bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024‒09‒29
forty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. Fast and quantitative mitophagy assessment by flow cytometry using the mito-QC reporter.
  2. Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection.
  3. Quality control of mitochondria involves lysosomes in multiple definitive ways.
  4. Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
  5. Differential mitochondrial adaptation and FNDC5 production in brown and white adipose tissue in response to cold and obesity.
  6. Modulating mitochondrial dynamics ameliorates left ventricular dysfunction by suppressing diverse cell death pathways after diabetic cardiomyopathy.
  7. Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
  8. Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
  9. Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.
  10. Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
  11. Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy.
  12. In vivo targeted-imaging of mitochondrial acidification in an aristolochic acid I-induced nephrotoxicity mouse model by a fluorescent/photoacoustic bimodal probe.
  13. N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy.
  14. Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.
  15. Inclusion body myositis: Correcting impaired mitochondrial and lysosomal autophagy as a potential therapeutic strategy.
  16. Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
  17. Icariin alleviates cellular injury induced by cardiac ischemia-reperfusion injury by inhibiting IRE1/JNK-induced ferroptosis.
  18. The role of mitochondria in cytokine and chemokine signalling during ageing.
  19. Ubiquitination of ATAD3A by TRIM25 exacerbates cerebral ischemia-reperfusion injury via regulating PINK1/Parkin signaling pathway-mediated mitophagy.
  20. HSP90-regulated mitophagy can alleviate heat stress damage by inhibiting pyroptosis in the hepatocytes of Wenchang chickens.
  21. Hederagenin inhibits mitochondrial damage in Parkinson's disease via mitophagy induction.
  22. The role of Drp1 - Pink1 - Parkin - mediated mitophagy in perfluorobutane sulfonate- induced hepatocyte damage.
  23. NPLOC4 aggravates heart failure by regulating ROS and mitochondrial function.
  24. Linoleic Acid Promotes Mitochondrial Biogenesis and Alleviates Acute Lung Injury.
  25. FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.
  26. Establishment of an Apical-Out Organoid Model for Directly Assessing the Function of Postbiotics.
  27. SENP1 prevents high fat diet-induced non-alcoholic fatty liver diseases by regulating mitochondrial dynamics.
  28. Epigenetic regulation of the human GDAP1 gene.
  29. Mitochondrial Dysfunction in Systemic Lupus Erythematosus: Insights and Therapeutic Potential.
  30. Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
  31. Integrative Analyses of Mitophagy-Related Genes and Mechanisms Associated with Type 2 Diabetes in Muscle Tissue.
  32. The suppressive effects of crocin from saffron on allergic airway inflammation through Drp1/Nfr1/Mfn2/Pgc1-alpha signaling pathway in mice.
  33. The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy.
  34. PPARγ agonist alleviates calcium oxalate nephrolithiasis by regulating mitochondrial dynamics in renal tubular epithelial cell.
  35. Novel insights into sevoflurane-induced developmental neurotoxicity mechanisms.
  36. Mesenchymal stem cells in tumor microenvironment: drivers of bladder cancer progression through mitochondrial dynamics and energy production.
  37. Environmentally relevant concentrations of perfluorobutane sulfonate impair locomotion behaviors and healthspan by downregulating mitophagy in C. elegans.
  38. A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
  39. Letter to the editor for the article "How mitochondrial dynamics imbalance affects the progression of breast cancer: a mini review".
  40. Dexamethasone Impairs ATP Production and Mitochondrial Performance in Human Trabecular Meshwork Cells.
  41. The Potential Role of Mitochondria in the Microbiota-Gut-Brain Axis: Implications for Brain Health.
  42. Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling.
  43. Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications.
  44. Enhancing terminal erythroid differentiation in human embryonic stem cells through TRIB3 overexpression.
  45. Exploring Mitochondrial Autophagy Dysregulation in Osteosarcoma: Its Implications for Prognosis and Targeted Therapy.
  46. The mitochondrial function of peripheral blood mononuclear cells in frail older patients.
  47. Dihydrotestosterone induces reactive oxygen species accumulation and mitochondrial fission leading to apoptosis of granulosa cells.
  48. DNA-PKcs modulates mouse lung homeostasis via the regulation of mitochondrial fission.
  49. ER Stress and Mitochondrial Perturbations Regulate Cell Death in Retinal Detachment: Exploring the Role of HIF1α.
  1. Front Cell Dev Biol. 2024 ;12 1460061
    Fast and quantitative mitophagy assessment by flow cytometry using the mito-QC reporter.
    Juan Ignacio Jiménez-Loygorri, Carlos Jiménez-García, Álvaro Viedma-Poyatos, Patricia Boya.
      Mitochondrial quality control is finely tuned by mitophagy, the selective degradation of mitochondria through autophagy, and mitochondrial biogenesis. Removal of damaged mitochondria is essential to preserve cellular bioenergetics and prevent detrimental events such as sustained mitoROS production, pro-apoptotic cytochrome c release or mtDNA leakage. The array of tools available to study mitophagy is very limited but in constant development. Almost a decade ago, we developed a method to assess mitophagy flux using MitoTracker Deep Red in combination with lysosomal inhibitors. Now, using the novel tandem-fluorescence reporter mito-QC (mCherry-GFP-FIS1101-152) that allows to differentiate between healthy mitochondria (mCherry+GFP+) and mitolysosomes (mCherry+GFP-), we have developed a robust and quantitative method to assess mitophagy by flow cytometry. This approach has been validated in ARPE-19 cells using PINK1/Parkin-dependent (CCCP) and PINK1/Parkin-independent (DFP) positive controls and complementary techniques. Furthermore, we show that the mito-QC reporter can be multiplexed, especially if using spectral flow cytometry, to simultaneously study other cellular parameters such as viability or ROS production. Using this technique, we evaluated and characterized two prospective mitophagy inducers and further dissected their mechanism of action. Finally, using mito-QC reporter mice, we developed a protocol to measure mitophagy levels in the retina ex vivo. This novel methodology will propel mitophagy research forward and accelerate the discovery of novel mitophagy modulators.
    Keywords:  FACS; Fisetin; SI; autophagy; mitochondria; phenanthroline; retina
    DOI:  https://doi.org/10.3389/fcell.2024.1460061
  2. J Cell Mol Med. 2024 Sep;28(18): e70074
    Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection.
    Sohrab Rahmani, Ali Roohbakhsh, Vahid Pourbarkhordar, A Wallace Hayes, Gholamreza Karimi.
      Despite extensive progress in the knowledge and understanding of cardiovascular diseases and significant advances in pharmacological treatments and procedural interventions, cardiovascular diseases (CVD) remain the leading cause of death globally. Mitochondrial dynamics refers to the repetitive cycle of fission and fusion of the mitochondrial network. Fission and fusion balance regulate mitochondrial shape and influence physiology, quality and homeostasis. Mitophagy is a process that eliminates aberrant mitochondria. Melatonin (Mel) is a pineal-synthesized hormone with a range of pharmacological properties. Numerous nonclinical trials have demonstrated that Mel provides cardioprotection against ischemia/reperfusion, cardiomyopathies, atherosclerosis and cardiotoxicity. Recently, interest has grown in how mitochondrial dynamics contribute to melatonin cardioprotective effects. This review assesses the literature on the protective effects of Mel against CVD via the regulation of mitochondrial dynamics and mitophagy in both in-vivo and in-vitro studies. The signalling pathways underlying its cardioprotective effects were reviewed. Mel modulated mitochondrial dynamics and mitophagy proteins by upregulation of mitofusin, inhibition of DRP1 and regulation of mitophagy-related proteins. The evidence supports a significant role of Mel in mitochondrial dynamics and mitophagy quality control in CVD.
    Keywords:  cardiovascular disease; dynamin‐related protein 1; heart; melatonin; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.1111/jcmm.70074
  3. Autophagy. 2024 Sep 26.
    Quality control of mitochondria involves lysosomes in multiple definitive ways.
    Xiaowen Ma, Wen-Xing Ding.
      Mitochondria are crucial organelles in maintaining cellular homeostasis. They are involved in processes such as energy production, metabolism of lipids and glucose, and cell death regulation. Mitochondrial dysfunction can lead to various health issues such as aging, cancer, neurodegenerative diseases, and chronic liver diseases. While mitophagy is the main process for getting rid of excess or damaged mitochondria, there are additional mechanisms for preserving mitochondrial quality. One such alternative mechanism we have discovered is a hybrid organelle called mitochondrial-lysosome-related-organelle (MLRO), which functions independently of the typical autophagy process. More recently, another type of vesicle called vesicle derived from the inner mitochondrial membrane (VDIM) has been identified to break down the inner mitochondrial membrane without involving the standard autophagy pathway. In this article, we will delve into the similarities and differences between MLRO and VDIM, including their structure, regulation, and relevance to human diseases.
    Keywords:  Autophagy; DNM1L/DRP1; MLRO; VDIM; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2408712
  4. FASEB J. 2024 Sep 30. 38(18): e70066
    Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
    Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.
      Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.
    Keywords:  membrane fusion; membrane potential; mitochondria; mitochondrial dynamics; proteostasis; reactive oxygen species
    DOI:  https://doi.org/10.1096/fj.202400313R
  5. Obesity (Silver Spring). 2024 Sep 26.
    Differential mitochondrial adaptation and FNDC5 production in brown and white adipose tissue in response to cold and obesity.
    Gabriela Neira, Ana Wenting Hernández-Pardos, Sara Becerril, Beatriz Ramírez, Víctor Valentí, Rafael Moncada, Victoria Catalán, Javier Gómez-Ambrosi, María A Burrell, Camilo Silva, Javier Escalada, Gema Frühbeck, Amaia Rodríguez.
      OBJECTIVE: Fibronectin type III domain-containing protein 5 (FNDC5) modulates adipocyte metabolism by increasing white and brown adipose tissue (WAT and BAT) browning and activity, respectively. We investigated whether FNDC5 can regulate visceral WAT and BAT adaptive thermogenesis by improving mitochondrial homeostasis in response to cold and obesity.METHODS: Adipose tissue expression of FNDC5 and factors involved in mitochondrial homeostasis were determined in patients with normal weight and obesity (n = 159) and in rats with diet-induced obesity after 1 week of cold exposure (n = 61). The effect of different FNDC5 concentrations on mitochondrial biogenesis, dynamics, and mitophagy was evaluated in vitro in human adipocytes.
    RESULTS: In human visceral adipocytes, FNDC5/irisin triggered mitochondrial biogenesis (TFAM) and fusion (MFN1, MFN2, and OPA1) while inhibiting peripheral fission (DNM1L and FIS1) and mitophagy (PINK1 and PRKN). Circulating and visceral WAT expression of FNDC5 was decreased in patients and experimental animals with obesity, whereas its receptor, integrin αV, was upregulated. Obesity increased mitochondrial fusion while decreasing mitophagy in visceral WAT from patients and rats. By contrast, in rat BAT, an upregulation of Fndc5 and genes involved in mitochondrial biogenesis and fission was observed. Cold exposure promoted mitochondrial biogenesis and healthy peripheral fission while repressing Fndc5 expression and mitophagy in BAT from rats.
    CONCLUSIONS: Depot differences in FNDC5 production and mitochondrial adaptations in response to obesity and cold might indicate a self-regulatory mechanism to control thermogenesis in response to energy needs.
    DOI:  https://doi.org/10.1002/oby.24132
  6. Int J Med Sci. 2024 ;21(12): 2324-2333
    Modulating mitochondrial dynamics ameliorates left ventricular dysfunction by suppressing diverse cell death pathways after diabetic cardiomyopathy.
    Fumin Zhi, Xiangyi Pu, Wei Wei, Li Liu, Chunyan Liu, Ye Chen, Xing Chang, Hongtao Xu.
      Diabetic cardiomyopathy (DCM) triggers a detrimental shift in mitochondrial dynamics, characterized by increased fission and decreased fusion, contributing to cardiomyocyte apoptosis and cardiac dysfunction. This study investigated the impact of modulating mitochondrial dynamics on DCM outcomes and underlying mechanisms in a mouse model. DCM induction led to upregulation of fission genes (Drp1, Mff, Fis1) and downregulation of fusion genes (Mfn1, Mfn2, Opa1). Inhibiting fission with Mdivi-1 or promoting fusion with Ginsenoside Rg1 preserved cardiac function, as evidenced by improved left ventricular ejection fraction (LVEF), fractional shortening (FS), and E/A ratio. Both treatments also reduced infarct size and attenuated cardiomyocyte apoptosis, indicated by decreased caspase-3 activity. Mechanistically, Mdivi-1 enhanced mitochondrial function by improving mitochondrial membrane potential, reducing reactive oxygen species (ROS) production, and increasing ATP generation. Ginsenoside Rg1 also preserved mitochondrial integrity and function under hypoxic conditions in HL-1 cardiomyocytes. These findings suggest that restoring the balance of mitochondrial dynamics through pharmacological interventions targeting either fission or fusion may offer a promising therapeutic strategy for mitigating MI-induced cardiac injury and improving patient outcomes.
    Keywords:  cardiomyocyte apoptosis; diabetic cardiomyopathy; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.7150/ijms.98065
  7. Nat Commun. 2024 Sep 27. 15(1): 8274
    Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
    Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.
      A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52183-y
  8. J Lipid Res. 2024 Sep 18. pii: S0022-2275(24)00148-2. [Epub ahead of print] 100643
    Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
    Kailash Venkatraman, Christopher T Lee, Itay Budin.
      Mitochondrial membranes are defined by their diverse functions, complex geometries, and unique lipidomes. In the inner mitochondrial membrane (IMM), highly-curved membrane folds known as cristae house the electron transport chain and are the primary sites of cellular energy production. The outer mitochondrial membrane (OMM) is flat by contrast, but is critical for the initiation and mediation of processes key to mitochondrial physiology: mitophagy, inter-organelle contacts, fission and fusion dynamics and metabolite transport. While the lipid composition of both the IMM and OMM have been characterized across a variety of cell types, a mechanistic understanding for how individual lipid classes contribute to mitochondrial structure and function remains nebulous. In this review, we address the biophysical properties of mitochondrial lipids and their related functional roles. We highlight the intrinsic curvature of the bulk mitochondrial phospholipid pool, with an emphasis on the nuances surrounding the mitochondrially-synthesized cardiolipin. We also outline emerging questions about other lipid classes, ether lipids and sterols, with potential roles in mitochondrial physiology. We propose that further investigation is warranted to elucidate the specific properties of these lipids and their influence on mitochondrial architecture and function.
    Keywords:  Cardiolipin; Curvature; Mitochondria; Phospholipids; Plasmalogens; Sterols
    DOI:  https://doi.org/10.1016/j.jlr.2024.100643
  9. Cell Rep. 2024 Sep 21. pii: S2211-1247(24)01134-3. [Epub ahead of print]43(10): 114783
    Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.
    Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, Shafi Kuchay.
      Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.
    Keywords:  CP: Metabolism; CP: Molecular biology; E3-ligase; F-box protein; FBXO10; HSP90; PDE6δ; mitochondria; prenylation; trafficking; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2024.114783
  10. Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01131-8. [Epub ahead of print]43(10): 114780
    Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
    Jiawei Yan, Xin Zhang, Huiying Wang, Xinglong Jia, Ruohong Wang, Shuangyang Wu, Zheng-Jiang Zhu, Minjia Tan, Tiffany Horng.
      Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.
    Keywords:  CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114780
  11. Exp Gerontol. 2024 Sep 24. pii: S0531-5565(24)00235-3. [Epub ahead of print]197 112589
    Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy.
    Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.
      Mitochondrial dysfunction with aging is associated with the development of age-related hearing loss. Mitophagy is a cardinal mechanism to maintain a healthy mitochondrial population through the turnover of damaged mitochondria. Declining mitophagy with age causes a buildup of damaged mitochondria, leading to sensory organ dysfunction. The effect of Urolithin A (UA), a mitophagy inducer, was investigated on age-related hearing loss in a mouse model. C57BL/6J mice were treated with UA from 6 to 10 months of age. UA attenuated an auditory brainstem responses (ABR) threshold shift at 8, 16, and 32 kHz frequencies, and improved mitochondrial DNA integrity and ATP production in the cochlea and auditory cortex. The mRNA levels of mitophagy-related genes and protein levels of PINK1, Parkin, BNIP3, and LC3B increased in the cochlea and auditory cortex. The expression of mitophagosomes and mitophagolysosomes in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus increased, together with the expression of Parkin and BNIP3 in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus. These results indicate that UA counteracted mitophagy decline in the auditory system and prevented age-related hearing loss. UA can be used as a potential agent to prevent age-related hearing loss.
    Keywords:  Age-related hearing loss; Mitochondria; Mitophagy; Urolithin A
    DOI:  https://doi.org/10.1016/j.exger.2024.112589
  12. Mater Today Bio. 2024 Oct;28 101240
    In vivo targeted-imaging of mitochondrial acidification in an aristolochic acid I-induced nephrotoxicity mouse model by a fluorescent/photoacoustic bimodal probe.
    Li Xu, Li Chen, Hongwen Liu, Xingwang Chen, Shenghang Zhang.
      Aristolochic acid I (AAI), a natural compound in aristolochia type Chinese medicinal herb, is generally acknowledged to have nephrotoxicity, which may be associated with mitophagy. Mitophagy is a cellular process with important functions that drive AAI-induced renal injury. Mitochondrial pH is currently measured by fluorescent probes in cell culture, but existing probes do not allow for in situ imaging of AAI-induced mitophagy in vivo. We developed a ratiometric fluorescent/PA dual-modal probe with a silicon rhodamine fluorophore and a pH-sensitive hemicyanine dye covalently linked via a short chain to obtain a FRET type probe. The probe was used to measure AAI-mediated mitochondrial acidification in live cells and in vivo. The Förster resonance energy transfer (FRET)-mediated ratiometric and bimodal method can efficiently eliminate signal variability associated with the commonly used one-emission and single detection mode by ratiometric two channels of the donor and acceptor. The probe has good water-solubility and low molecular weight with two positively charged, facilitating its precise targeting into renal mitochondria, where the fluorescent/PA changes in response to mitochondrial acidification, enabling dynamic and semi-quantitative mapping of subtle changes in mitochondrial pH in AAI-induced nephrotoxicity mouse model for the first time. Also, the joint use of L-carnitine could mitigate the mitophagy in AAI-induced nephrotoxicity.
    Keywords:  Aristolochic acid; Fluorescent imaging; In vivo mitophagy; Nephrotoxicity; Photoacoustic imaging
    DOI:  https://doi.org/10.1016/j.mtbio.2024.101240
  13. J Cell Physiol. 2024 Sep 22. e31448
    N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy.
    Pingping Qi, Wei Zhang, Yang Gao, Shengkui Chen, Minghe Jiang, Rong He, Wenzhong Chen, Xiawei Wei, Bingquan Hu, Hao Xu, Minsheng Wu, Rong Tang.
      N6-methyladenosine (m6A) is known to be crucial in various biological processes, but its role in sepsis-induced circulatory and cardiac dysfunction is not well understood. Specifically, mitophagy, a specialized form of autophagy, is excessively activated during lipopolysaccharide (LPS)-induced myocardial injury. This study aimed to investigate the impact of LPS-induced endotoxemia on m6A-RNA methylation and its role in regulating mitophagy in sepsis-induced myocardial dysfunction. Our research demonstrated that FTO (fat mass and obesity-associated protein), an m6A demethylase, significantly affects abnormal m6A modification in the myocardium and cardiomyocytes following LPS treatment. In mice, cardiac dysfunction and cardiomyocyte apoptosis worsened after adeno-associated virus serotype 9 (AAV9)-mediated FTO knockdown. Further analyses to uncover the cellular mechanisms improving cardiac function showed that FTO reduced mitochondrial reactive oxygen species, restored both basal and maximal respiration, and preserved mitochondrial membrane potential. We revealed that FTO plays a critical role in activating mitophagy by targeting BNIP3. Additionally, the cardioprotective effects of AAV-FTO were significantly compromised by mdivi-1, a mitophagy inhibitor. Mechanistically, FTO interacted with BNIP3 transcripts and regulated their expression in an m6A-dependent manner. Following FTO silencing, BNIP3 transcripts with elevated m6A modification levels in their coding regions were bound by YTHDF2 (YT521-B homology m6A RNA-binding protein 2), leading to mRNA destabilization and decreased BNIP3 protein levels. These findings highlight the importance of FTO-dependent cardiac m6A methylation in regulating mitophagy and enhance our understanding of this critical interplay, which is essential for developing therapeutic strategies to protect cardiac mitochondrial function, alleviate cardiac dysfunction, and improve survival during sepsis.
    Keywords:  BNIP3; FTO; N6‐methyladenosine; mitophagy; sepsis
    DOI:  https://doi.org/10.1002/jcp.31448
  14. Cells. 2024 Sep 13. pii: 1540. [Epub ahead of print]13(18):
    Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.
    Bernardo A Bustillos, Liam T Cocker, Mathew A Coban, Caleb A Weber, Jenny M Bredenberg, Paige K Boneski, Joanna Siuda, Jaroslaw Slawek, Andreas Puschmann, Derek P Narendra, Neill R Graff-Radford, Zbigniew K Wszolek, Dennis W Dickson, Owen A Ross, Thomas R Caulfield, Wolfdieter Springer, Fabienne C Fiesel.
      Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.
    Keywords:  PINK1; PRKN; Parkinson disease; mitophagy; parkin; ubiquitin
    DOI:  https://doi.org/10.3390/cells13181540
  15. Autoimmun Rev. 2024 Sep 19. pii: S1568-9972(24)00135-6. [Epub ahead of print]23(11): 103644
    Inclusion body myositis: Correcting impaired mitochondrial and lysosomal autophagy as a potential therapeutic strategy.
    Stefen Brady, Joanna Poulton, Sylviane Muller.
      Inclusion body myositis (IBM) is a late onset sporadic myopathy with a characteristic clinical presentation, but as yet unknown aetiology or effective treatment. Typical clinical features are early predominant asymmetric weakness of finger flexor and knee extensor muscles. Muscle biopsy shows endomysial inflammatory infiltrate, mitochondrial changes, and protein aggregation. Proteostasis (protein turnover) appears to be impaired, linked to potentially dysregulated chaperone-mediated autophagy and mitophagy (a type of mitochondrial quality control). In this review, we bring together the most recent clinical and biological data describing IBM. We then address the question of diagnosing this pathology and the relevance of the current biological markers that characterize IBM. In these descriptions, we put a particular emphasis on data related to the deregulation of autophagic processes and to the mitochondrial-lysosomal crosstalk. Finally, after a short description of current treatments, an overview is provided pointing towards novel therapeutic targets and emerging regulatory molecules that are being explored for treating IBM. Special attention is paid to autophagy inhibitors that may offer innovative breakthrough therapies for patients with IBM.
    Keywords:  Autoimmunity; Autophagy; Idiopathic inflammatory myopathies; Inclusion body myositis; Mitochondrial disease; Novel treatment
    DOI:  https://doi.org/10.1016/j.autrev.2024.103644
  16. Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]
    Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
    N Moradi, V C Sanfrancesco, S Champsi, D A Hood.
      Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.028
  17. Biochem Biophys Res Commun. 2024 Sep 19. pii: S0006-291X(24)01252-X. [Epub ahead of print]733 150716
    Icariin alleviates cellular injury induced by cardiac ischemia-reperfusion injury by inhibiting IRE1/JNK-induced ferroptosis.
    Zanrui Zhong, Kun Yang, Shilin Tang, Tianyi Ma.
      BACKGROUND: Ischemia-induced cellular damage and stress responses significantly impact cellular viability and function. Icariin (ICA), known for its protective effects, has been studied to understand its role in mitigating oxygen-glucose deprivation/reperfusion (OGD/R)-induced endoplasmic reticulum (ER) stress and ferroptosis in H9C2 cardiomyoblast cells.METHODS: We employed an in vitro OGD/R model using H9C2 cells. ICA's effects were analyzed across multiple concentrations. Key indicators of ER stress, autophagy, and ferroptosis-including markers like Bip, PERK, IRE1, ATF6, P62, FTH1, LC3II/LC3I, and NCOA4-were assessed using Western blotting, electron microscopy, and biochemical assays. Additionally, the role of the IRE1/JNK pathway in mitochondrial dynamics and its influence on mitochondrial dynamics protein was explored through specific inhibition and activation experiments.
    RESULTS: ICA significantly reduced the activation of UPR pathways, decreased autophagic vacuole formation, and maintained cell viability in response to OGD/R and Erastin-induced ferroptosis. These protective effects were associated with modulated autophagic processes, reduced lipid peroxidation, and decreased ferrous ion accumulation. Inhibition of the IRE1/JNK pathway and subsequent Drp1 activity demonstrated reduced mitochondrial recruitment and mitophagy, correlating with decreased ferroptosis markers and improved cell survival.
    CONCLUSION: Our findings highlight ICA's potential in modulating IRE1/JNK pathway, autophagy, providing a therapeutic avenue for mitigating ferroptosis in myocardial ischemia-reperfusion injury (MIRI).
    Keywords:  Autophagy; ER stress; Ferroptosis; Mitophagy; Oxygen-glucose deprivation/reperfusion; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150716
  18. Mech Ageing Dev. 2024 Sep 20. pii: S0047-6374(24)00093-9. [Epub ahead of print]222 111993
    The role of mitochondria in cytokine and chemokine signalling during ageing.
    Maria Kalykaki, Teresa Rubio-Tomás, Nektarios Tavernarakis.
      Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPRmt, in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.
    Keywords:  Age-related disease; Chemokine; Cytokine; Inflammageing; Mitochondrial dysfunction; Senescence
    DOI:  https://doi.org/10.1016/j.mad.2024.111993
  19. Free Radic Biol Med. 2024 Sep 20. pii: S0891-5849(24)00676-2. [Epub ahead of print]224 757-769
    Ubiquitination of ATAD3A by TRIM25 exacerbates cerebral ischemia-reperfusion injury via regulating PINK1/Parkin signaling pathway-mediated mitophagy.
    Xin Li, Liyang Guan, Zhi'en Liu, Zaixing Du, Qianhui Yuan, Fuxin Zhou, Xiaobo Yang, Mei Lv, Li Lv.
      BACKGROUND: Cerebral ischemia-reperfusion injury (CI/RI) is a complex process leading to neuronal damage and death, with mitophagy implicated in its pathogenesis. However, the significance of mitophagy in CI/RI remains debated.HYPOTHESIS: We hypothesized that TRIM25 reduces ATAD3A expression by ubiquitinating ATAD3A, promoting mitophagy via the PINK1/Parkin pathway, and aggravating CI/RI.
    STUDY DESIGN: Rat middle cerebral artery occlusion (MCAO) followed by reperfusion and oxygen-glucose deprivation and reoxygenation (OGD/R) in PC12 cells were used as animal and cell models, respectively.
    METHODS: To evaluate the success of the CI/R modeling, TTC and HE staining were employed. The determination of serum biochemical indexes was carried out using relative assay kits. The Western Blot analysis was employed to assess the expression of ATAD3A, TRIM25, as well as mitophagy-related proteins (PINK1, Parkin, P62, and LC3II/LC3I). The mRNA levels were detected using QRT-PCR. Mitochondrial membrane potential was assessed through JC-1 staining. Mitosox Red Assay Kit was utilized to measure mitochondrial reactive oxygen species levels in PC12 cells. Additionally, characterization of the mitophagy structure was performed using transmission electron microscopy (TEM).
    RESULTS: Our findings showed down-regulation of ATAD3A and up-regulation of TRIM25 in both in vivo and in vitro CI/RI models. Various experimental techniques such as Western Blot, JC-1 staining, Mitosox assay, Immunofluorescence assay, and TEM observation supported the occurrence of PINK1/Parkin signaling pathway-mediated mitophagy in both models. ATAD3A suppressed mitophagy, while TRIM25 promoted it during CI/RI injury. Additionally, the results indicated that TRIM25 interacted with and ubiquitinated ATAD3A via the proteasome pathway, affecting ATAD3A protein stability and expression.
    CONCLUSION: TRIM25 promoted Pink1/Parkin-dependent excessive mitophagy by destabilizing ATAD3A, exacerbating CI/RI. Targeting TRIM25 and ATAD3A may offer therapeutic strategies for mitigating CI/RI and associated neurological damage.
    Keywords:  ATAD3A; Cerebral ischemia-reperfusion injury; Mitophagy; PINK1/Parkin pathway; TRIM25
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.029
  20. Int J Biol Macromol. 2024 Sep 25. pii: S0141-8130(24)06788-6. [Epub ahead of print] 135979
    HSP90-regulated mitophagy can alleviate heat stress damage by inhibiting pyroptosis in the hepatocytes of Wenchang chickens.
    Jiachen Shi, Chengyun Li, Qijun Liang, Yujie Yao, Zeping Ji, Menglin Zhou, Jiawei Cai, Xu Yao, Xiaohui Zhang.
      Heat shock protein 90 (HSP90) has a recognized anti-heat stress injury effect, but its function and corresponding molecular mechanism in heat-stressed hepatocytes are not fully understood, especially in tropical animals. In the present study, we identified several key factors affecting resistance to injury liver tissues from heat-stressed Wenchang chickens (a typical tropical species), such as HSP90, cellular pyroptosis and mitophagy. Heat stress upregulated the NLRP3/Caspase-1/GSDMD-N-mediated cellular pyroptosis pathway and the Pink1/Parkin-mediated mitophagy pathway in chicken hepatocytes, accompanied by the upregulation of HSP90. We also found that HSP90 overexpression significantly reduced heat stress-induced hepatocyte pyroptosis and enhanced mitophagy in primary hepatocytes from Wenchang chickens (PHWCs). HSP90 knockdown significantly increased heat stress-induced hepatocyte pyroptosis and decreased mitophagy in PHWCs. Interestingly, we performed immunoprecipitation and immunofluorescence colocalization and found that HSP90 and Pink1 can interact and directly regulate the level of mitophagy in PHWCs. Our results suggest that HSP90, which regulates Pink1, is an important factor in mitophagy that attenuates heat stress injury by inhibiting cellular pyroptosis.
    Keywords:  Cellular pyroptosis; HSP90; Mitophagy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135979
  21. Free Radic Biol Med. 2024 Sep 21. pii: S0891-5849(24)00677-4. [Epub ahead of print]224 740-756
    Hederagenin inhibits mitochondrial damage in Parkinson's disease via mitophagy induction.
    Xiaoqian Li, Mengling Hu, Xiaogang Zhou, Lu Yu, Dalian Qin, Jianming Wu, Lan Deng, Lufeng Huang, Fang Ren, Bin Liao, Anguo Wu, Dongsheng Fan.
      BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons and the formation of α-synuclein aggregates. Mitochondrial dysfunction and oxidative stress are pivotal in PD pathogenesis, with impaired mitophagy contributing to the accumulation of mitochondrial damage. Hederagenin (Hed), a natural triterpenoid, has shown potential neuroprotective effects; however, its mechanisms of action in PD models are not fully understood.METHOD: We investigated the effects of Hed on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in SH-SY5Y cells by assessing cell viability, mitochondrial function, and oxidative stress markers. Mitophagy induction was evaluated using autophagy and mitophagy inhibitors and fluorescent staining techniques. Additionally, transgenic Caenorhabditis elegans (C. elegans) models of PD were used to validate the neuroprotective effects of Hed in vivo by focusing on α-synuclein aggregation, mobility, and dopaminergic neuron integrity.
    RESULTS: Hed significantly enhanced cell viability in 6-OHDA-treated SH-SY5Y cells by inhibiting cell death and reducing oxidative stress. It ameliorated mitochondrial damage, evidenced by decreased mitochondrial superoxide production, restored membrane potential, and improved mitochondrial morphology. Hed also induced mitophagy, as shown by increased autophagosome formation and reduced oxidative stress; these effects were diminished by autophagy and mitophagy inhibitors. In C. elegans models, Hed activated mitophagy and reduced α-synuclein aggregation, improved mobility, and mitigated the loss of dopaminergic neurons. RNA interference targeting the mitophagy-related genes pdr-1 and pink-1 partially reversed these benefits, underscoring the role of mitophagy in Hed's neuroprotective actions.
    CONCLUSION: Hed exhibits significant neuroprotective effects in both in vitro and in vivo PD models by enhancing mitophagy, reducing oxidative stress, and mitigating mitochondrial dysfunction. These findings suggest that Hed holds promise as a therapeutic agent for PD, offering new avenues for future research and potential drug development.
    Keywords:  6-OHDA; Caenorhabditis elegans; Hederagenin; Mitochondrial dysfunction; Mitophagy; Parkinson's disease; α-synuclein
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.030
  22. Ecotoxicol Environ Saf. 2024 Sep 20. pii: S0147-6513(24)01142-4. [Epub ahead of print]285 117066
    The role of Drp1 - Pink1 - Parkin - mediated mitophagy in perfluorobutane sulfonate- induced hepatocyte damage.
    Yuan Feng, Yongheng Huang, Bin Lu, Jianliang Xu, Hui Wang, Fei Wang, Nan Lin.
      Perfluorobutane sulfonate (PFBS) is recognized as a highly persistent environmental contaminant, notorious for its chemical stability and enduring presence in ecosystems. Its propensity for persistence and environmental mobility allows PFBS to infiltrate the human body, predominantly accumulating in the liver where it poses a potential risk for hepatic damage. This investigation aimed to explore the outcomes of PFBS on the physiological functionalities of hepatocytes in vitro. To this end, hepatocytes were exposed to 750 ug/ml PFBS, followed by an analysis of various cellular phenotypes and functionalities, including assessments of cell viability and mitochondrial integrity. The findings indicated that PFBS exposure led to a suppression of cell proliferation and an increase in apoptotic cell death. Moreover, PFBS exposure was found to augment the generation of reactive oxygen species (ROS) and induce significant mitochondrial dysfunction. Gene expression analysis identified significant changes in genes associated with numerous tumor signaling pathways and autophagy signaling pathways. Further examinations revealed an increase in cellular mitophagy following PFBS exposure, coupled with the activation of the mitophagy-associated Drp1/Pink1/Parkin pathway. Inhibition of mitophagy was observed to concurrently amplify cellular damage and inhibit the Drp1/Pink1/Parkin pathway. Together, these findings highlight PFBS's capacity to inflict hepatocyte injury through mitochondrial disruption, positioning Drp1/Pink1/Parkin-mediated mitophagy as a crucial cellular defense mechanism against PFBS-induced toxicity.
    Keywords:  Apoptosis; Cytotoxicity; Mitophagy; PFBS; ROS
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117066
  23. Int Immunopharmacol. 2024 Sep 26. pii: S1567-5769(24)01721-1. [Epub ahead of print]142(Pt B): 113199
    NPLOC4 aggravates heart failure by regulating ROS and mitochondrial function.
    Kaidi Ren, Yi Luan, Yuanyuan Sun, Siyuan Huang, Shuwei Zhang, Yang Yang, Yage Jin, Xing Chen.
      Heart failure (HF) is a leading cause of morbidity and mortality worldwide, necessitating the discovery of new therapeutic targets. NPLOC4 is known as an endoplasmic reticulum protein involved in protein degradation and cellular stress responses. Herein, NPLOC4 was investigated for its role in HF using a transverse aortic constriction (TAC) mouse model and an Angiotensin II (Ang II)-induced H9c2 cardiomyocyte model. Transcriptomic analysis revealed NPLOC4 upregulation in HF. NPLOC4 knockdown in the TAC model inhibited HF progression, as evidenced by reduced cardiac hypertrophy and fibrosis. Subsequent knockdown experiments showed the relievement in heart failure phenotypes, reduced reactive oxygen species (ROS) levels and enhanced mitochondrial function caused by NPLOC4 depletion in Ang II-induced H9c2 cells. STRING analysis predicted ERO1α as a potential NPLOC4 interactor, with further studies identifying that NPLOC4 knockdown increases ERO1α expression and disrupts mitochondria-associated membranes (MAMs). Additionally, NPLOC4 knockdown modulated the β-catenin/GSK3β pathway, enhancing mitochondrial dynamics and mitophagy. These findings suggest NPLOC4 as a promising therapeutic target for HF.
    Keywords:  ERO1α; Heart failure; Mitochondrial function; NPLOC4; β-catenin/GSK3β pathway
    DOI:  https://doi.org/10.1016/j.intimp.2024.113199
  24. Clin Respir J. 2024 Sep;18(9): e70004
    Linoleic Acid Promotes Mitochondrial Biogenesis and Alleviates Acute Lung Injury.
    Jie Liu, Yu Jiang, Qiuhong Zhang, Yin Qin, Kexin Li, Yu Xie, Tingting Zhang, Xiaoliang Wang, Xi Yang, Li Zhang, Gang Liu.
      INTRODUCTION: Acute lung injury (ALI) is a critical and lethal medical condition. This syndrome is characterized by an imbalance in the body's oxidation stress and inflammation. Linoleic acid (LA), a polyunsaturated fatty acid, has been extensively studied for its potential health benefits, including anti-inflammatory and antioxidant activities. However, the therapeutic effects of LA on ALI remain unexplored.METHODS: Lipopolysaccharide (LPS), found in gram-negative bacteria's outer membrane, was intraperitoneally injected to induce ALI in mice. In vitro model was established by LPS stimulation of mouse lung epithelial 12 (MLE-12) cells.
    RESULTS: LA treatment demonstrated a significant amelioration in LPS-induced hypothermia, poor state, and pulmonary injury in mice. LA treatment resulted in a reduction in the concentration of bronchoalveolar lavage fluid (BALF) protein and an increase in myeloperoxidase (MPO) activity in LPS-induced mice. LA treatment reduced the generation of white blood cells. LA treatment reduced cell-free (cfDNA) release and promote adenosine triphosphate (ATP) production. LA increased the levels of superoxide dismutase (SOD) and glutathione (GSH) but decreased the production of malondialdehyde (MDA). LA treatment enhanced mitochondrial membrane potential. LA attenuated LPS-induced elevations of inflammatory cytokines in both mice and cells. Additionally, LA exerted its protective effect against LPS-induced damage through activation of the peroxisome proliferator-activated receptor γ coactivator l alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/transcription factor A of the mitochondrion (TFAM) pathway.
    CONCLUSION: LA may reduce inflammation and stimulate mitochondrial biogenesis in ALI mice and MLE-12 cells.
    Keywords:  PGC‐1α; acute lung injury; inflammation; linoleic acid; lipopolysaccharide; mitochondrial biogenesis
    DOI:  https://doi.org/10.1111/crj.70004
  25. Res Sq. 2024 Sep 10. pii: rs.3.rs-4870330. [Epub ahead of print]
    FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.
    Swati Maitra, Minwoo Baek, Yun-Jeong Choe, Nam Chul Kim.
      Background Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 ( CHCHD10 ) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10 S59L , and human cell models expressing CHCHD10 S59L , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 S59L . Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 S59L -induced diseases. Methods An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10 S59L mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance. Results We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 S59L -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 S59L -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H S81L . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 S59L . Conclusion These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 S59L -induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.
    DOI:  https://doi.org/10.21203/rs.3.rs-4870330/v1
  26. J Microbiol Biotechnol. 2024 Sep 09. 34(11): 1-8
    Establishment of an Apical-Out Organoid Model for Directly Assessing the Function of Postbiotics.
    Yeonoh Cho, Moon-Hee Sung, Hee-Taik Kang, Jong Hun Lee.
      In vitro organoids that mimic the physiological properties of in vivo organs based on threedimensional cell cultures overcome the limitations of two-dimensional culture systems. However, because the lumen of a typical intestinal organoid is internal, we used an apical-out intestinal organoid model in which the lumen that absorbs nutrients is outside to directly assess the function of postbiotics. A composite culture supernatant of Lactiplantibacillus plantarum KM2 and Bacillus velezensis KMU01 was used as a postbiotic treatment. Expression of COX-2 decreased in apical-out organoids co-treated with a lipopolysaccharide (LPS) and postbiotics. Expression of tight-junction markers such as ZO-1, claudin, and Occludin increased, and expression of mitochondrial homeostasis factors such as PINK1, parkin, and PGC1a also increased. As a result, small and large intestine organoids treated with postbiotics protected tight junctions from LPS-induced damage and maintained mitochondrial homeostasis through mitophagy and mitochondrial biogenesis. This suggests that an apical-out intestinal organoid model can confirm the function of food ingredients.
    Keywords:  Apical-out organoid; mitochondria homeostasis; postbiotics; tight junction
    DOI:  https://doi.org/10.4014/jmb.2405.05034
  27. Biochim Biophys Acta Mol Basis Dis. 2024 Sep 25. pii: S0925-4439(24)00521-0. [Epub ahead of print] 167527
    SENP1 prevents high fat diet-induced non-alcoholic fatty liver diseases by regulating mitochondrial dynamics.
    Wenjing Zeng, Li Wang, Chaowen Wang, Xiaowei Xiong, Qianqian Huang, Sheng Chen, Chen Liu, Wentao Liu, Yuan Wang, Qiren Huang.
      Mitochondrial dynamics plays a crucial role in the occurrence and development of non-alcoholic fatty liver diseases (NAFLD). SENP1, a SUMO-specific protease, catalyzes protein de-SUMOylation and involves in various physiological and pathological processes. However, the exact role of SENP1 in NAFLD remains unclear. Therefore, we investigated the regulatory role of SENP1 in mitochondrial dynamics during the progression of NAFLD. In the study, the NAFLD in vivo model induced by high fat diet (HFD) and in vitro model induced by free fatty acids (FFA) were established to investigate the role and underlying mechanism of SENP1 through detecting mitochondrial morphology and dynamics. Our results showed that the down-regulation of SENP1 expression and the mitochondrial dynamics dysregulation occurred in the NAFLD, evidenced as mitochondrial fragmentation, up-regulation of p-Drp1 ser616 and down-regulation of MFN2, OPA1. However, over-expression of SENP1 significantly alleviated the NAFLD, rectified the mitochondrial dynamics disorder, reduced Cyt-c release and ROS levels induced by FFA or HFD; moreover, the over-expression of SENP1 also reduced the SUMOylation levels of Drp1 and prevented the Drp1 translocation to mitochondria. Our findings suggest that the possible mechanisms of SENP1 were through rectifying the mitochondrial dynamics disorder, reducing Cyt-c release and ROS-mediated oxidative stress. The findings would provide a novel target for the prevention and treatment of NALFD.
    Keywords:  Drp1; Mitochondrial dynamics; Non-alcoholic fatty liver disease; SENP1; SUMOylation
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167527
  28. Biochem Biophys Rep. 2024 Dec;40 101827
    Epigenetic regulation of the human GDAP1 gene.
    Kaja Karaś, Joanna Pastwińska, Anna Sałkowska, Iwona Karwaciak, Marcin Ratajewski.
      Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are linked to Charcot-Marie-Tooth (CMT) disease, a hereditary neurodegenerative condition. The protein encoded by this gene is involved in mitochondrial fission and calcium homeostasis. Recently, GDAP1 has also been implicated in the survival of patients with certain cancers. Despite its significant role in specific cellular processes and associated diseases, the mechanisms regulating GDAP1 expression are largely unknown. Here, we show for the first time that methylation of the CpG island in the proximal promoter of the GDAP1 gene inhibits its activity. Treating cells with low GDAP1 expression using methyltransferase and HDAC inhibitors induced the expression of this gene and its encoded protein. This induction was associated with promoter demethylation and increased association of acetylated histones with the GDAP1 promoter. Thus, we identified a mechanism that could be used to manipulate GDAP1 expression.
    Keywords:  CpG island; DNA methylation; Epigenetics; GDAP1; Histone acetylation
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101827
  29. Diseases. 2024 Sep 23. pii: 226. [Epub ahead of print]12(9):
    Mitochondrial Dysfunction in Systemic Lupus Erythematosus: Insights and Therapeutic Potential.
    Anastasia V Poznyak, Nikolay A Orekhov, Alexey V Churov, Irina A Starodubtseva, Dmitry F Beloyartsev, Tatiana I Kovyanova, Vasily N Sukhorukov, Alexander N Orekhov.
      Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by the presence of various serum autoantibodies and multi-system effects, predominantly affecting young female patients. The pathogenesis of SLE involves a combination of genetic factors, environmental triggers, and pathogen invasions that disrupt immune cell activation, leading to the release of autoantibodies and chronic inflammation. Mitochondria, as the primary cellular powerhouses, play a crucial role in SLE development through their control of energy generation, reactive oxygen species (ROS) production, and cellular apoptotic pathways. Dysregulation of mitochondrial structure and function can contribute to the immune dysregulation, oxidative stress, and inflammation seen in SLE. Recent research has highlighted the impact of mitochondrial dysfunction on various immune cells involved in SLE pathogenesis, such as T-lymphocytes, B-lymphocytes, neutrophils, and plasmacytoid dendritic cells. Mitochondrial dysfunction in these immune cells leads to increased ROS production, disrupted mitophagy, and alterations in energy metabolism, contributing to immune dysregulation and inflammation. Moreover, genetic variations in mitochondrial DNA (mtDNA) and abnormalities in mitochondrial dynamics have been linked to the pathogenesis of SLE, exacerbating oxidative stress and immune abnormalities. Targeting mitochondrial function has emerged as a promising therapeutic approach for SLE. Drugs such as sirolimus, N-acetylcysteine, coenzyme Q10, and metformin have shown potential in restoring mitochondrial homeostasis, reducing oxidative stress, and modulating immune responses in SLE. These agents have demonstrated efficacy in preclinical models and clinical studies by improving disease activity, reducing autoantibody titers, and ameliorating organ damage in SLE patients. In conclusion, this review underscores the critical role of mitochondria in the pathogenesis of SLE and the potential of targeting mitochondrial dysfunction as a novel therapeutic strategy for improving outcomes in SLE patients. Further investigation into the mechanisms underlying mitochondrial involvement in SLE and the development of targeted mitochondrial therapies hold promise for advancing SLE treatment and enhancing patient care.
    Keywords:  autoimmune disease; immune responses; inflammation; mitochondria; rheumatic diseases
    DOI:  https://doi.org/10.3390/diseases12090226
  30. Circ Res. 2024 Sep 27.
    Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
    Akira Yoshii, Timothy S McMillen, Yajun Wang, Bo Zhou, Hongye Chen, Durba Banerjee, Melisa Herrero, Pei Wang, Naoto Muraoka, Wang Wang, Charles E Murry, Rong Tian.
      BACKGROUND: Metabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood.METHODS: In a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31P NMR spectroscopy and substrate oxidation profile was assessed by 13C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes.
    RESULTS: HFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes.
    CONCLUSIONS: Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation.
    Keywords:  arginine methyl ester; fatty acids; heart diseases; mitophagy; ventricular dysfunction, left
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324103
  31. Curr Issues Mol Biol. 2024 Sep 18. 46(9): 10411-10429
    Integrative Analyses of Mitophagy-Related Genes and Mechanisms Associated with Type 2 Diabetes in Muscle Tissue.
    Wangjia Mao, Guannan Zong, Yuan Gao, Shen Qu, Xiaoyun Cheng.
      Type 2 diabetes (T2D) represents the most prevalent metabolic condition that is primarily distinguished by a range of metabolic imbalances, including hyperglycemia, hyperlipidemia, and insulin resistance (IR). Currently, mitophagy has become increasingly recognized as an important process involved in the pathogenesis and progression of T2D. Therefore, it is very important to explore the role of mitochondrial damage and autophagy-related genes in T2D. This study investigated the role of mitophagy in the development of T2D, and 12 MRHGs associated with T2D were identified using bioinformatic analysis and machine learning methods. Our findings provide the first insight into mitophagy-related genes and their mechanisms in T2D. This study aimed to investigate possible molecular targets for therapy and the underlying mechanisms involved in T2D. This information might be useful to further elucidate the pathogenesis of T2D-related diseases and identify more optimal therapeutic approaches.
    Keywords:  Type 2 diabetes; autophagy-related genes; mitophagy; molecular mechanisms; pathogenesis
    DOI:  https://doi.org/10.3390/cimb46090619
  32. J Ethnopharmacol. 2024 Sep 24. pii: S0378-8741(24)01161-9. [Epub ahead of print]337(Pt 2): 118862
    The suppressive effects of crocin from saffron on allergic airway inflammation through Drp1/Nfr1/Mfn2/Pgc1-alpha signaling pathway in mice.
    Fatima Abbasi Moajani, Narges Soozangar, Mojtaba Amani, Farhad Jeddi, Ramin Salimnejad, Mohammad Reza Aslani.
      ETHNOPHARMACOLOGICAL RELEVANCE: Saffron is derived from the dried stigmas of Crocus sativus L., which was considered by ancient nations for food and medicinal purposes. In traditional medicine, the therapeutic use of Crocus sativus includes antispasmodic, antitussive and expectorant.AIM OF THE STUDY: Mitochondrial fusion, fission, biogenesis, and mitophagy are essential processes for maintaining mitochondrial dynamics in response to cellular stress. The primary objective of this research was to examine how crocin affected the levels of important mitochondrial regulators, including Drp1, Pgc1α, Nrf1, and Mfn2, in the lung tissue of ovalbumin-sensitized mice.
    MATERIALS AND METHODS: A total of fifty male BALB/C mice were randomly assigned to five unique groups (n = 10 for each group), including the control group, ovalbumin-sensitized group (OVA), OVA group treated with 30 mg/kg of crocin, OVA group treated with 60 mg/kg of crocin, and OVA group treated with 1 mg/kg of dexamethasone. Post-sensitization and ovalbumin challenge, mice lung tissues were evaluated for the expression of Drp1, Pgc1α, Nrf1, and Mfn2 mRNA levels using real-time PCR as well as histopathological assessments.
    RESULTS: In the OVA group, there was a significant elevated in inflammatory cells such as eosinophils, neutrophils, macrophages, and lymphocytes; however, crocin (both concentrations) and dexamethasone intervention showed significant inhibitory effects (P < 0.01 to P < 0.001). Moreover, an increase in the expression of Drp1, Pgc1α, and Nrf1 levels was seen in the OVA group, while crocin and dexamethasone showed protective benefits (P < 0.05 to P < 0.001). Furthermore, the levels of Mfn2 were reduced in the lung tissue of mice exposed to ovalbumin, but this decrease was reversed by crocin 60 (P < 0.05) and dexamethasone treatment (P < 0.001).
    CONCLUSION: In mice with OVA sensitization, the balance of mitochondrial dynamics in lung tissue was disrupted, but intervention of crocin identified to have a protective effect.
    Keywords:  Asthma; Crocin; Mitochondria; Ovalbumin sensitization; Saffron
    DOI:  https://doi.org/10.1016/j.jep.2024.118862
  33. Cancer Metastasis Rev. 2024 Sep 23.
    The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy.
    Fanglu Chen, Yucheng Xue, Wenkan Zhang, Hao Zhou, Zhiyi Zhou, Tao Chen, Eloy YinWang, Hengyuan Li, Zhaoming Ye, Junjie Gao, Shengdong Wang.
      Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.
    Keywords:  Immunotherapy; Metabolism; Mitochondria transfer; Mitochondrial genetics; Mitophagy; Tumor metastasis
    DOI:  https://doi.org/10.1007/s10555-024-10211-9
  34. PLoS One. 2024 ;19(9): e0310947
    PPARγ agonist alleviates calcium oxalate nephrolithiasis by regulating mitochondrial dynamics in renal tubular epithelial cell.
    Junfa Liu, Xingyang Liu, Lizhe Guo, Xiongfei Liu, Qian Gao, E Wang, Zhitao Dong.
      BACKGROUND: Kidney stone formation is a common disease that causes a significant threat to human health. The crystallization mechanism of calcium oxalate, the most common type of kidney stone, has been extensively researched, yet the damaging effects and mechanisms of calcium oxalate crystals on renal tubular epithelial cells remain incompletely elucidated. Regulated mitochondrial dynamics is essential for eukaryotic cells, but its role in the occurrence and progression of calcium oxalate (CaOx) nephrolithiasis is not yet understood.METHODS: An animal model of calcium oxalate-related nephrolithiasis was established in adult male Sprague‒Dawley (SD) rats by continuously administering drinking water containing 1% ethylene glycol for 28 days. The impact of calcium oxalate crystals on mitochondrial dynamics and apoptosis in renal tubular epithelial cells was investigated using HK2 cells in vitro. Blood samples and bilateral kidney tissues were collected for histopathological evaluation and processed for tissue injury, inflammation, fibrosis, oxidative stress detection, and mitochondrial dynamics parameter analysis.
    RESULTS: Calcium oxalate crystals caused higher levels of mitochondrial fission and apoptosis in renal tubular epithelial cells both in vivo and in vitro. Administration of a PPARγ agonist significantly alleviated mitochondrial fission and apoptosis in renal tubular epithelial cells, and improved renal function, accompanied by reduced levels of oxidative stress, increased antioxidant enzyme expression, alleviation of inflammation, and reduced fibrosis in vivo.
    CONCLUSION: Our results indicated that increased mitochondrial fission in renal tubular epithelial cells is a critical component of kidney injury caused by calcium oxalate stones, leading to the accumulation of reactive oxygen species within the tissue and the subsequent initiation of apoptosis. Regulating mitochondrial dynamics represents a promising approach for calcium oxalate nephrolithiasis.
    DOI:  https://doi.org/10.1371/journal.pone.0310947
  35. Epigenomics. 2024 Sep 24. 1-22
    Novel insights into sevoflurane-induced developmental neurotoxicity mechanisms.
    Tingting Gao, Zeqing Huang.
      Aim: This study explores Sevoflurane (Sevo)-induced neurotoxicity mechanisms in neonates through transcriptome sequencing and models.Methods: Seven-day-old mice were exposed to 3% Sevo, and hippocampal tissue was collected for analysis of differentially expressed lncRNAs and mRNAs compared with normal mice. MiR-152-3p was selected, and the interaction between H19, USP30, and miR-152-3p was explored in BV2 microglial cells and mouse hippocampal neurons.Results: Sevo disrupts mitochondrial autophagy via USP30 upregulation, exacerbating neurotoxicity and activating NLRP1 inflammasome-mediated inflammation.Conclusion: Sevo neurotoxicity is mediated through the H19/miR-152-3p/USP30 axis, implicating microglial regulation of neuronal pyroptosis.
    Keywords:  H19; USP30; ceRNA network; miR-152-3p; microglial activation; neurotoxicity; pyroptosis; sevoflurane
    DOI:  https://doi.org/10.1080/17501911.2024.2395250
  36. Cell Death Dis. 2024 Sep 20. 15(9): 688
    Mesenchymal stem cells in tumor microenvironment: drivers of bladder cancer progression through mitochondrial dynamics and energy production.
    Enguang Yang, Suoshi Jing, Fang Wang, Hanzhang Wang, Shengjun Fu, Li Yang, Junqiang Tian, Dragan J Golijanin, Wafik S El-Deiry, Liang Cheng, Zhiping Wang.
      Mesenchymal stem cells (MSCs) in tumor microenvironment (TME) are crucial for the initiation, development, and metastasis of cancer. The impact and mechanism of MSCs on bladder cancer are uncertain. Here we analyzed 205 patient samples to explore the relationships between tumor-stroma ratio and clinicopathological features. A co-culture model and nude mouse transplantation were used to explore the biological roles and molecular mechanisms of MSCs on bladder cancer cells. We found that a high tumor-stroma ratio was significantly associated with a larger tumor size and higher T stage, pathological grade, number of vascular invasions, and poor overall survival. MSCs in TME promoted the ability of bladder cancer cells to proliferate, migrate, and invade in vitro and in vivo. Next, we demonstrated that MSCs enhance mitochondrial autophagy and mitochondrial biogenesis of bladder cancer cells, and increase energy production, thereby promoting bladder cancer cell progression. Kynurenine (Kyn) produced by MSCs could enhance mitochondrial function by activating the AMPK pathway. IDO1 inhibitor could reverse the tumor‑promoting effects of MSCs in vitro and in vivo. Our results demonstrated that tryptophan metabolites Kyn of MSCs in TME could enhance mitochondrial function by activating the AMPK pathway, thereby promoting bladder cancer cell progression.
    DOI:  https://doi.org/10.1038/s41419-024-07068-9
  37. J Hazard Mater. 2024 Sep 23. pii: S0304-3894(24)02517-2. [Epub ahead of print]480 135938
    Environmentally relevant concentrations of perfluorobutane sulfonate impair locomotion behaviors and healthspan by downregulating mitophagy in C. elegans.
    Yahui Shang, Kelie Chen, Heng Ni, Xiaoyu Zhu, Xiaoyu Yuan, Yuwei Wang, Xinxin Liu, Zhenyan Cui, Yuequn Niu, Yu Shi, Han Wu, Dajing Xia, Yihua Wu.
      Perfluorobutane sulfonate (PFBS), a chemical compound within the group of per- and polyfluoroalkyl substances (PFAS), has been utilized as an alternative to perfluorooctane sulfonate (PFOS) recently. Previous research has indicated that PFBS might be linked to a range of health concerns. However, the potential impacts of environmentally relevant concentrations of PFBS (25 nM) on aging as well as the underlying mechanisms remained largely unexplored. In this study, we investigated the impact of PFBS exposure on aging and the associated mechanisms in Caenorhabditis elegans. Our findings indicated that exposure to PFBS impaired healthspan of C. elegans. Through bioinformatic screening analyses, we identified that the dysfunctions of pink-1 mediated mitophagy might play a critical role in PFBS induced aging. The results furtherly revealed that PFBS exposure led to elevated levels of reactive oxygen species (ROS) and mitophagy impairment through downregulating pink-1/pdr-1 pathway. Furthermore, the mitophagy agonist Urolithin A (UA) effectively reversed PFBS-induced mitophagy dysfunction and enhanced healthspan in C. elegans. Taken together, our study suggested that exposure to environmentally relevant concentrations of PFBS could accelerate aging by downregulating the pink-1 mediated mitophagy. Promoting mitophagy within cells could be a promising therapeutic strategy for delaying PFBS-induced aging.
    Keywords:  Caenorhabditis elegans; Mitophagy; Perfluorobutane sulfonate; Reactive oxygen species; pink-1
    DOI:  https://doi.org/10.1016/j.jhazmat.2024.135938
  38. Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]
    A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.
    Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt
    DOI:  https://doi.org/10.1016/j.cell.2024.08.045
  39. Med Oncol. 2024 Sep 23. 41(10): 247
    Letter to the editor for the article "How mitochondrial dynamics imbalance affects the progression of breast cancer: a mini review".
    Yu Zhang, Lexin Wang, Gang Huang, Hao Chi.
      
    DOI:  https://doi.org/10.1007/s12032-024-02514-2
  40. Curr Issues Mol Biol. 2024 Sep 05. 46(9): 9867-9880
    Dexamethasone Impairs ATP Production and Mitochondrial Performance in Human Trabecular Meshwork Cells.
    Shane Kennedy, Clayton Williams, Emily Tsaturian, Joshua T Morgan.
      Mitochondrial damage occurs in human trabecular meshwork (HTM) cells as a result of normal aging and in open angle glaucoma. Using an HTM cell model, we quantified mitochondrial function and ATP generation rates after dexamethasone (Dex) and TGF-β2 treatments, frequently used as in vitro models of glaucoma. Primary HTM cells were assayed for metabolic function using a Seahorse XFp Analyzer. We additionally assessed the mitochondrial copy number and the expression of transcripts associated with mitochondrial biogenesis and oxidative stress regulation. Cells treated with Dex, but not TGF-β2, exhibited a significant decrease in total ATP production and ATP from oxidative phosphorylation relative to that of the control. Dex treatment also resulted in significant decreases in maximal respiration, ATP-linked O2 consumption, and non-mitochondrial O2 consumption. We did not observe significant changes in the level of mitochondrial genomes or mRNA transcripts of genes involved in mitochondrial biogenesis and oxidative stress regulation. Decreased mitochondrial performance and ATP production are consistent with the results of prior studies identifying the effects of Dex on multiple cell types, including HTM cells. Our results are also consistent with in vivo evidence of mitochondrial damage in open-angle glaucoma. Overall, these results demonstrate a decrease in mitochondrial performance in Dex-induced glaucomatous models in vitro, meriting further investigation.
    Keywords:  dexamethasone; glaucoma; mitochondria; trabecular meshwork
    DOI:  https://doi.org/10.3390/cimb46090587
  41. Pharmacol Res. 2024 Sep 25. pii: S1043-6618(24)00379-7. [Epub ahead of print] 107434
    The Potential Role of Mitochondria in the Microbiota-Gut-Brain Axis: Implications for Brain Health.
    Lei Qiao, Ge Yang, Peng Wang, Chunlan Xu.
      Mitochondria are crucial organelles that regulate cellular energy metabolism, calcium homeostasis, and oxidative stress responses, playing pivotal roles in brain development and neurodegeneration. Concurrently, the gut microbiota has emerged as a key modulator of brain physiology and pathology through the microbiota-gut-brain axis. Recent evidence suggests an intricate crosstalk between the gut microbiota and mitochondrial function, mediated by microbial metabolites that can influence mitochondrial activities in the brain. This review aims to provide a comprehensive overview of the emerging role of mitochondria as critical mediators in the microbiota-gut-brain axis, shaping brain health and neurological disease pathogenesis. We discuss how gut microbial metabolites such as short-chain fatty acids, secondary bile acids, tryptophan metabolites, and trimethylamine N-oxide can traverse the blood-brain barrier and modulate mitochondrial processes including energy production, calcium regulation, mitophagy, and oxidative stress in neurons and glial cells. Additionally, we proposed targeting the mitochondria through diet, prebiotics, probiotics, or microbial metabolites as a promising potential therapeutic approach to maintain brain health by optimizing mitochondrial fitness. Overall, further investigations into how the gut microbiota and its metabolites regulate mitochondrial bioenergetics, dynamics, and stress responses will provide valuable insights into the microbiota-gut-brain axis in both health and disease states.
    Keywords:  Brain; Gut microbiota; Microbiota-gut-brain axis; Mitochondria; Neurodegenerative diseases; Redox processes
    DOI:  https://doi.org/10.1016/j.phrs.2024.107434
  42. Biochem Pharmacol. 2024 Sep 20. pii: S0006-2952(24)00552-5. [Epub ahead of print]229 116552
    Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling.
    Warisara Parichatikanond, Sudhir Pandey, Supachoke Mangmool.
      Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9-39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9-39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.
    Keywords:  Cardioprotection; Exendin-4; GLP-1 receptor; High glucose; Mitochondrial dysfunction; mTOR
    DOI:  https://doi.org/10.1016/j.bcp.2024.116552
  43. Biochem Pharmacol. 2024 Sep 25. pii: S0006-2952(24)00556-2. [Epub ahead of print] 116556
    Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications.
    Ting Chen, Dacheng Bai, Changyong Gong, Yu Cao, Xiaoqing Yan, Renyi Peng.
      Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca2+) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H2S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.
    Keywords:  Anti-aging; Cell senescence; Diabetes; Hydrogen sulfide; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.bcp.2024.116556
  44. Heliyon. 2024 Sep 30. 10(18): e37463
    Enhancing terminal erythroid differentiation in human embryonic stem cells through TRIB3 overexpression.
    Xiaoling Wang, Tiantian Cui, Hao Yan, Lingping Zhao, Ruge Zang, Hongyu Li, Haiyang Wang, Biao Zhang, Junnian Zhou, Yiming Liu, Wen Yue, Jiafei Xi, Xuetao Pei.
      Tribbles pseudokinase 3 (TRIB3) expression significantly increases during terminal erythropoiesis in vivo. However, we found that TRIB3 expression remained relatively low during human embryonic stem cell (hESC) erythropoiesis, particularly in the late stage, where it is typically active. TRIB3 was expressed in megakaryocyte-erythrocyte progenitor cells and its low expression was necessary for megakaryocyte differentiation. Thus, we proposed that the high expression during late stage of erythropoiesis could be the clue for promotion of maturation of hESC-derived erythroid cells. To our knowledge, the role of TRIB3 in the late stage of erythropoiesis remains ambiguous. To address this, we generated inducible TRIB3 overexpression hESCs, named TRIB3tet-on OE H9, based on a Tet-On system. Then, we analyzed hemoglobin expression, condensed chromosomes, organelle clearance, and enucleation with or without doxycycline treatment. TRIB3tet-on OE H9 cells generated erythrocytes with a high proportion of orthochromatic erythroblast in flow cytometry, enhanced hemoglobin and related protein expression in Western blot, decreased nuclear area size, promoted enucleation rate, decreased lysosome and mitochondria number, more colocalization of LC3 with LAMP1 (lysosome marker) and TOM20 (mitochondria marker) and up-regulated mitophagy-related protein expression after treatment with 2 μg/mL doxycycline. Our results showed that TRIB3 overexpression during terminal erythropoiesis may promote the maturation of erythroid cells. Therefore, our study delineates the role of TRIB3 in terminal erythropoiesis, and reveals TRIB3 as a key regulator of UPS and downstream mitophagy by ensuring appropriate mitochondrial clearance during the compaction of chromatin.
    Keywords:  Human embryonic stem cell; Mitophagy; Terminal erythropoiesis; Tribbles pseudokinase 3
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37463
  45. Comb Chem High Throughput Screen. 2024 Sep 18.
    Exploring Mitochondrial Autophagy Dysregulation in Osteosarcoma: Its Implications for Prognosis and Targeted Therapy.
    Xiangpan Kong, Dawei He, Quan Wang.
      OBJECTIVE: This study aimed to investigate the differential expression of mitophagyrelated genes in osteosarcoma patients with distinct prognostic outcomes and explore potential molecular regulatory mechanisms.METHODS: We analyzed microarray data from metastatic and nonmetastatic osteosarcoma patients using the UCSC dataset. Differential gene screening and intersection of mitophagy-related genes were performed using NetworkAnalyst. Random forest and LASSO regression were employed to screen selected genes and establish a risk prediction model. Functional enrichment analysis, protein- protein interaction (PPI) networks, immunoassays, and in vitro experiments were conducted to validate the findings.
    RESULTS: Seven differentially expressed genes were identified, and a robust risk prediction model was developed (AUC=0.886). PPI and functional enrichment analyses provided insights into relevant molecules and regulatory pathways. The immunoassay results revealed differences in the immune environment between the metastatic and nonmetastatic groups. Immunohistochemistry demonstrated significant downregulation of EPHA3 expression in the metastatic group, and in vitro experiments indicated that inhibiting EPHA3 increased the proliferative activity and migration ability of osteosarcoma cells.
    CONCLUSION: Our study suggests that the downregulation of EPHA3 may contribute to mitochondrial autophagy dysfunction, thereby increasing the risk of osteosarcoma metastasis.
    Keywords:  EPHA3.; Osteosarcoma; bioinformatics research; mitophagy
    DOI:  https://doi.org/10.2174/0113862073314265240828170126
  46. Exp Gerontol. 2024 Sep 24. pii: S0531-5565(24)00240-7. [Epub ahead of print] 112594
    The mitochondrial function of peripheral blood mononuclear cells in frail older patients.
    Tingting Huang, Li Qin, Danmei Zhang, Qiangwei Tong, Qianqian Zhu, Guoxian Ding, Juan Liu.
      BACKGROUND: Frailty increases the incidence of geriatric syndromes and even the risk of death in old adults. However, the diagnostic criteria for frailty are inconsistent because of complex pathological processes and diverse clinical manifestations. To determine the effective biomarker and recognize frail status early, we investigated the correlation of mitochondrial morphology and function of human peripheral blood mononuclear cells (PBMCs) with frailty status in older adults.METHODS: This Cross-sectional study followed 393 participants (aged 25-100 years, female 31.04 %) from the First Affiliated Hospital of Nanjing Medical University. The frailty status of subjects was assessed by the physical frailty phenotype (PFP) scale. We analyzed mitochondria functions including mitochondria copy number (mtDNAcn), the mRNA expressions of mitochondrial dynamics-related genes mitofusin 1(MFN1), mitofusin 2(MFN2), optic atrophy protein-1(OPA1), fission protein-1(FIS1) and dynamin-related protein 1(DRP1), mitochondrial oxidative respiration and reactive oxygen species(ROS) levels in PBMCs. Mitochondria morphology, size, and number were observed by transmission electron microscopy (TEM).
    RESULTS: After adjustment for sex and BMI, mtDNAcn, the mRNA expression of FIS1, mitochondrial respiratory function (proton leak, maximum oxygen consumption, and respiratory reserve) and ROS level were significantly correlated with age (P = 0.031, 0.030, 0.042, 0.003, 0.002, 0.022, respectively). After correcting for age, sex, and BMI, mtDNAcn and the mRNA expression of OPA1 were correlated with 4 m gait speed respectively (P = 0.003, 0.028, respectively). Compared with non-frail people, mtDNAcn, the mRNA expression of MFN1, mitochondrial basal respiration, proton leak, maximum oxygen consumption, ATP production and space capacity were significantly decreased in frail older adults (P = 0.013, 0.036, 0.026, 0.024, 0.012, 0.029, 0.032, 0.020, respectively). ROS levels were significantly increased in the frail group (P = 0.016). Compared with non-frail people, the number, length, and perimeter, area of mitochondria were reduced in frail group under TEM (all P < 0.001).
    CONCLUSION: Mitochondrial dysfunctions (decreased mtDNAcn, impaired mitochondrial morphology, imbalanced mitochondrial dynamic, impaired mitochondrial respiratory function, and increased ROS levels) were significantly correlated with frail status.
    Keywords:  Aging; Frailty; Mitochondrial function; Peripheral blood mononuclear cells
    DOI:  https://doi.org/10.1016/j.exger.2024.112594
  47. Toxicology. 2024 Sep 25. pii: S0300-483X(24)00239-7. [Epub ahead of print] 153958
    Dihydrotestosterone induces reactive oxygen species accumulation and mitochondrial fission leading to apoptosis of granulosa cells.
    Xiaoyan Li, Ying He, Qi Yan, Dan Kuai, Huiying Zhang, Yingmei Wang, Kan Wang, Wenyan Tian.
      Dihydrotestosterone (DHT), which has significant androgenic activity，is a major player in follicle development and ovary function in females. However, an excess of androgens may result in increased follicular apoptosis with adverse effects on female fertility. This study aimed to explore the mechanism by which DHT induces apoptosis in human ovarian granulosa cells (GCs). The association between DHT and GC apoptosis was explored by the construction of rat models of polycystic ovary syndrome (PCOS). It was found that serum DHT levels were negatively correlated with thickness of the GC layer in PCOS model rats (R2=0.8342, p＜0.0001), compared with control rats, together with significant increases in cofactors (Fis1: p=0.008; MFF: p=0.044). The GC SVOG cell line was used to clarify the mechanism by which DHT influenced GC apoptosis in in vitro experiments. The results confirmed that apoptosis in SVOG cells was positively associated with the DHT dose. The expression of the autophagy-related proteins LC3A/B (p=0.027) and the proapoptotic protein Bax (p=0.0095) were increased, while that of the anti-apoptotic protein Bcl-2 (p=0.0005) was decreased in the high-dose DHT group. ROS levels were significantly increased (p=0.0237) and the mitochondrial membrane potential ΔΨm was decreased (p=0.0194). Moreover, ultrastructural analysis of the mitochondria indicated significant damage. The results of RT-qPCR and western blotting showed that two fission cofactor-Fis1（p=0.034） and MFF (p=0.039) were significantly increased after treatment with high doses of DHT. Even though the overall expression of Drp1 did not change significantly (p=0.5961), that of activated Phosphor-Drp1(Ser616) was significantly increased (p=0.046), while the expression of Phosphor-Drp1 (Ser637) was markedly reduced (p=0.007) following exposure to high concentrations of DHT. All these effects could be reversed by the Drp1 inhibitor Mdivi-1. These findings indicated the impact of DHT on ROS aggregation and mitochondrial fission, resulting in GC apoptosis. An imbalance in Drp1 phosphorylation may be the key link in DHT-induced excessive mitochondrial fission.
    Keywords:  Dihydrotestosterone，Hyperandrogen; apoptosis; granulosa cells; mitochondrial fission; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.tox.2024.153958
  48. Life Sci. 2024 Sep 25. pii: S0024-3205(24)00668-4. [Epub ahead of print] 123078
    DNA-PKcs modulates mouse lung homeostasis via the regulation of mitochondrial fission.
    Yi Xiao, Jiahe Zhang, Xinran Li, Pinxuan Liu, Bo Gou, Zeyu Gao, Moshi Song.
      BACKGROUND: The role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is multifaceted, paradoxically promoting both cell survival and cell death across multiple organs. However, its impact on lung homeostasis remains elusive. Here, we investigate the function of DNA-PKcs in mouse lungs, aiming to elucidate its role for lung abnormalities associated with DNA-PKcs deficiency.MATERIALS AND METHODS: Histological assessment and immunohistochemistry were used to reveal the pathological changes of the lungs in DNA-PKcs-deficient mice. Transcriptomic analysis identified differentially expressed genes and pathways in DNA-PKcs-deficient lungs. Furthermore, mitochondrial dysfunction induced by DNA-PKcs deficiency was investigated by qPCR and immunoblotting. Mouse primary lung fibroblasts were used to evaluate the potential therapeutic effect of inhibiting mitochondrial fission with Mdivi-1.
    KEY FINDINGS: In DNA-PKcs-deficient mouse lungs, we observed pathological changes including alveolar septal thickening, capillary congestion and hemorrhage, along with lung cell proliferation. Transcriptome analysis revealed an upregulation of the reactive oxygen species (ROS) biosynthesis process and the apoptotic signaling pathway caused by DNA-PKcs deficiency. Further investigations demonstrated that DNA-PKcs deficiency led to mitochondrial dysfunction and increased oxidative stress, along with increased cell apoptosis in the mouse lungs. Notably, we detected enhanced phosphorylation of the mitochondrial fission protein DRP1 in DNA-PKcs-deficient mouse lungs. Intriguingly, inhibiting mitochondrial fission using Mdivi-1 suppressed cell death in primary mouse lung fibroblasts with siRNA-mediated DNA-PKcs knockdown.
    SIGNIFICANCE: Our study provides insights into the crucial role of DNA-PKcs in sustaining lung homeostasis via the maintenance of mitochondrial functionality and provides a therapeutic strategy targeting mitochondrial fission against DNA-PKcs deficiency-associated lung diseases.
    Keywords:  Apoptosis; DNA-PKcs; Lung homeostasis; Mitochondrial fission; Mitochondrial oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2024.123078
  49. Invest Ophthalmol Vis Sci. 2024 Sep 03. 65(11): 39
    ER Stress and Mitochondrial Perturbations Regulate Cell Death in Retinal Detachment: Exploring the Role of HIF1α.
    Bhavneet Kaur, Bruna Miglioranza Scavuzzi, Mengling Yang, Jingyu Yao, Lin Jia, Steven F Abcouwer, David N Zacks.
      Purpose: Retinal detachment (RD) leads to photoreceptor (PR) hypoxia due to separation from the retinal pigment epithelium (RPE). Hypoxia stabilizes retinal hypoxia-inducible factor 1-alpha (HIF1α), crucial for PR survival during RD. This study explores the regulatory role of HIF1α in PR cell survival pathways during RD.Methods: Experimental RD was created in C57BL/6J and HIF1αΔrod mice by injecting 1% hyaluronic acid into the subretinal space. The 661W photoreceptor cells were exposed to hypoxic conditions. Markers of endoplasmic reticulum stress (ERS), mitophagy, and accumulation of polyubiquinated proteins were evaluated using RT-PCR and western blot analyses. Cell death of PR cells was quantified using trypan blue exclusion assay and TUNEL staining. Retinal cell death was assessed using a DNA fragmentation assay.
    Results: In C57BL/6J mice and 661W cells, there were increases in HIF1α protein levels: 2.2-fold after RD (P = 0.04) and threefold after hypoxia (P = 0.057). Both the in vivo and in vitro RD models showed increased protein expression of ERS markers (including BIP, CHOP, and IRE1α), mitophagy markers (Parkin, PINK, and FUNDC1), and polyubiquitinated proteins. In 661W cells, hypoxia resulted in a loss of mitochondrial membrane potential, an increase in mitochondrial reactive oxygen species, and a decrease in intracellular adenosine triphosphate levels. Lack of HIF1α in rods blocked the upregulation of mitophagy markers after RD.
    Conclusions: RD results in the activation of ERS, mitophagy, mitochondrial dysfunction, and accumulation of polyubiquitinated proteins. Results suggest a role for HIF1α in activation of the mitophagy pathway after RD, which may serve to protect the PR cells.
    DOI:  https://doi.org/10.1167/iovs.65.11.39
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