bims-mikwok 2024-10-27 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–10–27
37 papers selected by
Gavin McStay, Liverpool John Moores University

Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.
Mitochondrial quality control in alcohol-associated liver disease.
YAP1 exacerbates pyroptosis and senescence in nucleus pulposus cells by promoting BNIP3-mediated mitophagy.
Mitochondrial Quality Control Orchestrates the Symphony of B Cells and Plays Critical Roles in B Cell-Related Diseases.
Multiple roles of mitochondrial autophagy receptor FUNDC1 in mitochondrial events and kidney disease.
Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
ASI-RIM neuronal axis regulates systemic mitochondrial stress response via TGF-β signaling cascade.
Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.
HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.
Po-Ge-Jiu-Xin decoction alleviate sepsis-induced cardiomyopathy via regulating phosphatase and tensin homolog-induced putative kinase 1 /parkin-mediated mitophagy.
Renal denervation ameliorates atrial remodeling in type 2 diabetic rats by regulating mitochondrial dynamics.
Unfractionated Heparin Enhances Sepsis Prognosis Through Inhibiting Drp1-Mediated Mitochondrial Quality Imbalance.
Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis.
Homoplantaginin alleviates high glucose-induced vascular endothelial senescence by inhibiting mtDNA-cGAS-STING pathway via blunting DRP1-mitochondrial fission-VDAC1 axis.
MiR-21-3p inhibitor exerts myocardial protective effects by altering macrophage polarization state and reducing excessive mitophagy.
Copper dyshomeostasis and its relationship to AMPK activation, mitochondrial dynamics, and biogenesis of mitochondria: A systematic review of in vivo studies.
The broad-spectrum deubiquitinating enzyme inhibitor PR-619 protects retinal ganglion cell and augments parkin-mediated mitophagy in experimental glaucoma.
PRDM1 promotes nucleus pulposus cell pyroptosis leading to intervertebral disc degeneration via activating CASP1 transcription.
Mitochondrial pathways and sarcopenia in the geroscience era.
Mifepristone and rapamycin have non-additive benefits for life span in mated female Drosophila.
Bag2 protects against doxorubicin-induced cardiotoxicity by maintaining Pink1-mediated mitophagy.
[Regulation of mitophagy and mitochondrial biogenesis by monocarbonyl analogues of curcumin in the cerebral cortex of rats in experimental Alzheimer's disease].
Corrigendum: Protective effects of inhibition of mitochondrial fission on organ function after sepsis.
Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate.
RNA-seq analysis of mitochondria-related genes regulated by AMPK in the human trophoblast cell line BeWo.
Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.
The MICOS Complex Subunit Mic60 is Hijacked by Intracellular Bacteria to Manipulate Mitochondrial Dynamics and Promote Bacterial Pathogenicity.
High concentration hydrogen attenuates sepsis-induced acute kidney injury by promoting mitochondrial biogenesis and fusion.
Resveratrol Mitigates Uremic Toxin-Induced Intestinal Barrier Dysfunction in Chronic Kidney Disease by Promoting Mitophagy and Inhibiting Apoptosis Pathways.
Apelin regulates mitochondrial dynamics by inhibiting Mst1-JNK-Drp1 signaling pathway to reduce neuronal apoptosis after spinal cord injury.
Diallyl disulfide alleviates hepatic steatosis by the conservative mechanism from fish to tetrapod: Augment Mfn2/Atgl-Mediated lipid droplet-mitochondria coupling.
Mitochondrial Bioenergetics of Functional Wound Closure is Dependent on Macrophage-Keratinocyte Exosomal Crosstalk.
PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system.
PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells.
The potential mechanism of mitochondrial homeostasis in postoperative neurocognitive disorders: an in-depth review.

Int J Med Sci. 2024 ;21(13): 2502-2509

Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.

Zhijiang Guo, Yingjie Tian, Nanyang Liu, Ye Chen, Xiaohan Chen, Guoxing Yuan, An Chang, Xing Chang, Jie Wu, Hao Zhou.

  Hypoxic injury is a critical pathological factor in the development of various cardiovascular diseases, such as congenital heart disease, myocardial infarction, and heart failure. Mitochondrial quality control is essential for protecting cardiomyocytes from hypoxic damage. Under hypoxic conditions, disruptions in mitochondrial homeostasis result in excessive reactive oxygen species (ROS) production, imbalances in mitochondrial dynamics, and initiate pathological processes including oxidative stress, inflammatory responses, and apoptosis. Targeted interventions to enhance mitochondrial quality control, such as coenzyme Q10 and statins, have shown promise in mitigating hypoxia-induced mitochondrial dysfunction. These treatments offer potential therapeutic strategies for hypoxia-related cardiovascular diseases by regulating mitochondrial fission and fusion, restoring mitochondrial biogenesis, reducing ROS production, and promoting mitophagy.

Keywords:  Hypoxia; Mitochondrial Homeostasis; Myocardial Injury

DOI:  https://doi.org/10.7150/ijms.99359
Hepatol Commun. 2024 Nov 01. pii: e0534. [Epub ahead of print]8(11):

Mitochondrial quality control in alcohol-associated liver disease.

Themis Thoudam, Hui Gao, Yanchao Jiang, Nazmul Huda, Zhihong Yang, Jing Ma, Suthat Liangpunsakul.

Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.

DOI: https://doi.org/10.1097/HC9.0000000000000534
Int Immunopharmacol. 2024 Oct 22. pii: S1567-5769(24)01956-8. [Epub ahead of print]143(Pt 2): 113434

YAP1 exacerbates pyroptosis and senescence in nucleus pulposus cells by promoting BNIP3-mediated mitophagy.

Xin Peng, Hang-Yu Ji, Jia-Wei Gao, Shang-Hao Hong, Tong Zhang, Guang Yang, Xiaotao Wu, Yanzheng Gao, Kun Wang.

  Yes-associated protein 1 (YAP1) is a crucial downstream effector of the Hippo pathway that plays a role in regulating inflammation and mitochondrial function. However, whether YAP1 regulates pyroptosis in nucleus pulposus (NP) cells caused by inflammation via mitophagy remains unclear. This study aimed to investigate the effects of YAP1 on the pyroptosis of NP cells induced by LPS. Here, we demonstrated that the protein expression of YAP1 in the NP tissue of degenerative discs was significantly reduced. Next, we found that NLRP3 inflammasome activation in YAP1-overexpressing (YAP1-ov) NP cells was further enhanced in the LPS-induced inflammatory microenvironment. YAP1-ov strongly aggravated inflammation-induced pyroptosis and senescence, but these effects were reversed by the inhibition of BNIP3-mediated mitophagy. However, comparative analysis of the overexpression of YAP1 in normal discs and discs after annulus fibrosus puncture revealed that YAP1-ov accelerated the degeneration of normal discs and attenuated the degeneration of annulus fibrosus punctured discs in vivo. Additionally, YAP1-ov upregulated the expression of TNFAIP3, an anti-inflammatory protective protein, and CLPP, a vital protein in the mitochondrial unfolded protein response, in NP cells. Collectively, the above results revealed that YAP1 exacerbates LPS-induced pyroptosis and senescence of NP cells by promoting BNIP3-mediated mitophagy, which causes disc degeneration. Notably, YAP1-ov mitigated the degeneration of the disc caused by annular needle puncture in vivo, suggesting its potential as a therapeutic candidate foracute IDD injury.

Keywords:  Inflammation; Mitophagy; NLRP3; Nucleus pulposus; YAP1

DOI:  https://doi.org/10.1016/j.intimp.2024.113434
J Immunol Res. 2024 ;2024 5577506

Mitochondrial Quality Control Orchestrates the Symphony of B Cells and Plays Critical Roles in B Cell-Related Diseases.

Wuhao Li, Peiyang Cai, Ye Xu, Weihong Tian, Licong Jing, Qiaoyi Lv, Yangjing Zhao, Hui Wang, Qixiang Shao.

  B cells are essential for humoral immune response due to their ability to secrete antibodies. The development of B cells from the bone marrow to the periphery is tightly regulated by a complex set of immune signals, and each subset of B cells has a unique metabolic profile. Mitochondria, which serve as cellular energy powerhouses, play an essential role in regulating cell survival and immune responses. To maintain metabolic homeostasis, mitochondria dynamically adjust their morphology, distribution, and mass via biogenesis, fusion and fission, translocation, and mitophagy. Despite its extreme importance, the role of mitochondrial quality control (MQC) in B cells has not been thoroughly summarized, unlike in T cells. This article aims to review the mechanism of MQC that shapes B cell fate and functions. In addition, we will discuss the physiological and pathological implications of MQC in B cells, providing new insights into potential therapeutic targets for diseases associated with B cell abnormalities.

Keywords:  B cell; B cell-related diseases; mitochondria; mitochondrial dynamics; mitochondrial quality control

DOI:  https://doi.org/10.1155/2024/5577506
Front Cell Dev Biol. 2024 ;12 1453365

Multiple roles of mitochondrial autophagy receptor FUNDC1 in mitochondrial events and kidney disease.

Kaiqing Li, Xue Xia, Ying Tong.

  This article reviews the latest research progress on the role of mitochondrial autophagy receptor FUN14 domain containing 1 (FUNDC1) in mitochondrial events and kidney disease. FUNDC1 is a protein located in the outer membrane of mitochondria, which maintains the function and quality of mitochondria by regulating mitochondrial autophagy, that is, the selective degradation process of mitochondria. The structural characteristics of FUNDC1 enable it to respond to intracellular signal changes and regulate the activity of mitochondrial autophagy through phosphorylation and dephosphorylation. During phosphorylation, unc-51-like kinase 1 (ULK1) promotes the activation of mitophagy by phosphorylating Ser17 of FUNDC1. In contrast, Src and CK2 kinases inhibit the interaction between FUNDC1 and LC3 by phosphorylating Tyr18 and Ser13, thereby inhibiting mitophagy. During dephosphorylation, PGAM5 phosphatase enhances the interaction between FUNDC1 and LC3 by dephosphorylating Ser13, thereby activating mitophagy. BCL2L1 inhibits the activity of PGAM5 by interacting with PGAM5, thereby preventing the dephosphorylation of FUNDC1 and inhibiting mitophagy. FUNDC1 plays an important role in mitochondrial events, participating in mitochondrial fission, maintaining the homeostasis of iron and proteins in mitochondrial matrix, and mediating crosstalk between mitochondria, endoplasmic reticulum and lysosomes, which have important effects on cell energy metabolism and programmed death. In the aspect of kidney disease, the abnormal function of FUNDC1 is closely related to the occurrence and development of many diseases. In acute kidney injury (AKI), cardiorenal syndrome (CRS), diabetic nephropathy (DN), chronic kidney disease (CKD) ,renal fibrosis (RF) and renal anemia, FUNDC1-mediated imbalance of mitophagy may be one of the key factors in disease progression. Therefore, in-depth study of the regulatory mechanism and function of FUNDC1 is of great significance for understanding the pathogenesis of renal disease and developing new treatment strategies.

Keywords:  FUNDC1; dephosphorylation; kidney disease; mitochondrial autophagy; phosphorylation

DOI:  https://doi.org/10.3389/fcell.2024.1453365
Nat Cell Biol. 2024 Oct 21.

Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.

Patrizia Romani, Giada Benedetti, Martina Cusan, Mattia Arboit, Carmine Cirillo, Xi Wu, Georgia Rouni, Vassiliki Kostourou, Mariaceleste Aragona, Costanza Giampietro, Paolo Grumati, Graziano Martello, Sirio Dupont.

Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.

DOI: https://doi.org/10.1038/s41556-024-01527-3
Nat Commun. 2024 Oct 19. 15(1): 8997

ASI-RIM neuronal axis regulates systemic mitochondrial stress response via TGF-β signaling cascade.

Zihao Wang, Qian Zhang, Yayun Jiang, Jun Zhou, Ye Tian.

Morphogens play a critical role in coordinating stress adaptation and aging across tissues, yet their involvement in neuronal mitochondrial stress responses and systemic effects remains unclear. In this study, we reveal that the transforming growth factor beta (TGF-β) DAF-7 is pivotal in mediating the intestinal mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans under neuronal mitochondrial stress. Two ASI sensory neurons produce DAF-7, which targets DAF-1/TGF-β receptors on RIM interneurons to orchestrate a systemic UPRmt response. Remarkably, inducing mitochondrial stress specifically in ASI neurons activates intestinal UPRmt, extends lifespan, enhances pathogen resistance, and reduces both brood size and body fat levels. Furthermore, dopamine positively regulates this UPRmt activation, while GABA acts as a systemic suppressor. This study uncovers the intricate mechanisms of systemic mitochondrial stress regulation, emphasizing the vital role of TGF-β in metabolic adaptations that are crucial for organismal fitness and aging during neuronal mitochondrial stress.

DOI: https://doi.org/10.1038/s41467-024-53093-9
Ageing Res Rev. 2024 Oct 19. pii: S1568-1637(24)00367-2. [Epub ahead of print]102 102549

Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.

Luigi Ferrucci, Flora Guerra, Cecilia Bucci, Emanuele Marzetti, Anna Picca.

  Mitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the endosomal-lysosomal system has revealed additional mechanisms of mitophagy and mitochondrial quality control that operate via the production of mitochondria-derived vesicles (MDVs). Circulating MDVs can be isolated and characterized to provide an unprecedented opportunity to study this type of mitochondrial recycling in vivo and to relate it to human physiology and pathology. Defining the role of MDVs in human physiology, pathology, and aging is hampered by the lack of standardized methods to isolate, validate, and characterize these vesicles. Hence, some basic questions about MDVs remain unanswered. While MDVs are generated directly through the extrusion of mitochondrial membranes within the cell, a set of circulating extracellular vesicles leaking from the endosomal-lysosomal system and containing mitochondrial portions have also been identified and warrant investigation. Preliminary research indicates that MDV generation serves multiple biological roles and contributes to restoring cell homeostasis. However, studies have shown that MDVs may also be involved in pathological conditions. Therefore, further research is warranted to establish when/whether MDVs are supporting disease progression and/or are extracting damaged mitochondrial components to alleviate cellular oxidative burden and restore redox homeoastasis. This information will be relevant for exploiting these vesicles for therapeutic purpose. Herein, we provide an overview of preclinical and clinical studies on MDVs in aging and associated conditions and discuss the interplay between MDVs and some of the hallmarks of aging (mitophagy, inflammation, and proteostasis). We also outline open questions on MDV research that should be prioritized by future investigations.

Keywords:  Exosomes; Extracellular vesicles; Inflammaging; Mitochondrial DNA; Mitochondrial quality control; Mitophagy

DOI:  https://doi.org/10.1016/j.arr.2024.102549
Am J Physiol Endocrinol Metab. 2024 Oct 23.

The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.

Elya Janis Ritenis, Camila S Padilha, Matthew B Cooke, Christos George Stathis, Andrew Philp, Donny M Camera.

  Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.

Keywords:  Exercise; Mitochondrial Dynamics; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpendo.00311.2024
Circ Res. 2024 Oct 25. 135(10): 1018-1020

HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.

Xi Fang, Åsa B Gustafsson.



Keywords:  Editorials; diet, high-fat; heart failure; metabolism; mitochondria, heart; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325501
J Ethnopharmacol. 2024 Oct 17. pii: S0378-8741(24)01251-0. [Epub ahead of print] 118952

Po-Ge-Jiu-Xin decoction alleviate sepsis-induced cardiomyopathy via regulating phosphatase and tensin homolog-induced putative kinase 1 /parkin-mediated mitophagy.

Zheng Wang, Yu Wang, Chen Dong, Kaihui Miao, Bing Jiang, Dan Zhou, Kang Dong, Yanjun Wang, Zheng Zhang.

   ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis is a life-threatening systemic syndrome usually accompanied by myocardial dysfunction. Po-Ge-Jiu-Xin decoction (PGJXD), a traditional Chinese prescription medicine, has been used clinically to treat cardiovascular disease including heart failure, sepsis-induced cardiomyopathy (SIC) and even septic shock. Previous clinical studies suggested PGJXD has shown promising results in improving cardiac function and treating heart failure in sepsis. However, more research is needed to elucidate the mechanisms underlying PGJXD's therapeutic effects in sepsis-induced cardiomyopathy.
MATERIALS AND METHODS: Initially, we identified the major compounds of PGJXD through ultra-performance liquid chromatography-mass spectrometry technology analysis. We established in a SIC rat model using cecal ligation and puncture(CLP) and treated by PGJXD and levosimendan. We evaluated pathological damage by hematoxylin and eosin staining and measured serum myocardial injury biomarkers. Myocardial apoptosis was detected by Tunel staining and quantifying specific biomarker protein levels. Subsequently, we evaluated myocardium mitochondrial quality using Transmission electron microscope (TEM), antioxidant stress indexes and tissue adenosine triphosphate(ATP) content. We detected the expression of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), parkin, LC3, and p62 using Western blotting and Quantitative real time polymerase chain reaction(qRT-PCR). (Lipopolysaccharides, LPS)-induced H9c2 cell model was established to further explore the mechanism of PGJXD on SIC. In addition to measuring cell viability, we measured mitochondrial membrane potential using JC-1 staining. Additionally, Parkin-siRNA transfected into H9c2 cells to validate whether PGJXD conducted protective effects against SIC through PINK1/Parkin-mediated mitophagy.
RESULTS: It has been demonstrated that PGJXD reduced mortality in septic rat, contributed to ameliorating myocardium injury, suppressed inflammatory response and ameliorated the myocardial apoptosis. PGJXD could also alleviate mitochondrial structural abnormality, mitigated oxidative stress injury and promoted energy synthesis in CLP models. Western blotting and qRT-PCR have further confirmed that PGJXD can activate PINK1/parkin pathway-mediated mitophagy, resulting in preserving mitochondrial quality in the myocardium. Furthermore, Parkin siRNA partially reversed the beneficial effect of PGJXD on mitochondrial fission/fusion and mitophagy in vitro. Therefore, the cardioprotective effect of PGJXD is achieved by inducing PINK1/Parkin-mediated mitophagy in maintaining mitochondrial homeostasis.
CONCLUSIONS: These results suggest that the potential therapeutic effect of PGJXD on cardiac dysfunction during sepsis and support its mechanism of targeted induction of PINK1-Parkin-mediated mitophagy.

Keywords:  Mitophagy; PINK1/Parkin Signal transduction pathway; Po-Ge-Jiu-Xin Decoction; Sepsis induced cardiomyopathy; Traditional Chinese Medicine

DOI:  https://doi.org/10.1016/j.jep.2024.118952
J Physiol Biochem. 2024 Oct 22.

Renal denervation ameliorates atrial remodeling in type 2 diabetic rats by regulating mitochondrial dynamics.

Jun-Yu Huo, Can Hou, Xiao-Long Li, Ling Yang, Wan-Ying Jiang.

  There is no effective treatment for diabetes-related atrial remodeling currently. This study aimed to investigate the effects of renal denervation (RDN) on diabetes-related atrial remodeling and explore the related mechanisms. A type 2 diabetes mellitus model was established by high-fat diet feeding and low-dose streptozotocin injection in Sprague‒Dawley rats. After successful modeling, the diabetic rats were randomly assigned to two groups according to whether they were subjected to RDN or sham RDN surgery. At the end of the experiment, cardiac function and structure were evaluated by echocardiography and histology, respectively. Mitochondrial morphology, function and mitochondrial dynamics were assessed by multiple methods. Mdivi1 was used to verify the mechanism by which RDN improves atrial remodeling. In the 10th week, diabetic rats exhibited obvious atrial remodeling, including atrial enlargement and diastolic dysfunction. Pathological staining showed that diabetic rats had cardiomyocyte hypertrophy and interstitial fibrosis in atrial tissues. In terms of mitochondrial morphology and function, diabetic rats exhibited fragmented mitochondria, reduced adenosine triphosphate production and decreased mitochondrial membrane potential levels. Abnormal mitochondrial dynamics in diabetic rats were characterized by the inhibition of mitochondrial fusion, excessive mitochondrial fission, and the suppression of mitophagy. However, RDN effectively ameliorated diabetes-induced pathological atrial remodeling. In addition, RDN significantly improved mitochondrial morphological and functional abnormalities and corrected the disorders of mitochondrial dynamics. Furthermore, the protective effects of RDN against atrial remodeling were related to the regulation of mitochondrial dynamics. RDN prevented diabetes-induced atrial remodeling. These protective effects might be related to improvements in mitochondrial dynamics.

Keywords:  Atrial remodeling; Diabetes mellitus; Mitochondrial dynamics; Renal denervation

DOI:  https://doi.org/10.1007/s13105-024-01054-7
Adv Sci (Weinh). 2024 Oct 24. e2407705

Unfractionated Heparin Enhances Sepsis Prognosis Through Inhibiting Drp1-Mediated Mitochondrial Quality Imbalance.

Ruixue Liu, He Huang, Dongyao Hou, Shuai Hao, Qiao Guo, Haitang Liao, Rui Song, Yu Tian, Qian Chen, Zhenchun Luo, Daqing Ma, Liangming Liu, Chenyang Duan.

  Unfractionated heparin (UFH) is commonly used as an anticoagulant in sepsis treatment and has recently been found to have non-anticoagulant effects, but underlying mechanisms remain unclear. This retrospective clinical data showed that UFH has significant protective effects in sepsis compared to low-molecular-weight heparin and enoxaparin, indicating potential benefits of its non-anticoagulant properties. Recombinant protein chip screening, surface plasmon resonance, and molecular docking data demonstrated that UFH specifically bound to the cytoplasmic Drp1 protein through its zone 2 non-anticoagulant segment. In-vitro experiments verified that UFH's specific binding to Drp1 suppressed Drp1 translocation to mitochondria following "sepsis" challenge, thereby improving mitochondrial morphology, function and metabolism in vascular endothelial cells. Consequently, UHF comprehensively protected mitochondrial quality, thus reducing vascular leakage and improving prognosis in a sepsis rat model. These findings highlight the potential of UFH as a sepsis treatment strategy targeting non-anticoagulation mechanism.

Keywords:  Drp1; endothelial dysfunction; mitochondria quality; sepsis; unfractionated heparin

DOI:  https://doi.org/10.1002/advs.202407705
Int J Biol Sci. 2024 ;20(13): 5145-5161

Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis.

Junyan Wang, Haowen Zhuang, Xiaocui Yang, Zhijiang Guo, Kainan Zhou, Nanyang Liu, Yang An, Ye Chen, Zhongzheng Zhang, Mengyuan Wang, Jinhong Chen, Chun Li, Xing Chang.

  Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Compared to small cell lung cancer, NSCLC cells grow and divide more slowly, and their metastasis occurs at a later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) is a flavonoid compound extracted from the plant Caesalpinia sappan, known for its antitumor, redox-regulating, and anti-inflammatory properties. Recent studies have investigated the interaction of SA with mitochondrial pathways in regulating cell death through the Nrf-2/GPX-4/xCT axis. This study specifically explores the mechanism by which SA affects mitochondrial morphology and structure through the regulation of mitophagy and mitochondrial biogenesis in tumor cells. The study primarily utilizes second-generation transcriptomic sequencing data and molecular docking techniques to elucidate the role of SA in regulating programmed cell death in tumor cells. The omics results indicate that SA treatment significantly targets genes involved in oxidative phosphorylation, mitophagy, mitochondrial dynamics, and oxidative stress. Further findings confirmed that the Nrf-2/GPX4/xCT pathway serves as a crucial target of SA in the treatment of NSCLC. Knockdown of Nrf-2 (si-Nrf-2) and Nrf-2 overexpression (ad-Nrf-2) were shown to modulate the therapeutic efficacy of SA to varying degrees. Additionally, modifications to the GPX4/xCT genes significantly affected the regulatory effects of SA on mitochondrial autophagy, biogenesis, and energy metabolism. These regulatory mechanisms may be mediated through the caspase pathway and ferroptosis-related signaling. Molecular biology experiments have demonstrated that SA intervention further inhibits the phosphorylation of FUNDC1 at Tyr18 and downregulates TOM20 expression. SA treatment was found to reduce the expression of PGC1α, Nrf-1, and Tfam, resulting in a decrease in mitochondrial respiration and energy metabolism. Overexpression of Nrf-2 was shown to counteract the regulatory effects of SA on mitophagy and mitochondrial biogenesis. Confocal microscopy experiments further revealed that SA treatment increases mitochondrial fragmentation, subsequently inducing mitochondrial pathway-mediated programmed cell death. However, genetic modification of the Nrf-2/GPX4/xCT pathway significantly altered the regulatory effects of SA on tumor cells. In conclusion, SA has been identified as a promising therapeutic agent for NSCLC. The mitochondrial pathway-mediated apoptosis and ferroptosis may represent key mechanisms in regulating tumor cell death. Targeting the Nrf-2/GPX-4/xCT axis offers a novel therapeutic approach for maintaining mitochondrial homeostasis within the cellular microenvironment.

Keywords:  Non-small-cell carcinoma; Nrf-2/GPX-4/xCT; ferroptosis; mitochondrial; sappanone A

DOI:  https://doi.org/10.7150/ijbs.96748
FASEB J. 2024 Oct 31. 38(20): e70127

Homoplantaginin alleviates high glucose-induced vascular endothelial senescence by inhibiting mtDNA-cGAS-STING pathway via blunting DRP1-mitochondrial fission-VDAC1 axis.

Lei Wang, Xueying Zhang, Xi Huang, Xiaotong Sha, Xulu Li, Jianmei Zheng, Shitong Li, Zhifeng Wei, Feihua Wu.

  Vascular endothelial senescence is a major risk factor for diabetic vascular complications. Abnormal mitochondrial fission by dynamically related protein 1 (DRP1) accelerates vascular endothelial cell senescence. Homoplantaginin (Hom) is a flavonoid in Salvia plebeia R. Br. with protecting mitochondrial and repairing vascular properties. However, the relevant mechanism of Hom against diabetic vascular endothelial cell senescence remains unclear. Here, we used db/db mice and high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs) to assess the anti-vascular endothelial cell senescence of Hom. We found that Hom inhibited senescence-associated β-galactosidase activity, decreased the levels of senescence markers, and senescence-associated secretory phenotype factors. Additionally, Hom inhibited the expression of cGAS-STING pathway and downstream inflammatory factors. STING inhibitor H-151 delayed endothelial senescence, whereas STING overexpression attenuated the anti-endothelial senescence effect of Hom. Furthermore, we observed that Hom reduced mitochondrial fragmentation and inhibited abnormal mitochondrial fission using transmission electron microscopy. Importantly, Hom has a stronger effect on mitochondrial fission protein than mitochondrial fusion protein, especially downregulated the expression of DRP1. DRP1 inhibitor Mdivi-1 suppressed cGAS-STING pathway and vascular endothelial senescence, yet DRP1 agonist FCCP attenuated the effect of Hom. Surprisingly, Hom blunted abnormal mitochondrial fission mediated by DRP1 mitochondrial localization, suppressed interaction of DRP1 with VDAC1 and prevented VDAC1 oligomerization, which was necessary for mtDNA escape and subsequent cGAS-STING pathway activation. These results revealed a previously unrecognized mechanism that Hom alleviated vascular endothelial senescence by inhibited mtDNA-cGAS-STING signaling pathway via blunting DRP1-mitochondrial fission-VDAC1 axis.

Keywords:  DRP1; high glucose; homoplantaginin; mitochondrial fission; vascular endothelial senescence

DOI:  https://doi.org/10.1096/fj.202401299RR
Commun Biol. 2024 Oct 22. 7(1): 1371

MiR-21-3p inhibitor exerts myocardial protective effects by altering macrophage polarization state and reducing excessive mitophagy.

Yujing Huang, Yalin Huang, Zhaoling Cai, Markus W Ferrari, Chengyi Li, Tianzhang Zhang, Guorong Lyu, Zhenhua Wang.

Chronic heart failure (CHF) is closely associated with inflammation and mitochondrial dysfunction in cardiomyocytes. This study attempts to investigate the effects of microRNA-21-3p (miR-21-3p) on macrophage polarization and mitophagy in CHF. Here we found miR-21-3p was upregulated in CHF and negatively correlated with carnitine palmitoyl transferase 1A (CPT1A). L-palmitoyl carnitine (L-PC) exacerbated isoproterenol (ISO)-induced myocardial structural disruption and fibrosis in rats, which was exacerbated by miR-21-3p. Mechanistically, miR-21-3p accelerated M1 macrophage polarization. Both miR-21-3p inhibitor and CPT1A overexpression suppressed mitophagy. The inhibition of CPT1A on mitophagy was reversed by miR-21-3p. MiR-21-3p targeted CPT1A mRNA and co-localized with CPT1A protein in cardiomyocytes. In the co-culture system of M1 macrophages and H9c2 cells, miR-21-3p mimics in H9c2 cells promoted M1 polarization, whereas miR-21-3p inhibitor reduced M1 phenotype. M1 macrophages exacerbated H9c2 cell damage. These findings support the potential therapeutic targeting of miR-21-3p to regulate inflammation and mitophagy by inducing CPT1A in CHF.

DOI: https://doi.org/10.1038/s42003-024-07050-3
J Trace Elem Med Biol. 2024 Oct 11. pii: S0946-672X(24)00169-X. [Epub ahead of print]86 127549

Copper dyshomeostasis and its relationship to AMPK activation, mitochondrial dynamics, and biogenesis of mitochondria: A systematic review of in vivo studies.

Sarah Maria van Tol Amaral Guerra, Letícia Cordeiro Koppe de França, Katriane Neto da Silva, Fabielly Scolari Grotto, Viviane Glaser.

   INTRODUCTION: Copper dyshomeostasis can be related to an increase in copper levels, resulting in toxicity, or to a decrease in tissues levels, impairing cuproenzyme activities. Inside cells, copper can be found in the cytoplasm and inside organelles, and the main organelle that compartmentalizes copper is the mitochondrion. This organelle can form networks and may fuse or fission from this, determining the mitochondrial fusion and fission processes, respectively. Together with mitophagy (autophagy of mitochondria) and mitochondrial biogenesis, mitochondrial fusion and fission (denominated mitochondrial dynamics) determine the number of mitochondria in a cell. A master regulator of mitochondrial dynamics and biogenesis of new mitochondria is AMPK. Considering that both a decrease and an increase in copper levels can influence mitochondrial turnover, especially in diseases related to copper dyshomeostasis, the objective of this systematic review was to verify the current knowledge on the influence of copper homeostasis on AMPK activation, mitochondrial dynamics, and biogenesis of new mitochondria in vivo.
METHODS: PubMed (MEDLINE), Embase, and Web of Science databases were used to search for articles in the literature. Data about the effects of a decrease or an increase in copper levels on the expression of proteins involved in mitochondrial dynamics or biogenesis, and data about AMPK and p-AMPK levels were extracted.
RESULTS: Meta-analysis has demonstrated that high copper levels increase mitochondrial fission and inhibit mitochondrial fusion. Additionally, an increase in copper levels results in AMPK activation. Few studies have analyzed the effects of high copper levels on proteins related to mitochondrial biogenesis, as well as the impact of a decrease in this metal on mitochondrial dynamics and biogenesis, and on AMPK activation.
CONCLUSIONS: Despite the results gathered in this review, other studies are necessary to completely understand the role of copper in regulating AMPK activation, mitochondrial dynamics, and the biogenesis of new mitochondria, since the cell response to a copper dyshomeostasis could be different depending on the species and tissues analyzed.

Keywords:  AMPK; Meta-analysis; Metal; Mitochondria

DOI:  https://doi.org/10.1016/j.jtemb.2024.127549
Sci Rep. 2024 10 21. 14(1): 24654

The broad-spectrum deubiquitinating enzyme inhibitor PR-619 protects retinal ganglion cell and augments parkin-mediated mitophagy in experimental glaucoma.

Xinxin Hu, Juntao Zhang, Haixia Ma, Wei Lian, Wenqiu Song, Chao Du, Shengcan Chen, Dandan Wang, Jiaqi Wei, Qinkang Lu.

  Glaucoma is a leading cause of irreversible visual impairment worldwide, characterized by the progressive death of retinal ganglion cells (RGCs). Deubiquitinating enzyme (DUB) inhibitors have shown promise as pharmacological interventions for neurodegenerative disorders. Our study focuses on the pan-DUB inhibitor PR-619 and its potential neuroprotective effects on RGCs through modulation of parkin-mediated mitophagy in experimental glaucoma models. The results show that impaired mitophagy exists in RGCs of our experimental glaucomatous model. In vivo, PR-619 increased RGCs survival in glaucomatous rats. In vitro, it protected RGCs against excitotoxicity and reduced ubiquitin-specific protease (USP) 15 expression. Additionally, PR-619 upregulated parkin expression, increased LC3-II/LC3-I ratios, and elevated LAMP1 levels, indicating enhanced mitophagy in vivo and in vitro. Moreover, numbers of mitophagosomes were increased in optic nerves of PR-619-treated ocular hypertensive rats in vivo. Furthermore, parkin knockdown negated the salutary effects of PR-619 and attenuated expression of parkin-dependent mitophagy effectors in RGCs subjected to glutamate excitotoxicity in vitro. Collectively, these findings implicate augmented parkin-mediated mitophagy as the mechanistic substrate underscoring the neuroprotective capacity of PR-619 in experimental glaucoma. These revelations engender the prospect that pharmacological agents or biotherapeutics augmenting parkin-mediated mitophagy may proffer viable therapeutic modalities for glaucomatous neurodegeneration characterized by impaired mitophagy.

Keywords:  Glaucoma; Mitophagy; PR-619; Parkin; Retinal ganglion cell

DOI:  https://doi.org/10.1038/s41598-024-75562-3
Cell Biol Toxicol. 2024 Oct 21. 40(1): 89

PRDM1 promotes nucleus pulposus cell pyroptosis leading to intervertebral disc degeneration via activating CASP1 transcription.

Cheng Yu, Jianjun Li, Wenhao Kuang, Songjia Ni, Yanlin Cao, Yang Duan.

  Intervertebral disc degeneration (IVDD) is a primary contributor to low back pain and poses a considerable burden to society. However, the molecular mechanisms underlying IVDD remain to be elucidated. PR/SET domain 1 (PRDM1) regulates cell proliferation, apoptosis, and inflammatory responses in various diseases. Despite these regulatory functions, the mechanism of action of PRDM1 in IVDD remains unexplored. In this study, we investigated the role and underlying mechanisms of action of PRDM1 in IVDD progression. The expression of PRDM1 in nucleus pulposus (NP) tissues and NP cells (NPCs) was assessed using western blotting, immunohistochemistry, and immunofluorescence. The effects of PRDM1 on IVDD progression were investigated in vitro and in vivo. Mechanistically, mRNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to confirm that PRDM1 triggered CASP1 transcription. Our study demonstrated for the first time that PRDM1 expression was substantially upregulated in degenerated NP tissues and NPCs. PRDM1 overexpression promoted NPCs pyroptosis by inhibiting mitophagy and exacerbating IVDD progression, whereas PRDM1 silencing exerted the opposite effect. Furthermore, PRDM1 activated CASP1 transcription, thereby promoting NPCs pyroptosis in vitro. Notably, CASP1 silencing reversed the effects of PRDM1 on the NPCs. To the best of our knowledge, this study is the first to demonstrate that PRDM1 silencing inhibits NPCs pyroptosis by repressing CASP1 transcription, which may be a promising new therapeutic target for IVDD.

Keywords:  CASP1; Intervertebral disc degeneration; Mitophagy; PRDM1; Pyroptosis

DOI:  https://doi.org/10.1007/s10565-024-09932-y
J Nutr Health Aging. 2024 Oct 19. pii: S1279-7707(24)00485-8. [Epub ahead of print]28(12): 100397

Mitochondrial pathways and sarcopenia in the geroscience era.

Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Anna Picca.

  Sarcopenia is associated with structural, ultrastructural, and molecular abnormalities of skeletal muscle. Mitochondrial dysfunction is a pivotal factor involved in muscle aging and sarcopenia. Mitochondrial bioenergetics are significantly reduced in muscles of older adults which is associated with whole-body aerobic capacity, muscle strength, and physical performance. Transcriptional profiling of muscle samples from older adults also revealed inverse correlations between gene expression patterns of autophagy and mitophagy and muscle volume and physical performance. This is in line with the proposition that mitochondrial quality control (MQC) processes are key to organellar and tissue health. MQC encompasses mitochondrial biogenesis, dynamics, and mitophagy. The latter has recently been included among the hallmarks of aging and alterations in MQC have been associated with chronic sterile inflammation as well as muscle atrophy and dysfunction. Several biomarkers spanning MQC, inflammation, metabolism, intercellular communication, and gut microbiota have been linked to sarcopenia. Findings from these initial studies hold promise to inform geroscience-based research in the field of sarcopenia by offering a plausible biological framework for developing gerotherapeutics and monitoring their effects.

Keywords:  Biology of aging; Extracellular vesicles; Inflammaging; Mitochondrial quality control; Multi-Marker; Omics

DOI:  https://doi.org/10.1016/j.jnha.2024.100397
Fly (Austin). 2024 Dec;18(1): 2419151

Mifepristone and rapamycin have non-additive benefits for life span in mated female Drosophila.

Gary N Landis, Britta Baybutt, Shoham Das, Yijie Fan, Kate Olsen, Karissa Yan, John Tower.

  The drugs mifepristone and rapamycin were compared for their relative ability to increase the life span of mated female Drosophila melanogaster. Titration of rapamycin indicated an optimal concentration of approximately 50 μM, which increased median life span here by average +81%. Meta-analysis of previous mifepristone titrations indicated an optimal concentration of approximately 466 μM, which increased median life span here by average +114%. Combining mifepristone with various concentrations of rapamycin did not produce further increases in life span, and instead reduced life span relative to either drug alone. Assay of maximum midgut diameter indicated that rapamycin was equally efficacious as mifepristone in reducing mating-induced midgut hypertrophy. The mito-QC mitophagy reporter is a previously described green fluorescent protein (GFP)-mCherry fusion protein targeted to the outer mitochondrial membrane. Inhibition of GFP fluorescence by the acidic environment of the autophagolysosome yields an increased red/green fluorescence ratio indicative of increased mitophagy. Creation of a multi-copy mito-QC reporter strain facilitated assay in live adult flies, as well as in dissected midgut tissue. Mifepristone was equally efficacious as rapamycin in activating the mito-QC mitophagy reporter in the adult female fat-body and midgut. The data suggest that mifepristone and rapamycin act through a common pathway to increase mated female Drosophila life span, and implicate increased mitophagy and decreased midgut hypertrophy in that pathway.

Keywords:  Drosophila; ageing; hypertrophy; midgut; mifepristone; mitophagy; plasticity; rapamycin; sex peptide; steroid

DOI:  https://doi.org/10.1080/19336934.2024.2419151
Toxicology. 2024 Oct 21. pii: S0300-483X(24)00261-0. [Epub ahead of print] 153980

Bag2 protects against doxorubicin-induced cardiotoxicity by maintaining Pink1-mediated mitophagy.

Hongkai Xiao, Siyu Liang, Qinhong Cai, Jinghu Liu, Liang Jin, Xiaochao Chen.

  The clinical application of Doxorubicin (DOX) is limited due to its cardiotoxicity. Mitophagy dysfunction is the primary cause of DOX-induced cardiotoxicity (DIC). However, the precise mechanism by which DOX regulates mitophagy remains elusive. Bag2 (BCL2-associated athanogene 2) is a cochaperone implicated in multiple pathological states. The aim of this study was to investigate the potential cardio-protective effects of Bag2 in DIC. C57BL/6 mice and AC16 cells were used to establish DIC model. The expression of Bag2 were measured by western blotting and immunohistochemical. The effects of Bag2 on DIC were assessed through functional gain and loss experiments. Through in vitro and in vivo experiments, we found that Bag2 expression was significantly reduced after DOX treatment. Both Bag2 knockdown and DOX administration resulted in apoptosis, mitochondrial dysfunction, and impaired mitophagy. Conversely, Bag2 overexpression exerted protective effects against these phenotypes induced by DOX stimulation. Mechanistically, Bag2 maintained mitophagy activation by binding to Pink1 and protecting it from proteasome-dependent degradation, thereby preserving mitochondrial function and protecting against myocardial lesions. Our findings suggest that Bag2 may serve as a promising therapeutic target for the treatment of DIC.

Keywords:  Bag2; cardiotoxicity; doxorubicin; mitophagy

DOI:  https://doi.org/10.1016/j.tox.2024.153980
Zh Nevrol Psikhiatr Im S S Korsakova. 2024 ;124(9): 109-114

[Regulation of mitophagy and mitochondrial biogenesis by monocarbonyl analogues of curcumin in the cerebral cortex of rats in experimental Alzheimer's disease].

D I Pozdnyakov, A A Vichor.

   OBJECTIVE: To evaluate the effect of monocarbonyl analogues of curcumin on changes in the processes of mitophagy and mitochondrial biogenesis in the cerebral cortex of rats with experimental Alzheimer's disease.
MATERIAL AND METHODS: Alzheimer's disease was modeled in Wistar rats of both sexes by injection of β-amyloid fragments into the hippocampus of the animal. Compounds (1E, 4E)-1.5-bis (3.4.5-trimethoxyphenyl) penta-1.4-diene-3-one (AZBAX4 code) and (1E, 4E)-1.5-bis (2.4.6-trimethoxyphenyl) penta-1.4-diene-3-one (AZBAX6 code) at a dose of 20 mg/ kg (orally) and the reference drug donepezil at a dose of 50 mg/kg (orally) were administered for 30 days, after which changes in the activity of succinate dehydrogenase, cytochrome-c oxidase and citrate synthase as enzymatic biomarkers of mitochondrial biogenesis and mitophagy, respectively, were evaluated in the mitochondrial fraction of the cerebral cortex.
RESULTS: The administration of AZBAX4 and AZBAX6 compounds led to an increase in the activity of succinate dehydrogenase; cytochrome-c oxidase, as well as citrate synthase in relation to the same indicators of the group of untreated animals. The use of the analyzed compounds was equally effective in both female and male rats. At the same time, it should be noted that the analyzed compounds significantly exceeded the activity level of the reference donepezil.
CONCLUSION: AZBAX4 and AZBAX6 contribute to an increase in the intensity of mitochondrial biogenesis and mitophagy reactions in the cerebral cortex of rats with Alzheimer's disease, which makes them potentially effective neuroprotective compounds.

Keywords:  Alzheimer’s disease; curcumin derivatives; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.17116/jnevro2024124091109
Front Pharmacol. 2024 ;15 1493530

Corrigendum: Protective effects of inhibition of mitochondrial fission on organ function after sepsis.

Yu Zhu, Lei Kuang, Yue Wu, Haoyue Deng, Han She, Yuanqun Zhou, Jie Zhang, Liangming Liu, Tao Li.

  [This corrects the article DOI: 10.3389/fphar.2021.712489.].

Keywords:  Drp1; Mdivi-1; mitochondrial fission; organ function; sepsis

DOI:  https://doi.org/10.3389/fphar.2024.1493530
Mol Med. 2024 Oct 22. 30(1): 183

Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate.

Haotian Luo, Hio Cheng Ieong, Runze Li, Delan Huang, Danying Chen, Xin Chen, Yuqing Guo, Yangqiao Qing, Bingyan Guo, Ruoyu Li, Yungshan Teng, Wenfeng Li, Yang Cao, Chen Zhou, Weicai Wang.

   BACKGROUND: Overconsumption of retinoic acid (RA) or its analogues/derivatives has been linked to severe craniomaxillofacial malformations, such as cleft palate and midface hypoplasia. It has been noted that RA disturbed the proliferation and migration of embryonic palatal mesenchymal (EPM) cells in these malformations, yet the exact mechanisms underlying these disruptions remained unclear.
METHODS: A model of retinoic acid (RA)-induced cleft palate in fetal mice was successfully established. Histological alterations in the palate were evaluated using Hematoxylin and Eosin (H&E) staining and RNA in situ hybridization (RNAscope). Cellular proliferation levels were quantified via the Cell Counting Kit-8 (CCK-8) assay and EdU incorporation assay, while cell migration capabilities were investigated using wound healing and Transwell assays. Mitochondrial functions were assessed through Mito-Tracker fluorescence, mitochondrial reactive oxygen species (ROS) measurement, ATP level quantification, and mitochondrial DNA (mtDNA) copy number analysis. Differential gene expression and associated signaling pathways were identified through bioinformatics analysis. Alterations in the transcriptional and translational levels of Lhx6 and genes associated with mitophagy were quantified using quantitative PCR (qPCR) and Western blot analysis, respectively. Mitochondrial morphology and the mitochondrial autophagosomes within cells were examined through transmission electron microscopy (TEM).
RESULTS: Abnormal palatal development in mice, along with impaired proliferation and migration of human embryonic palatal mesenchymal (HEPM) cells, was associated with RA affecting mitochondrial function and concomitant downregulation of Lhx6. Knockdown of Lhx6 in HEPM cells resulted in altered cell proliferation, migration, and mitochondrial function. Conversely, the aberrant mitochondrial function, proliferation, and migration observed in RA-induced HEPM cells were ameliorated by overexpression of Lhx6. Subsequent research demonstrated that Lhx6 ameliorated RA-induced dysfunction in HEPM cells by modulating PINK1/Parkin-mediated mitophagy, thereby activating the MAPK signaling pathways.
CONCLUSION: Lhx6 is essential for mitochondrial homeostasis via tuning PINK1/Parkin-mediated mitophagy and MAPK signaling pathways. Downregulation of Lhx6 by RA transcriptionally disturbs the mitochondrial homeostasis, which in turn leads to the proliferation and migration defect in HEPM cells, ultimately causing the cleft palate.

Keywords:  Cleft palate; Embryonic palatal mesenchymal cells; Lhx6; Mitophagy; PINK1; Retinoic acid

DOI:  https://doi.org/10.1186/s10020-024-00960-2
Animal Model Exp Med. 2024 Oct 24.

RNA-seq analysis of mitochondria-related genes regulated by AMPK in the human trophoblast cell line BeWo.

Bin Wu, Albert Gao, Bin He, Yun Chen, Xiangfeng Kong, Fayuan Wen, Haijun Gao.

   BACKGROUND: How AMP activated protein kinase (AMPK) signaling regulates mitochondrial functions and mitophagy in human trophoblast cells remains unclear. This study was designed to investigate potential players mediating the regulation of AMPK on mitochondrial functions and mitophagy by next generation RNA-seq.
METHODS: We compared ATP production in protein kinase AMP-activated catalytic subunit alpha 1/2 (PRKAA1/2) knockdown (AKD) and control BeWo cells using the Seahorse real-time ATP rate test, then analyzed gene expression profiling by RNA-seq. Differentially expressed genes (DEG) were examined by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Then protein-protein interactions (PPI) among mitochondria related genes were further analyzed using Metascape and Ingenuity Pathway Analysis (IPA) software.
RESULTS: Both mitochondrial and glycolytic ATP production in AKD cells were lower than in the control BeWo cells (CT), with a greater reduction of mitochondrial ATP production. A total of 1092 DEGs were identified, with 405 upregulated and 687 downregulated. GO analysis identified 60 genes associated with the term 'mitochondrion' in the cellular component domain. PPI analysis identified three clusters of mitochondria related genes, including aldo-keto reductase family 1 member B10 and B15 (AKR1B10, AKR1B15), alanyl-tRNA synthetase 1 (AARS1), mitochondrial ribosomal protein S6 (MRPS6), mitochondrial calcium uniporter dominant negative subunit beta (MCUB) and dihydrolipoamide branched chain transacylase E2 (DBT).
CONCLUSIONS: In summary, this study identified multiple mitochondria related genes regulated by AMPK in BeWo cells, and among them, three clusters of genes may potentially contribute to altered mitochondrial functions in response to reduced AMPK signaling.

Keywords:  AMPK; ATP production; RNA‐seq; gene expression; mitochondria; trophoblast

DOI:  https://doi.org/10.1002/ame2.12475
Nat Commun. 2024 Oct 21. 15(1): 9063

Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.

Cristiane Dos Santos, Amanda Cambraia, Shristi Shrestha, Melanie Cutler, Matthew Cottam, Guy Perkins, Varda Lev-Ram, Birbickram Roy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Danielle Dean, Jean Philippe Cartailler, Patrick E MacDonald, Martin Hetzer, Mark Ellisman, Rafael Arrojo E Drigo.

Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.

DOI: https://doi.org/10.1038/s41467-024-53127-2
Free Radic Biol Med. 2024 Oct 22. pii: S0891-5849(24)00997-3. [Epub ahead of print]

Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.

Zaida Abad-Jiménez, Sandra López-Domènech, María Pelechá, Laura Perea-Galera, Susana Rovira-Llopis, Celia Bañuls, Ana Blas-García, Nadezda Apostolova, Carlos Morillas, Víctor Manuel Víctor, Milagros Rocha.

   BACKGROUND: Although it is established that caloric restriction offers metabolic and clinical benefits, the molecular mechanisms underlying these effects remain unclear. Thus, this study aimed to investigate whether caloric restriction can modulate mitochondrial function and remodelling and stimulate autophagic flux in the PBMCs of patients with obesity.
METHODS: This was an interventional study of 38 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical variables, mitochondrial function parameters (by fluorescence imaging of mitochondrial ROS and membrane potential), and protein expression of markers of mitochondrial dynamics (MNF1, MFN2, OPA, DRP1 and FIS1) and autophagy (LC3, Beclin, BCL2 and NBR1) by western blot.
RESULTS: Caloric restriction induced an improvement in metabolic outcomes that was accompanied by an increase in AMPK expression, a decrease of mitochondrial ROS and mitochondrial membrane potential, which was associated with increased markers of mitochondrial dynamics (MFN2, DRP1 and FIS1) and activation of autophagy as evidenced by augmented LC3 II/I, Beclin1 and NBR1, and a decrease in BCL2.
CONCLUSION: These findings shed light on the specific molecular mechanisms by which caloric restriction facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis and cell recovery, including mitochondrial function and dynamics and autophagy.

Keywords:  Obesity; PBMCs; VLCD; autophagy; mitochondrial quality control; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.295
Adv Sci (Weinh). 2024 Oct 21. e2406760

The MICOS Complex Subunit Mic60 is Hijacked by Intracellular Bacteria to Manipulate Mitochondrial Dynamics and Promote Bacterial Pathogenicity.

Changyong Cheng, Mianmian Chen, Jing Sun, Jiali Xu, Simin Deng, Jing Xia, Yue Han, Xian Zhang, Jing Wang, Lei Lei, Ruidong Zhai, Qin Wu, Weihuan Fang, Houhui Song.

  Host mitochondria undergo fission and fusion, which bacteria often exploit for their infections. In this study, the underlying molecular mechanisms are aimed to clarify through which Listeria monocytogenes (L. monocytogenes), a human bacterial pathogen, manipulates mitochondrial dynamics to enhance its pathogenicity. It is demonstrated that L. monocytogenes triggers transient mitochondrial fission through its virulence factor listeriolysin O (LLO), driven by LLO's interaction with Mic60, a core component of the mitochondrial contact site and the cristae organizing system (MICOS). Specifically, Phe251 within LLO is identify as a crucial residue for binding to Mic60, crucial for LLO-induced mitochondrial fragmentation and bacterial pathogenicity. Importantly, it is that Mic60 affect the formation of F-actin tails recruited by L. monocytogenes, thereby contributing to intracellular bacterial infection. Mic60 plays a critical role in mediating changes in mitochondrial morphology, membrane potential, and reactive oxidative species (ROS) production, and L. monocytogenes infection exacerbates these changes by affecting Mic60 expression. These findings unveil a novel mechanism through which intracellular bacteria exploit host mitochondria, shedding light on the complex interplay between hosts and microbes during infections. This knowledge holds promise for developing innovative strategies to combat bacterial infections.

Keywords:  MICOS; Mic60; host‐microbe interplay; listeriolysin O (LLO); mitochondrial fragmentation

DOI:  https://doi.org/10.1002/advs.202406760
Int Immunopharmacol. 2024 Oct 20. pii: S1567-5769(24)01932-5. [Epub ahead of print]143(Pt 2): 113410

High concentration hydrogen attenuates sepsis-induced acute kidney injury by promoting mitochondrial biogenesis and fusion.

Shuaijie Pei, Lina Zheng, Zhigang Tian, Shuqi Meng, Zhiwei Wang, Yan Fan, Jianfeng Liu, Yan Cui, Keliang Xie.

  Sepsis is a major cause of mortality among critical patients. Acute kidney injury (AKI) is the common complication in patients with sepsis, characterized by rapid deterioration of renal function. The purpose of this study is to assess the impact of inhaling high concentration hydrogen on septic mice with AKI and to examine the involvement of mitochondria in this process. High concentration hydrogen does not cause hypoxia and can alleviate AKI and improve 7-day survival in septic mice. Inflammatory factors are markedly elevated in the serum and renal tissues in CLP group which are dramatically down-regulated by hydrogen. The activities of both antioxidant enzymes are significantly reduced after CLP, whereas hydrogen markedly increases the activities of SOD and CAT. MMP is found to be significantly lower in CLP group whereas this effect is reversed by hydrogen. The trend of ATP content in renal tissues corresponded with that of MMP. There is a substantial downregulation of PGC-1α, Nrf2, and TFAM protein in CLP group. Drp1 expression is significantly higher in CLP group compared to Sham group, while the opposite trend is observed for MFN2. Hydrogen can reverse these changes. Inhalation of high concentration hydrogen can improve acute kidney injury, 7-day survival, inflammatory response and oxidative stress in septic mice. The mechanism may be related to inhibit renal mitochondrial fission and promote mitochondrial fusion and biogenesis.

Keywords:  Acute kidney injury; Hydrogen; Mitochondria; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2024.113410
Int J Med Sci. 2024 ;21(13): 2437-2449

Resveratrol Mitigates Uremic Toxin-Induced Intestinal Barrier Dysfunction in Chronic Kidney Disease by Promoting Mitophagy and Inhibiting Apoptosis Pathways.

Cai-Mei Zheng, Yi-Chou Hou, Kuo-Wang Tsai, Wan-Chung Hu, Hsiu-Chien Yang, Min-Tser Liao, Kuo-Cheng Lu.

  Background: Chronic Kidney Disease (CKD) is a systemic progressive disorder related to uremic toxins. Uremic toxins disturb intestinal epithelial destruction and barrier dysfunction leading to gut-renal axis disorders in CKD. We examine the protective role of Resveratrol (RSV) against uremic toxin indoxyl sulphate (IS) related intestinal barrier disturbances among CKD.
METHODS: 5/6 nephrectomized mice and isolated primary mouse intestinal epithelial cells (IEC-6) are used to assess the influence of IS on intestinal epithelial tight junction barriers. Serum biochemistry parameters, hematoxylin & eosin (H&E) and immunohistochemistry staining (IHC), Western blot analysis, q-PCR, and si-RNA targeted against AhR were used in this study.
RESULTS: IS decreases the expression of tight junction proteins (TJPs) ZO-1 and claudins, increases the apoptosis and impairs mitophagy within IECs. Treatment with RSV not only reduces the loss of TJPs but also modulates mitophagy markers LC3 and P62, and concurrently decreases the levels of apoptosis-related proteins. Significantly, RSV ameliorates intestinal barrier dysfunction in CKD by modulating mitophagy via the IRF1-DRP1 axis, restoring autophagy, and inhibiting apoptosis through the activation of the PI3K/Akt-Ho-1 anti-oxidant pathway, and mTOR regulated pathways.
CONCLUSION: This study establishes RSV as a potential therapeutic agent that can ameliorate gut-renal axis disturbances in CKD. These findings provide valuable insights into mechanisms underlying RSV RSV-mediated gut-renal axis, highlighting its effectiveness as a potential treatment option for CKD-associated intestinal barrier dysfunction.

Keywords:  apoptosis; autophagy; indoxyl sulfate; intestinal barrier; mitophagy; resveratrol; tight junction proteins

DOI:  https://doi.org/10.7150/ijms.100963
Neurochem Int. 2024 Oct 19. pii: S0197-0186(24)00212-2. [Epub ahead of print]180 105885

Apelin regulates mitochondrial dynamics by inhibiting Mst1-JNK-Drp1 signaling pathway to reduce neuronal apoptosis after spinal cord injury.

Qixuan Guo, Qing Liu, Shuai Zhou, Yabin Lin, Ang Lv, Luping Zhang, Liming Li, Fei Huang.

  In the secondary injury stage of spinal cord injury, mitochondrial dysfunction leads to decreased ATP production, increased ROS production, and activation of the mitochondria-mediated apoptosis signaling pathway. This ultimately intensifies neuronal death and promotes the progression of the injury. Apelin, a peptide produced by the APLN gene, has demonstrated promise in the treatment of spinal cord injury. The aim of this study was to investigate how Apelin protects neurons after spinal cord injury by influencing the mitochondrial dynamics. The results showed that Apelin has the ability to reduce mitochondrial fission, enhance the mitochondrial membrane potential, improve antioxidant capacity, facilitate the clearance of excess ROS, and ultimately decrease apoptosis in PC12 cells. Moreover, Apelin is overexpressed in neurons in the damaged part of the spinal cord, contributing to reduce mitochondrial fission, improve antioxidant capacity, increase ATP production, decrease apoptosis, promote spinal cord morphological repair, maintain the number of nissl bodies, and enhance signal transduction in the descending spinal cord pathway. Apelin exerts its protective effect by inhibiting the Mst1-JNK-Drp1 signaling pathway. In summary, our study further improved the effect of Apelin in the treatment of spinal cord injury, revealed the mechanism of Apelin in protecting damaged neurons after spinal cord injury by maintaining mitochondrial homeostasis, and provided a new therapeutic mechanism for Apelin in spinal cord injury.

Keywords:  Apelin; Apoptosis; Mitochondria; Mst1-JNK-Drp1; Spinal cord injury

DOI:  https://doi.org/10.1016/j.neuint.2024.105885
Redox Biol. 2024 Oct 15. pii: S2213-2317(24)00373-2. [Epub ahead of print]77 103395

Diallyl disulfide alleviates hepatic steatosis by the conservative mechanism from fish to tetrapod: Augment Mfn2/Atgl-Mediated lipid droplet-mitochondria coupling.

Ling-Jiao Wang, Xiao-Hong Lai, Zhi Luo, Guang-Li Feng, Yu-Feng Song.

  Despite increasing evidences has highlighted the importance of mitochondria-lipid droplet (LD) coupling in maintaining lipid homeostasis, little progress in unraveling the role of mitochondria-LD coupling in hepatic lipid metabolism has been made. Additionally, diallyl disulfide (DADS), a garlic organosulfur compound, has been proposed to prevent hepatic steatosis; however, no studies have focused on the molecular mechanism to date. To address these gaps, this study investigated the systemic control mechanisms of mitochondria-LD coupling regulating hepatic lipid metabolism, and also explored their function in the process of DADS alleviating hepatic steatosis. To this end, an animal model of lipid metabolism, yellow catfish Pelteobagrus fulvidraco were fed four different diets (control, high-fat, DADS and high-fat + DADS diet) in vivo for 8 weeks; in vitro experiments were conducted to inhibit Mfn2/Atgl-mediated mitochondria-LD coupling in isolated hepatocytes. The key findings are: (1) the activations of hepatic LDs lipolysis and mitochondrial β-oxidation are likely the major drivers for DADS alleviating hepatic steatosis; (2) the underlying mechanism is that DADS enhances mitochondria-LD coupling by promoting the interaction between mitochondrion-localized Mfn2 with LD-localized Atgl, which facilitates the hepatic LDs lipolysis and the transfer of fatty acids (FAs) from LDs to mitochondria for subsequent β-oxidation; (3) Mfn2-mediated mitochondrial fusion facilitates mitochondria to form more PDM, which possess higher β-oxidation capacity in hepatocytes. Significantly, the present research unveils a previously undisclosed mechanism by which Mfn2/Atgl-mitochondria-LD coupling relieves hepatic LDs accumulation, which is a conserved strategy from fish to tetrapod. This study provides another dimension for mitochondria-LD coupling and opens up new avenues for the therapeutic interventions in hepatic steatosis.

Keywords:  Diallyl disulfide; Hepatic steatosis; Lipid droplet-mitochondria coupling; Mfn2/Atgl; Mitochondrial dynamic

DOI:  https://doi.org/10.1016/j.redox.2024.103395
ACS Nano. 2024 Oct 25.

Mitochondrial Bioenergetics of Functional Wound Closure is Dependent on Macrophage-Keratinocyte Exosomal Crosstalk.

Anu Sharma, Rajneesh Srivastava, Surya C Gnyawali, Pramod Bhasme, Adam J Anthony, Yi Xuan, Jonathan C Trinidad, Chandan K Sen, David E Clemmer, Sashwati Roy, Subhadip Ghatak.

  Tissue nanotransfection (TNT)-based fluorescent labeling of cell-specific exosomes has shown that exosomes play a central role in physiological keratinocyte-macrophage (mϕ) crosstalk at the wound-site. Here, we report that during the early phase of wound reepithelialization, macrophage-derived exosomes (Exomϕ), enriched with the outer mitochondrial membrane protein TOMM70, are localized in leading-edge keratinocytes. TOMM70 is a 70 kDa adaptor protein anchored in the mitochondrial outer membrane and plays a critical role in maintaining mitochondrial function and quality. TOMM70 selectively recognizes cytosolic chaperones by its tetratricopeptide repeat (TPR) domain and facilitates the import of preproteins lacking a positively charged mitochondrial targeted sequence. Exosomal packaging of TOMM70 in mϕ was independent of mitochondrial fission. TOMM70-enriched Exomϕ compensated for the hypoxia-induced depletion of epidermal TOMM70, thereby rescuing mitochondrial metabolism in leading-edge keratinocytes. Thus, macrophage-derived TOMM70 is responsible for the glycolytic ATP supply to power keratinocyte migration. Blockade of exosomal uptake from keratinocytes impaired wound closure with the persistence of proinflammatory mϕ in the wound microenvironment, pointing toward a bidirectional crosstalk between these two cell types. The significance of such bidirectional crosstalk was established by the observation that in patients with nonhealing diabetic foot ulcers, TOMM70 is deficient in keratinocytes of wound-edge tissues.

Keywords:  TOMM70; functional wound closure; keratinocyte migration; macrophage-derived exosomes; macrophage–keratinocyte crosstalk; tissue nanotransfection; “don’t eat me” plasmid

DOI:  https://doi.org/10.1021/acsnano.4c07610
FEBS J. 2024 Oct 21.

PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system.

Simona Eleuteri, Bao Wang, Gianni Cutillo, Tracy Shi Zhang Fang, Kai Tao, Yan Qu, Qian Yang, Wenyi Wei, David K Simon.

  Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F-box/WD repeat domain-containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin-proteasome system (UPS) and leads to the clearance of PGC-1α. Here, we elucidate a novel post-translational mechanism for regulating PGC-1α levels in neurons. We show that enhancing chaperone-mediated autophagy (CMA) activity promotes the CMA-mediated degradation of FBXW7 and consequently increases PGC-1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC-1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal-associated membrane protein 2A (LAMP2A) in TH-Cre-LAMP2-loxp conditional mice. We further demonstrate that these mice are protected against MPTP-induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC-1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD.

Keywords:  CMA; Fbxw7; PGC‐1α; Parkinson's disease

DOI:  https://doi.org/10.1111/febs.17276
Cancer Res Commun. 2024 Oct 23.

PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells.

Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Wei Lou, Alan P Lombard, Chengfei Liu, Ai-Ming Yu, Nicholas Mitsiades, Allen C Gao.

Olaparib, a PARP inhibitor, is a targeted therapy used in treating various cancers including castration-resistant prostate cancer (CRPC). Despite its efficacy, resistance to Olaparib remains a significant challenge. Understanding the molecular mechanisms underpinning this resistance is crucial for developing more effective treatment strategies. This study focuses on elucidating the role of mitochondrial alterations and the PINK1 gene in conferring Olaparib resistance in CRPC cells. We investigated the transcriptomic and functional differences in mitochondrial activity between Olaparib-resistant (2B-OlapR, LN-OlapR) and treatment naïve prostate cancer (PCa) cells (C4-2B, LNCaP) in both castration sentitive and resistant settings. Through RNA sequencing and Gene Set Enrichment Analysis (GSEA), we identified significant enrichment of mitochondrial and oxidative phosphorylation-related gene sets in Olaparib Resistant derived cell lines. Resistant lines exhibited enhanced mitochondrial functionality including increased basal and maximal respiration rates, as well as elevated ATP production and spare respiratory capacity compared to parental cells. Subsequent investigations revealed a substantial increase in mitochondrial mass and electron transport chain complex I activity in Olaparib-resistant cells. Furthermore, overexpression of the PINK1 gene was observed in resistant cells, which was correlated with resistance to Olaparib and poor clinical outcomes in prostate cancer patients. Inhibition of PINK1 expression significantly reduced mitochondrial function and mass, impaired cell growth, and decreased resistance to Olaparib. These findings suggest that PINK1 plays a crucial role in modulating mitochondrial dynamics that confer therapeutic resistance, highlighting its potential as a therapeutic target for overcoming Olaparib resistance in PCa.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0339
Ann Med. 2024 Dec;56(1): 2411012

The potential mechanism of mitochondrial homeostasis in postoperative neurocognitive disorders: an in-depth review.

Fan Ye, Changwei Wei, Anshi Wu.

  Postoperative neurocognitive disorders (PND) are the most common neurological disorders following surgery and anaesthesia before and within 12 months after surgery, with a high prevalence in the geriatric population. PND can severely deteriorate the quality of life of patients, especially among the elderly, mainly manifested as memory loss, attention, decline and language comprehension disorders, mostly in elderly patients, with an incidence as high as 31%. Previous studies have also raised the possibility of accelerated cognitive decline and underlying neuropathological processes associated with diseases that affect cognitive performance (e.g. Alzheimer's dementia) for reasons related to anaesthesia and surgery. Currently, most research on PND has focused on various molecular pathways, especially in the geriatric population. The various hypotheses that have been proposed regarding the mechanisms imply peripheral neuroinflammation, oxidative stress, mitochondrial homeostasis, synaptic function, autophagy disorder, blood-brain barrier dysfunction, the microbiota-gut-brain axis and lack of neurotrophic support. However, the underlying pathogenesis and molecular mechanisms of PND have not yet been uncovered. Recent research has focused on mitochondrial homeostasis. In this paper, we present a review of various studies to better understand and characterize the mechanisms of associated cognitive dysfunction. As the biochemical basis of PND becomes more clearly defined, future treatments based on mitochondrial homeostasis modulation can prove to be very promising.

Keywords:  Autophagy; cognitive dysfunction; mitochondrial dynamics; neurological disorder

DOI:  https://doi.org/10.1080/07853890.2024.2411012