap prognosis by inducing the expression of the adenosine monophosphate-activated protein kinase (AMPK10) signaling pathway, further promoting mitophagy and inhibiting ferroptosis. These effects collectively contributed to the survival of the skin flap. Overall, our research elucidates the protective effects of EMPA on flap survival and its specific mechanisms, offering new insights into solving post-transplant flap necrosis.
    Keywords:  AMPK; Empagliflozin; ferroptosis; human umbilical vein endothelial cells; mitophagy; skin flap
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177207
  34. Int J Mol Sci. 2024 Dec 04. pii: 13040. [Epub ahead of print]25(23):
    A Reduction in Mitophagy Is Associated with Glaucomatous Neurodegeneration in Rodent Models of Glaucoma.
    Renuka M Chaphalkar, Bindu Kodati, Prabhavathi Maddineni, Shaoqing He, Calvin D Brooks, Dorota L Stankowska, Shaohua Yang, Gulab Zode, Raghu R Krishnamoorthy.
      Glaucoma is a heterogenous group of optic neuropathies characterized by the degeneration of optic nerve axons and the progressive loss of retinal ganglion cells (RGCs), which could ultimately lead to vision loss. Elevated intraocular pressure (IOP) is a major risk factor in the development of glaucoma, and reducing IOP remains the main therapeutic strategy. Endothelin-1 (ET-1), a potent vasoactive peptide, has been shown to produce neurodegenerative effects in animal models of glaucoma. However, the detailed mechanisms underlying ET-1-mediated neurodegeneration in glaucoma are not completely understood. In the current study, using a Seahorse Mitostress assay, we report that ET-1 treatment for 4 h and 24 h time points causes a significant decline in various parameters of mitochondrial function, including ATP production, maximal respiration, and spare respiratory capacity in cultured RGCs. This compromise in mitochondrial function could trigger activation of mitophagy as a quality control mechanism to restore RGC health. Contrary to our expectation, we observed a decrease in mitophagy following ET-1 treatment for 24 h in cultured RGCs. Using Morrison's model of ocular hypertension in rats, we investigated here, for the first time, changes in mitophagosome formation by analyzing the co-localization of LC-3B and TOM20 in RGCs. We also injected ET-1 (24 h) into transgenic GFP-LC3 mice to analyze the formation of mitophagosomes in vivo. In Morrison's model of ocular hypertension, as well as in ET-1 injected GFP-LC3 mice, we found a decrease in co-localization of LC3 and TOM20, indicating reduced mitophagy. Taken together, these results demonstrate that both ocular hypertension and ET-1 administration in rats and mice lead to reduced mitophagy, thus predisposing RGCs to neurodegeneration.
    Keywords:  glaucoma; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms252313040
  35. Int J Mol Sci. 2024 Nov 25. pii: 12643. [Epub ahead of print]25(23):
    Trehalose Alleviates D-Galactose-Induced Aging-Related Granulosa Cell Death in Ovaries.
    Huaming Xi, Xinyu Chen, Kai Liang, Xianglong Wang, Feng Jiang, Yuan Li, Dong Niu.
      Ovarian dysfunction caused by aging restricts female reproductive capacity and is accompanied by oxidative stress and impaired autophagy. Recent studies have shown that trehalose (Tre) can activate autophagy and have antioxidant effects. However, whether Tre can be used to attenuate ovarian aging remains unclear. Therefore, the anti-aging effects of Tre on the ovary were explored both in vivo and in vitro. D-galactose (D-gal) was administered i.p. daily (200 mg/kg body weight) for 8 weeks to establish the mouse ovarian aging model (n = 10). We found that Tre significantly reversed ovarian weight loss and reduced the number of TUNEL-positive granulosa cells caused by D-gal in mouse ovaries. Tre elevated the protein expression levels of LC3-II, Parkin, PINK1, Beclin1, and LAMP2 in ovaries. Mitochondrial-related proteins TOM20 and COX IV expression levels were increased by Tre administration. In vitro studies further supported these findings, showing that Tre treatment significantly reduced the number of SA-β-gal and PI-positive cells, and decreased ROS levels in cultured granulosa cells. Thus, Tre alleviates ovarian aging by activating mitophagy and reducing oxidative stress, suggesting its potential as an anti-aging agent for ovarian health.
    Keywords:  aging; granulosa cell; mitophagy; ovary; trehalose
    DOI:  https://doi.org/10.3390/ijms252312643
  36. Int J Mol Sci. 2024 Dec 06. pii: 13148. [Epub ahead of print]25(23):
    Hesperetin Increases Lifespan and Antioxidant Ability Correlating with IIS, HSP, mtUPR, and JNK Pathways of Chronic Oxidative Stress in Caenorhabditis elegans.
    Run-Jia Wang, Ya-Jing Ni, Yan-Qiang Liu.
      Hesperetin (Hst) is a common citrus fruit flavonoid with antioxidant, anti-inflammatory, and anti-neurodegenerative effects. To explore the antioxidant and anti-aging effects and mechanisms of Hst, we induced chronic oxidative stress in Caenorhabditis elegans (C. elegans) using low-concentration H2O2 and examined its effects on lifespan, healthy life index, reactive oxygen species (ROS), antioxidant enzymes, and transcriptomic metrics. Hst significantly prolonged lifespan, increased body bending and pharyngeal pumping frequency, decreased ROS accumulation, and increased antioxidant enzyme activity in normal and stressed C. elegans. Hst significantly upregulated daf-18, daf-16, gst-2, gst-3, gst-4, gst-39, hsp-16.11, sip-1, clpp-1, and dve-1 and downregulated ist-1 and kgb-1 mRNAs in stressed C. elegans. These genes are involved in the insulin/insulin-like growth factor-1 signaling (IIS), heat shock protein (HSP), mitochondrial unfolded protein response (mtUPR), and c-Jun N-terminal kinase (JNK) pathways. In summary, Hst increases lifespan and antioxidant ability, correlating with these pathways, during chronic oxidative stress in C. elegans.
    Keywords:  Caenorhabditis elegans; antioxidative; hesperetin; lifespan; transcriptomic metrics
    DOI:  https://doi.org/10.3390/ijms252313148
  37. Adv Healthc Mater. 2024 Dec 20. e2403817
    Ginsenoside Rd-Loaded Antioxidant Polymersomes to Regulate Mitochondrial Homeostasis for Bone Defect Healing in Periodontitis.
    Congjiao Hu, Junqiu Shi, Fan Zhang, Mingchen Lv, Zhenghong Ge, Meiting Feng, Zhen Fan, Danqing Liu, Jianzhong Du, Yao Sun.
      Periodontitis is the leading cause of tooth loss in adults. Initially triggered by bacterial infection, it is characterized by subsequent dysregulation of mitochondrial homeostasis, leading to ongoing loss of periodontal tissue. Mitophagic flux, a critical physiological mechanism for maintaining mitochondrial homeostasis, is compromised in periodontitis. Additionally, increased release of reactive oxygen species (ROS) exacerbates mitochondrial damage. In this study, a ginsenoside Rd (Rd)-loaded antioxidative polymersome (RdAP) is designed, which is self-assembled from a mitochondrial-protective and ROS-scavenging block copolymer, poly(ethylene oxide)-block-poly(phenylboronic acid pinacol ester-conjugated polylysine) (PEO113-b-P(Lys-PAPE)60). The phenylboronic acid pinacol ester (PAPE) segment exhibits excellent ROS-responsive properties, enabling effective ROS scavenging through antioxidant production. Rd significantly enhances mitophagic flux by 2.5-fold in periodontal ligament stem cells (PDLSCs) under oxidative stress. Together with the antioxidative polymersome, RdAPs restore mitochondrial homeostasis and enhance the osteogenic capacity of PDLSCs, bringing it closer to that of healthy controls. In a mouse model of periodontitis, the bone mass in the RdAP-treated group is 1.37 times greater than that in the untreated periodontitis group. Overall, the findings propose a novel strategy for addressing refractory periodontitis, which may also be applicable to other diseases characterized by mitochondrial homeostasis imbalance.
    Keywords:  ROS‐responsive polymersomes; mitochondrial homeostasis; mitophagic flux; periodontitis; self‐assembly
    DOI:  https://doi.org/10.1002/adhm.202403817
  38. Cell Calcium. 2024 Dec 13. pii: S0143-4160(24)00144-1. [Epub ahead of print]125 102986
    A role for lysosomal calcium channels in mitigating mitochondrial damage and oxidative stress.
    Leandro C Clementino, Andrew P Thomas, Emily M Rocha, Sabine Hilfiker.
      Elevated free fatty acids and oxidative stress may function as pathogenic factors in endothelial dysfunction that is associated with various cardiovascular complications. In recent work, Feng and colleagues report that activation of a lysosomal Ca2+ channel may be a viable option to alleviate oxidative damage by boosting lysosome biogenesis and mitophagy.
    Keywords:  Calcium signaling; Lysosome; Mitophagy; Reactive oxygen species; TFEB; TRPML1
    DOI:  https://doi.org/10.1016/j.ceca.2024.102986
  39. Front Cell Neurosci. 2024 ;18 1496163
    Aging promotes an increase in mitochondrial fragmentation in astrocytes.
    Ana Paula Bergamo Araujo, Gabriele Vargas, Lívia de Sá Hayashide, Isadora Matias, Cherley Borba Vieira Andrade, Jorge José de Carvalho, Flávia Carvalho Alcantara Gomes, Luan Pereira Diniz.
       Introduction: Brain aging involves a complex interplay of cellular and molecular changes, including metabolic alterations and the accumulation of senescent cells. These changes frequently manifest as dysregulation in glucose metabolism and mitochondrial function, leading to reduced energy production, increased oxidative stress, and mitochondrial dysfunction-key contributors to age-related neurodegenerative diseases.
    Methods: We conducted experiments on two models: young (3-4 months) and aged (over 18 months) mice, as well as cultures of senescent and control mouse astrocytes. Mitochondrial content and biogenesis were analyzed in astrocytes and neurons from aged and young animals. Cultured senescent astrocytes were examined for mitochondrial membrane potential and fragmentation. Quantitative PCR (qPCR) and immunocytochemistry were used to measure fusion- and fission-related protein levels. Additionally, transmission electron microscopy provided morphological data on mitochondria.
    Results: Astrocytes and neurons from aged animals showed a significant reduction in mitochondrial content and a decrease in mitochondrial biogenesis. Senescent astrocytes in culture exhibited lower mitochondrial membrane potential and increased mitochondrial fragmentation. qPCR and immunocytochemistry analyses revealed a 68% increase in fusion-related proteins (mitofusin 1 and 2) and a 10-fold rise in DRP1, a key regulator of mitochondrial fission. Transmission electron microscopy showed reduced perimeter, area, and length-to-diameter ratio of mitochondria in astrocytes from aged mice, supported by elevated DRP1 phosphorylation in astrocytes of the cerebral cortex.
    Discussion: Our findings provide novel evidence of increased mitochondrial fragmentation in astrocytes from aged animals. This study sheds light on mechanisms of astrocytic metabolic dysfunction and mitochondrial dysregulation in brain aging, highlighting mitochondrial fragmentation as a potential target for therapeutic interventions in age-related neurodegenerative diseases.
    Keywords:  astrocytes; brain aging; mitochondrial biogenesis and neurodegeneration; mitochondrial dysfunction; mitochondrial fragmentation
    DOI:  https://doi.org/10.3389/fncel.2024.1496163
  40. Aging Cell. 2024 Dec 15. e14449
    Age-associated accumulation of RAB9 disrupts oocyte meiosis.
    Min Gao, Fang Wang, Tengteng Xu, Yanling Qiu, Tianqi Cao, Simiao Liu, Wenlian Wu, Yitong Zhou, Haiying Liu, Fenghua Liu, Junjiu Huang.
      The critical role of some RAB family members in oocyte meiosis has been extensively studied, but their role in oocyte aging remains poorly understood. Here, we report that the vesicle trafficking regulator, RAB9 GTPase, is essential for oocyte meiosis and aging in humans and mice. RAB9 was mainly located at the meiotic spindle periphery and cortex during oocyte meiosis. In humans and mice, we found that the RAB9 protein level were significantly increased in old oocytes. Age-related accumulation of RAB9 inhibits first polar body extrusion and reduces the developmental potential of oocytes. Further studies showed that increased Rab9 disrupts spindle formation and chromosome alignment. In addition, Rab9 overexpression disrupts the actin cap formation and reduces the cortical actin levels. Mechanically, Rab9-OE increases ROS levels, decreases mitochondrial membrane potential, ATP content and the mtDNA/nDNA ratio. Further studies showed that Rab9-OE activates the PINK1-PARKIN mitophagy pathway. Importantly, we found that reducing RAB9 protein expression in old oocytes could partially improve the rate of old oocyte maturation, ameliorate the accumulation of age-related ROS levels and spindle abnormalities, and partially rescue ATP levels, mtDNA/nDNA ratio, and PINK1 and PARKIN expression. In conclusion, our results suggest that RAB9 is required to maintain the balance between mitochondrial function and meiosis, and that reducing RAB9 expression is a potential strategy to ameliorate age-related deterioration of oocyte quality.
    Keywords:  RAB9; aging; meiosis; mitochondrial function; oocyte
    DOI:  https://doi.org/10.1111/acel.14449
  41. J Integr Med. 2024 Nov 13. pii: S2095-4964(24)00402-3. [Epub ahead of print]
    Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma.
    Chun-Yan Feng, Cheng-Song Cai, Xiao-Qian Shi, Zhi-Juan Zhang, Dan Su, Yun-Qing Qiu.
       OBJECTIVE: Resveratrol (Res) is a promising anticancer drug against hepatocellular carcinoma (HCC), but whether its anti-HCC effects implicate mitophagy remains unclear. Therefore, we aimed to explore the specific role of Res in mitophagy and the related mechanisms during the treatment of HCC.
    METHODS: HepG2 cells and tumor-grafted nude mice were used to investigate the effects of low-, middle- and high-dose of Res on HCC progression and mitophagy in vitro and in vivo, respectively. A series of approaches including cell counting kit-8, flow cytometry, wound healing and transwell assays were used to evaluate tumor cell functions. Transmission electron microscopy, immunofluorescence and Western blotting were used to assess mitophagy. Mitochondrial oxygen consumption rate, reactive oxygen species and membrane potential were used to reflect mitochondrial function. After disrupting the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), miR-143-3p, and ribonucleoside reductase M2 (RRM2), the effects of the MALAT1/miR-143-3p/RRM2 axis on cell function and mitophagy under Res treatment were explored in vitro. Additionally, dual-luciferase reporter and chromatin immunoprecipitation were used to confirm interactions between target genes.
    RESULTS: Res significantly inhibited the proliferation and promoted apoptosis of HCC cells in vitro, while significantly suppressing tumor growth in a dose-dependent manner and inducing mitophagy and mitochondrial dysfunction in vivo. Interestingly, MALAT1 was highly expressed in HCC cells and its knockdown upregulated miR-143-3p expression in HCC cells, which subsequently inhibited RRM2 expression. Furthermore, in nude mice grafted with HCC tumors and treated with Res, the expression of MALAT1, miR-143-3p and RRM2 were altered significantly. In vitro data further supported the targeted binding relationships between MALAT1 and miR-143-3p and between miR-143-3p and RRM2. Therefore, a series of cell-based experiments were carried out to study the mechanism of the MALAT1/miR-143-3p/RRM2 axis involved in mitophagy and HCC; these experiments revealed that MALAT1 knockdown, miR-143-3p mimic and RRM silencing potentiated the antitumor effects of Res and its activation of mitophagy.
    CONCLUSION: Res facilitated mitophagy in HCC and exerted anti-cancer effects by targeting the MALAT1/miR-143-3p/RRM2 axis. Please cite this article as: Feng CY, Cai CS, Shi XQ, Zhang ZJ, Su D, Qiu YQ. Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma. J Integr Med. 2024; Epub ahead of print.
    Keywords:  Hepatocellular carcinoma; MALAT1; Mitophagy; Resveratrol; miR-143-3p
    DOI:  https://doi.org/10.1016/j.joim.2024.11.003
  42. Adv Sci (Weinh). 2024 Dec 16. e2412593
    Susceptibility of Mitophagy-Deficient Tumors to Ferroptosis Induction by Relieving the Suppression of Lipid Peroxidation.
    Shan Liu, Jing-Hong Chen, Li-Chao Li, Zhi-Peng Ye, Jian-Nan Liu, Yu-Hong Chen, Bing-Xin Hu, Jia-Hong Tang, Gong-Kan Feng, Zhi-Ming Li, Chu-Xia Deng, Rong Deng, Xiao-Feng Zhu, Hai-Liang Zhang.
      The identification of ferroptosis-sensitive cancers is critical for the application of ferroptosis-inducing therapies in cancer therapy. Here, patient-derived organoid screening models of colorectal cancer are established to identify tumors that are sensitive to ferroptosis-inducing therapy. This study discovers that patient-derived tumors characterized by mitophagy deficiency are hypersensitive to ferroptosis-inducing therapies. Mechanistically, a novel negative feedback regulatory pathway of lipid peroxidation is identified, which is one of the important intrinsic anti-ferroptosis mechanisms of cancer cells. Lipid peroxidation-mediated endoplasmic reticulum stress transcriptionally upregulates Parkin to promote mitophagy through ATF4. Mitophagy limits the generation of lipid peroxidation products and subsequently inhibits ferroptosis by inhibiting the accumulation of mitochondrial ROS. Mitophagy-deficient tumors lack this anti-ferroptotic mechanism, unleashing the generation of lipid peroxidation and potent ferroptotic cell death induced by erastin, RSL3, cysteine deprivation, radiotherapy, and immunotherapy. More importantly, ferroptosis-inducing therapy selectively inhibits the growth and distant metastasis of mitophagy-deficient tumors in vivo. In summary, patient-derived organoids of colorectal cancer patients for screening ferroptosis-sensitive tumors are established, providing a paradigm for identifying that patient-derived tumors are sensitive to ferroptosis-inducing therapies. This study concludes that mitophagy-deficient tumors are vulnerable to ferroptosis induction, which may lead to the development of new therapeutic strategies for tumors deficient in mitophagy.
    Keywords:  ferroptosis; lipid peroxidation; mitophagy‐deficient tumors; parkin
    DOI:  https://doi.org/10.1002/advs.202412593
  43. Redox Biol. 2024 Dec 12. pii: S2213-2317(24)00445-2. [Epub ahead of print]79 103467
    Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.
    Chao Song, Wu Zheng, Guoming Liu, Yiyang Xu, Zhibo Deng, Yu Xiu, Rongsheng Zhang, Linhai Yang, Yifei Zhang, Guoyu Yu, Yibin Su, Jun Luo, Bingwei He, Jie Xu, Hanhao Dai.
      In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.
    Keywords:  E-syt1; Mitochondria; Mitophagy; Myogenesis; Sarcopenic obesity
    DOI:  https://doi.org/10.1016/j.redox.2024.103467
  44. Autophagy. 2024 Dec 15.
    Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
    Isabel Gordaliza-Alaguero, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Laura Villarreal, Gianluca Arauz-Garofalo, Marina Gay, Marta Martinez-Vicente, Jorge Seco, Pau Martin-Malpartida, Marta Vilaseca, María J Macías, Manuel Palacin, Saška Ivanova, Antonio Zorzano.
      MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA. HA-affinity isolation followed by mass spectrometry identified potential interactors of MFN1 and MFN2. A substantial proportion of interactors were common for MFN1 and MFN2 and were regulated by nutrient deprivation. We validated novel ER and endosomal partners of MFN1 and/or MFN2 with a potential role in interorganelle communication. We characterized RAB5C (RAB5C, member RAS oncogene family) as an endosomal modulator of mitochondrial homeostasis, and SLC27A2 (solute carrier family 27 (fatty acid transporter), member 2) as a novel partner of MFN2 relevant in autophagy. We conclude that MFN proteins participate in nutrient-modulated pathways involved in organelle communication and autophagy.
    Keywords:  Autophagosomes; endosomes; mitochondria; mitochondria-endoplasmic reticulum contact sites; mitochondrial dynamics; nutrient deprivation
    DOI:  https://doi.org/10.1080/15548627.2024.2440843
  45. Med J Islam Repub Iran. 2024 ;38 82
    Exploring Co-expression Modules-Traits Correlation through Weighted Gene Co-expression Network Analysis: A Promising Approach in Wound Healing Research.
    Mansoureh Farhangniya, Ali Samadikuchaksaraei, Farzaneh Mohamadi Farsani.
       Background: The skin is the biggest organ in the body and has several important functions in protection and regulation. However, wound development can disrupt the natural healing process, leading to challenges such as chronic wounds, persistent infections, and impaired angiogenesis. These issues not only affect individuals' well-being but also pose significant economic burdens on healthcare systems. Despite advancements in wound care research, managing chronic wounds remains a pressing concern, with obstacles such as persistent infection and impaired angiogenesis hindering the healing process. Understanding the complex genetic pathways involved in wound healing is crucial for developing effective therapeutic strategies and reducing the socio-economic impact of chronic wounds. Weighted Gene Co-Expression Network Analysis (WGCNA) offers a promising approach to uncovering key genes and modules associated with different stages of wound healing, providing valuable insights for targeted interventions to enhance tissue repair and promote efficient wound healing.
    Methods: Data collection involved retrieving microarray gene expression datasets from the Gene Expression Omnibus website, with 65 series selected according to inclusion and exclusion criteria. Preprocessing of raw data was performed using the Robust MultiArray Averaging approach for background correction, normalization, and gene expression calculation. Weighted Gene Co-Expression Network Analysis was employed to identify co-expression patterns among genes associated with wound healing processes. This involved steps such as network construction, topological analysis, module identification, and association with clinical traits. Functional analysis included enrichment analysis and identification of hub genes through gene-gene functional interaction network analysis using the GeneMANIA database.
    Results: The analysis using WGCNA indicated significant correlations between wound healing and the black, brown, and light green modules. These modules were further examined for their relevance to wound healing traits and subjected to functional enrichment analysis. A total of 16 genes were singled out as potential hub genes critical for wound healing. These hub genes were then scrutinized, revealing a gene-gene functional interaction network within the module network based on the KEGG enrichment database. Noteworthy pathways such as MAPK, EGFR, and ErbB signaling pathways, as well as essential cellular processes including autophagy and mitophagy, emerged as the most notable significant pathways.
    Conclusion: We identified consensus modules relating to wound healing across nine microarray datasets. Among these, 16 hub genes were uncovered within the brown and black modules. KEGG enrichment analysis identified co-expression genes within these modules and highlighted pathways most closely associated with the development of wound healing traits, including autophagy and mitophagy. The hub genes identified in this study represent potential candidates for future research endeavors. These findings serve as a stepping stone toward further exploration of the implications of these co-expressed modules on wound healing traits.
    Keywords:  Autophagy; Gene Expression; Mitophagy; Network Analysis; Wound Healing
    DOI:  https://doi.org/10.47176/mjiri.38.82
  46. Subcell Biochem. 2024 ;107 173-181
    The Role of Calorie Restriction in Modifying the Ageing Process through the Regulation of SIRT1 Expression.
    Monia Kittana, Vasso Apostolopoulos, Lily Stojanovska.
      Calorie restriction (CR), as a dietary approach of reducing caloric intake while maintaining nutritional adequacy, has gained significant attention due to its potential role in promoting longevity and enhancing health. Central to the beneficial effects of CR is SIRT1. SIRT1 belongs to a family of NAD+ dependent deacetylases and plays an important role in regulating various cellular processes, including histone deacetylation, oxidative stress response, and mitochondrial biogenesis. This chapter reviews the evidence regarding the effect of CR on SIRT1 expression and mitochondrial biogenesis. Both pre-clinical and human studies have consistently demonstrated that CR promotes an increase in SIRT1 expression and activity in different tissues. This is also associated with other favourable health outcomes, such as delayed neurodegeneration and improved cognitive function. Moderate CR (25% restriction) has shown an impact on promoting mitochondrial biogenesis, reflected in markers such as mitochondrial DNA and transcription factors. However, this is reviewed in light of some methodological limitations, as data varied in response to different CR regimens. Herein, we highlight the potential of CR in up-regulating SIRT1 and promoting mitochondrial biogenesis, which can have significant implications for developing strategies to manage and promote healthy ageing.
    Keywords:  Ageing; Aging; Calorie restriction; Healthy ageing; Mitochondrial biogenesis; SIRT1; Sirtuins
    DOI:  https://doi.org/10.1007/978-3-031-66768-8_8
  47. Evol Lett. 2024 Dec;8(6): 916-926
    Assessing the role of mitonuclear interactions on mitochondrial function and organismal fitness in natural Drosophila populations.
    Stefano Bettinazzi, Jane Liang, Enrique Rodriguez, Marion Bonneau, Ruben Holt, Ben Whitehead, Damian K Dowling, Nick Lane, M Florencia Camus.
      Mitochondrial function depends on the effective interactions between proteins and RNA encoded by the mitochondrial and nuclear genomes. Evidence suggests that both genomes respond to thermal selection and promote adaptation. However, the contribution of their epistatic interactions to life history phenotypes in the wild remains elusive. We investigated the evolutionary implications of mitonuclear interactions in a real-world scenario that sees populations adapted to different environments, altering their geographical distribution while experiencing flow and admixture. We created a Drosophila melanogaster panel with replicate native populations from the ends of the Australian east-coast cline, into which we substituted the mtDNA haplotypes that were either predominant or rare at each cline-end, thus creating putatively mitonuclear matched and mismatched populations. Our results suggest that mismatching may impact phenotype, with populations harboring the rarer mtDNA haplotype suffering a trade-off between aerobic capacity and key fitness aspects such as reproduction, growth, and survival. We discuss the significance of mitonuclear interactions as modulators of life history phenotypes in the context of future adaptation and population persistence.
    Keywords:  Drosophila melanogaster; OXPHOS; fitness; local adaptation; mitochondria; mitonuclear interactions
    DOI:  https://doi.org/10.1093/evlett/qrae043
  48. Int J Mol Sci. 2024 Nov 29. pii: 12860. [Epub ahead of print]25(23):
    Maternal Low-Protein Diet Leads to Mitochondrial Dysfunction and Impaired Energy Metabolism in the Skeletal Muscle of Male Rats.
    Vipin A Vidyadharan, Ancizar Betancourt, Craig Smith, Chellakkan S Blesson, Chandra Yallampalli.
      A prenatal low-protein (LP) diet disrupts glucose homeostasis in adult offspring. Skeletal muscles are one of the main sites of glucose clearance, and mitochondria residing in the muscle fibers are central to glucose homeostasis. Our previous studies indicated that impaired mitochondrial health is central to dysregulated glucose metabolism in the gastrocnemius muscle of the LP-programmed female rats. In addition, dysfunctional mitochondria are often an indicator of underlying irregularities in energy metabolism and metabolic inflexibility. Therefore, this study examined the mitochondrial function and metabolic flexibility in the skeletal muscles of prenatal LP-programmed adult male rats. Pregnant Wistar rats were randomly allotted to a control diet (20% protein) or an isocaloric LP diet (6% protein). Standard laboratory rat chow was given to the dams and the pups after delivery and weaning. Gene and protein expressions, mtDNA copy number, and electron microscopy were assessed in gastrocnemius (GS) muscle, and the mitochondrial oxygen consumption rate was determined using isolated flexor digitorum brevis muscle fibers. The genes associated with mitochondrial outer membrane fusion, mitofusin1 and 2 (Mfn1 and Mfn2), fission (Fis1), and biogenesis (Pgc1B, Nrf1, and Esrra) were lower in the LP group. Further, our functional studies showed that the ATP-linked oxygen consumption rate (OCR), maximal, spare respiratory, and non-mitochondrial respiration-associated OCRs were lower in the LP rats. Further, the mRNA and protein expressions of Ndufb8, a key factor involved in the complex-I catalytic activity, were downregulated in the LP group. In addition, the expression of genes linked to mitochondrial pyruvate transport (Mpc1) and metabolism (Pdha1) was lower in the LP group. In contrast, the expression of mitochondrial fatty acid transporters (Cpt1a and Cpt2) was higher in the LP when compared to the control group. However, electron microscopic analysis exhibited no difference in the mitochondrial ultrastructure in the LP muscle compared to the control. Altogether, our results indicate that the LP diet affects the mitochondrial complex-I integrity and dynamics and leads to altered expression of genes associated with substrate oxidation and mitochondrial dysfunction in the skeletal muscle of the male LP offspring.
    Keywords:  energy metabolism; fetal programming; low-protein diet; mitochondria; mitochondrial dynamics; mitochondrial dysfunction; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms252312860
  49. Int J Nanomedicine. 2024 ;19 13287-13300
    Eugenol Nanoparticles Ameliorate Doxorubicin-Induced Spermatogenic Dysfunction by Inhibiting the PINK1/Parkin and BNIP3/NIX Signaling Pathways.
    Yang Fu, Peipei Yuan, Manyv Wang, Yajuan Zheng, Yan Zhang, Lirui Zhao, Qingyun Ma, Pengsheng Wang, Xiaotian Sun, Xiaoke Zheng, Weisheng Feng.
       Purpose: Doxorubicin (DOX) precipitates cell apoptosis in testicular tissues, and it is imperative to develop drugs to alleviate the spermatogenic disorders it causes. Eugenia caryophyllata Thunb is often used to treat male sexual disorders. Eugenol, a major component of Eugenia caryophyllata Thunb. has inadequate stability and low solubility, which limits its pharmacological effects. Eugenol nanoparticles (NPs) (ENPs) are expected to overcome these limitations. The protective effects of ENPs against DOX-induced reproductive toxicity were studied in mice.
    Methods: Eugenol was encapsulated in Methoxy-Poly(ethylene glycol)-Poly(lactide-co-glycolide) nanoparticles (mPEG-PLGA-NPs), and their role in ameliorating spermatogenic dysfunction was verified in vivo and in vitro.
    Results: We present a promising delivery system that encapsulates eugenol into mPEG-PLGA-NPs and forms them into nanocomposites. In vitro, ENPs significantly reduced doxorubicin-induced ROS and inflammatory factors in GC-1 cells and regulated the expression of the mitochondrial autophagy protein PINK1 and meiosis-related protein SCP3. In vivo, ENPs significantly increased sperm motility in mice, reduced apoptosis and oxidative stress in the testes, inhibited the testicular PINK1/Parkin and BNIP3/NIX signaling pathways, and enhanced the expression of factors associated with meiosis.
    Conclusion: Given their safety and efficacy, these ENPs have potential application prospects in mitigating doxorubicin-induced spermatogenic dysfunction.
    Keywords:  Doxorubicin; Eugenol nanoparticles; Mitochondrial autophagy; PINK1/Parkin and BNIP3/NIX signaling pathways; spermatogenic dysfunction
    DOI:  https://doi.org/10.2147/IJN.S494056
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