bims-mikwok 2024-08-25 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–08–25
24 papers selected by
Gavin McStay, Liverpool John Moores University

Panaxadiol Saponin alleviates LPS-induced cardiomyopathy similar to dexamethasone via improving mitochondrial quality control.
FAM210A: An emerging regulator of mitochondrial homeostasis.
Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.
Accumulation of damaged mitochondria in aging astrocytes due to mitophagy dysfunction: Implications for susceptibility to mitochondrial stress.
Targeting mitochondrial quality control: new therapeutic strategies for major diseases.
Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.
Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
Knocking down EGR1 inhibits nucleus pulposus cell senescence and mitochondrial damage through activation of PINK1-Parkin dependent mitophagy, thereby delaying intervertebral disc degeneration.
Salvianolic acid B improves mitochondrial dysfunction of septic cardiomyopathy via enhancing ATF5-mediated mitochondrial unfolded protein response.
Inner membrane turns inside out to exit mitochondrial organelles.
Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.
Myocardial ischemia-reperfusion injury: The balance mechanism between mitophagy and NLRP3 inflammasome.
Mitochondrial elongation confers protection against doxorubicin-induced cardiotoxicity.
Novel Drp1 GTPase Inhibitor, Drpitor1a: Efficacy in Pulmonary Hypertension.
Editorial: Mitochondrial plasticity and quality control in health and disease.
CKIP-1 silencing suppresses OSCC via mitochondrial homeostasis-associated TFAM/cGAS-STING signalling axis.
O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.
3-Nitrotyrosine shortens axons of non-dopaminergic neurons by inhibiting mitochondrial motility.
hUMSCs restore ovarian function in POI mice by regulating GSK3β-mediated mitochondrial dynamic imbalances in theca cells.
MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
Ferulic acid restores mitochondrial dynamics and autophagy via AMPK signaling pathway in a palmitate-induced hepatocyte model of metabolic syndrome.
FTMT-dependent mitophagy is crucial for ferroptosis resistance in cardiac fibroblast.
Construction of a mitophagy-related prognostic signature for predicting prognosis and tumor microenvironment in lung adenocarcinoma.
Drosophila model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy.

Shock. 2024 Aug 23.

Panaxadiol Saponin alleviates LPS-induced cardiomyopathy similar to dexamethasone via improving mitochondrial quality control.

Zhaoyun Yang, Yan Gao, Dongyang Li, Lijing Zhao, Yanwei Du.

ABSTRACT: Septic cardiomyopathy is linked to a dysregulation in mitochondrial integrity and elevated mortality rates, for which an efficacious treatment remains elusive. PDS, a panaxadiol saponin extracted from ginseng stem and leaf. This study identified the protective effects of PDS and DEX in LPS-induced cardiomyopathy and explored the mechanism of them treating LPS-induced cardiomyopathy from the perspectives of mitochondrial quality control. DEX and PDS enhance antioxidant defense by degrading Keap1 to activate Nrf2, activate mitochondrial occurrence protein PGC-1α and fusion protein OPA1, Mfn1, Mfn2 expression, inhibit phosphorylation of mitochondrial fission protein Drp1, aiming to maintain normal structure and function of mitochondrial, thereby preserving oxidative phosphorylation capacity. In summary, our findings highlighted that the protective efficacy of PDS and DEX in maintaining mitochondrial in LPS-induced cardiomyopathy, and mechanism improving mitochondrial quality control at least in part by promoting Nrf2 activation.

DOI: https://doi.org/10.1097/SHK.0000000000002449
Bioessays. 2024 Aug 19. e2400090

FAM210A: An emerging regulator of mitochondrial homeostasis.

Yubo Wang, Feng Yue.

  Mitochondrial homeostasis serves as a cornerstone of cellular function, orchestrating a delicate balance between energy production, redox status, and cellular signaling transduction. This equilibrium involves a myriad of interconnected processes, including mitochondrial dynamics, quality control mechanisms, and biogenesis and degradation. Perturbations in mitochondrial homeostasis have been implicated in a wide range of diseases, including neurodegenerative diseases, metabolic syndromes, and aging-related disorders. In the past decades, the discovery of numerous mitochondrial proteins and signaling has led to a more complete understanding of the intricate mechanisms underlying mitochondrial homeostasis. Recent studies have revealed that Family with sequence similarity 210 member A (FAM210A) is a novel nuclear-encoded mitochondrial protein involved in multiple aspects of mitochondrial homeostasis, including mitochondrial quality control, dynamics, cristae remodeling, metabolism, and proteostasis. Here, we review the function and physiological role of FAM210A in cellular and organismal health. This review discusses how FAM210A acts as a regulator on mitochondrial inner membrane to coordinate mitochondrial dynamics and metabolism.

Keywords:  FAM210A; cristae remodeling; energy metabolism; mitochondrial dynamics; proteostasis; quality control

DOI:  https://doi.org/10.1002/bies.202400090
Cell Signal. 2024 Aug 19. pii: S0898-6568(24)00321-8. [Epub ahead of print] 111353

Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.

Yongshu Wu, Yang Yang, Xiaodong Qin, Zhixiong Zhang, Munib Ullah, Yanmin Li, Zhidong Zhang.

  The mitochondrial unfolded protein response (UPRmt) is triggered through eIF2α phosphorylation in mammals. However, the mechanisms of UPRmt activation and the influence of eIF2α phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt is a rapid and specific stress response that occurs through pharmacological induction of eIF2α phosphorylation, along with the phosphorylation of eIF2α, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2α phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interactions with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2α phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, including its implications for human disease and pathobiology.

Keywords:  Heme-regulated inhibitor; Mitochondrial proteostasis; Mitochondrial unfolded protein response; eIF2α phosphorylation

DOI:  https://doi.org/10.1016/j.cellsig.2024.111353
Biochim Biophys Acta Mol Basis Dis. 2024 Aug 15. pii: S0925-4439(24)00463-0. [Epub ahead of print]1870(8): 167470

Accumulation of damaged mitochondria in aging astrocytes due to mitophagy dysfunction: Implications for susceptibility to mitochondrial stress.

Luan Pereira Diniz, Ana Paula Bergamo Araujo, Clara Fernandes Carvalho, Isadora Matias, Lívia de Sá Hayashide, Mariana Marques, Bruna Pessoa, Cherley Borba Vieira Andrade, Gabriele Vargas, Daniela Dias Queiroz, Jorge José de Carvalho, Antonio Galina, Flávia Carvalho Alcantara Gomes.

  Aging disrupts brain function, leading to cognitive decline and neurodegenerative diseases. Senescent astrocytes, a hallmark of aging, contribute to this process through unknown mechanisms. This study investigates how senescence impacts astrocytic mitochondrial dynamics, which are critical for brain health. Our research, conducted using aged mouse brains, represents the first evidence of morphologically damaged mitochondria in astrocytes, along with functional alterations in mitochondrial respiration. In vitro experiments revealed that senescent astrocytes exhibit an increase in mitochondrial fragmentation and impaired mitophagy. Concurrently, there was an upregulation of mitochondrial biogenesis, indicating a compensatory response to mitochondrial damage. Importantly, these senescent astrocytes were more susceptible to mitochondrial stress, a vulnerability reversed by rapamycin treatment. These findings suggest a potential link between senescence, impaired mitochondrial quality control, and increased susceptibility to mitochondrial stress in astrocytes. Overall, our study highlights the importance of addressing mitochondrial dysfunction and senescence-related changes in astrocytes as a promising approach for developing therapies to counter age-related neurodegeneration and improve brain health.

Keywords:  Aging; Astrocytes; Mitochondria and senescence

DOI:  https://doi.org/10.1016/j.bbadis.2024.167470
Mil Med Res. 2024 Aug 21. 11(1): 59

Targeting mitochondrial quality control: new therapeutic strategies for major diseases.

Wei-Long Hong, He Huang, Xue Zeng, Chen-Yang Duan.

  Mitochondria play a crucial role in maintaining the normal physiological state of cells. Hence, ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases. Previous reviews on this topic have however been inconsistencies and lack of systematic organization. Therefore, this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases. This review systematically summarizes three fundamental characteristics of mitochondrial quality control, including mitochondrial morphology and dynamics, function and metabolism, and protein expression and regulation. It also extensively examines how imbalances in mitochondrial quality are linked to major diseases, such as ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, degenerative conditions, and tumors. Additionally, the review explores innovative approaches to target mitochondrial quality control, including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality, nanomolecular materials designed for precise targeting of mitochondria, and novel cellular therapies, such as vesicle therapy and mitochondrial transplantation. This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.

Keywords:  Major diseases; Mitochondrial quality control; Mitochondrial targeted therapy

DOI:  https://doi.org/10.1186/s40779-024-00556-1
Autophagy. 2024 Aug 23.

Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.

Katharina C Lorentzen, Alan R Prescott, Ian G Ganley.

  Macroautophagy/autophagy enables lysosomal degradation of a diverse array of intracellular material. This process is essential for normal cellular function and its dysregulation is implicated in many diseases. Given this, there is much interest in understanding autophagic mechanisms of action in order to determine how it can be best targeted therapeutically. In mitophagy, the selective degradation of mitochondria via autophagy, mitochondria first need to be primed with signals that allow the recruitment of the core autophagy machinery to drive the local formation of an autophagosome around the target mitochondrion. To determine how the recruitment of different core autophagy components can drive mitophagy, we took advantage of the mito-QC mitophagy assay (an outer mitochondrial membrane-localized tandem mCherry-GFP tag). By tagging autophagy proteins with an anti-mCherry (or anti-GFP) nanobody, we could recruit them to mitochondria and simultaneously monitor levels of mitophagy. We found that targeting ULK1, ATG16L1 and the different Atg8-family proteins was sufficient to induce mitophagy. Mitochondrial recruitment of ULK1 and the Atg8-family proteins induced a conventional mitophagy pathway, requiring RB1CC1/FIP200, PIK3C3/VPS34 activity and ATG5. Surprisingly, the mitophagy pathway upon recruitment of ATG16L1 proceeded independently of ATG5, although it still required RB1CC1 and PIK3C3/VPS34 activity. In this latter pathway, mitochondria were alternatively delivered to lysosomes via uptake into early endosomes.

Keywords:  ATG16L1; Atg8; ULK1; nanobody; targeted organelle degradation

DOI:  https://doi.org/10.1080/15548627.2024.2395149
Nature. 2024 Aug 21.

Lysosomes drive the piecemeal removal of mitochondrial inner membrane.

Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.

Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.

DOI: https://doi.org/10.1038/s41586-024-07835-w
Free Radic Biol Med. 2024 Aug 14. pii: S0891-5849(24)00601-4. [Epub ahead of print]224 9-22

Knocking down EGR1 inhibits nucleus pulposus cell senescence and mitochondrial damage through activation of PINK1-Parkin dependent mitophagy, thereby delaying intervertebral disc degeneration.

Zuo-Long Wu, Ke-Ping Wang, Ya-Jun Chen, Wei Song, Yong Liu, Kai-Sheng Zhou, Peng Mao, Zhong Ma, Hai-Hong Zhang.

  Mitophagy plays a crucial role in maintaining the homeostasis of intervertebral disc (IVD). Early Growth Response 1 (EGR1), a conservative transcription factor, is commonly upregulated under oxidative stress conditions and participates in regulating cellular senescence, apoptosis, and inflammatory responses. However, the specific role of EGR1 in nucleus pulposus (NP) cell senescence and mitophagy remains unclear. In this study, through bioinformatics analysis and validation using human tissue specimens, we found that EGR1 is significantly upregulated in IVD degeneration (IDD). Further experimental results demonstrate that knockdown of EGR1 inhibits TBHP-induced NP cell senescence and mitochondrial dysfunction while promoting the activation of mitophagy. The protective effect of EGR1 knockdown on NP cell senescence and mitochondrion disappears upon inhibition of mitophagy with mdivi1. Mechanistic studies reveal that EGR1 suppresses NP cell senescence and mitochondrial dysfunction by modulating the PINK1-Parkin dependent mitophagy pathway. Additionally, EGR1 knockdown delays acupuncture-induced IDD in rats. In conclusion, our study demonstrates that under TBHP-induced oxidative stress, EGR1 knockdown mitigates NP cell senescence and mitochondrial dysfunction through the PINK1-Parkin dependent mitophagy pathway, thereby alleviating IDD.

Keywords:  Cell senescence; EGR1; IDD; Mitophagy; Oxidative stress; PINK1; Parkin

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.015
Toxicol Appl Pharmacol. 2024 Aug 15. pii: S0041-008X(24)00270-9. [Epub ahead of print]491 117072

Salvianolic acid B improves mitochondrial dysfunction of septic cardiomyopathy via enhancing ATF5-mediated mitochondrial unfolded protein response.

Renshan Chen, Anran Zheng, Yunjing Wang, Liyou Guo, Huaqian Dou, Liangyan Lu, Muhammad Rafiq, Peihua Li, Xiuhui Chen, Qing Xiao.

   AIMS: Septic cardiomyopathy is characterized by impaired contractile function and mitochondrial activity dysregulation. Salvianolic acid B (Sal B) is a potent therapeutic compound derived from the traditional Chinese medicine Salvia miltiorrhiza. This study explored the protective effects of Sal B on septic heart injury, emphasizing the mitochondrial unfolded protein response (UPRmt).
MATERIALS AND METHODS: An in vivo mouse model of lipopolysaccharide (LPS)-induced heart injury was utilized to assess Sal B's protective role in septic cardiomyopathy. Additionally, cell models stimulated by LPS were developed to investigate the mechanisms of Sal B on UPRmt. Quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence were employed for molecular analysis.
RESULTS: Sal B, administered at doses of 10, 30, and 60 mg/kg, demonstrated protective effects on cardiac contractile function, reduced heart inflammation, and mitigated cardiac injury in LPS-exposed mice. In cardiomyocytes, LPS induced apoptosis, elevated mitochondrial ROS levels, promoted mitochondrial fission, and decreased mitochondrial membrane potential, all of which were alleviated by Sal B. Mechanistically, Sal B was found to induce UPRmt both in vivo and in vitro. ATF5, identified as a UPRmt activator, was modulated by LPS and Sal B, resulting in increased ATF5 expression and its translocation from the cytosol to the nucleus. ATF5-siRNA delivery reversed UPRmt upregulation, exacerbating mitochondrial dysfunction in LPS-stimulated cardiomyocytes and counteracting the mitochondrial function enhancement in Sal B-treated cardiomyocytes.
CONCLUSIONS: This study provides evidence that Sal B confers cardiac protection by enhancing UPRmt, highlighting its potential as a therapeutic approach for mitigating mitochondrial dysfunction in septic cardiomyopathy.

Keywords:  ATF5; Mitochondrial dysfunction; Mitochondrial unfolded protein response; Salvianolic acid B; Septic cardiomyopathy

DOI:  https://doi.org/10.1016/j.taap.2024.117072
Nature. 2024 Aug;632(8027): 987-988

Inner membrane turns inside out to exit mitochondrial organelles.

David Pla-Martín, Andreas S Reichert.



Keywords:  Biochemistry; Cell biology

DOI:  https://doi.org/10.1038/d41586-024-02528-w
Elife. 2024 Aug 19. pii: e97027. [Epub ahead of print]13

Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.

Sara Bitar, Timo Baumann, Christopher Weber, Majd Abusaada, Liliana Rojas-Charry, Patrick Ziegler, Thomas Schettgen, Isabella Eva Randerath, Vivek Venkataramani, Bernhard Michalke, Eva-Maria Hanschmann, Giuseppe Arena, Rejko Krueger, Li Zhang, Axel Methner.

  Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila orthologue of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.

Keywords:  D. melanogaster; cell biology; human; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.97027
Life Sci. 2024 Aug 20. pii: S0024-3205(24)00588-5. [Epub ahead of print]355 122998

Myocardial ischemia-reperfusion injury: The balance mechanism between mitophagy and NLRP3 inflammasome.

Li Chen, Lin-Shen Mao, Jin-Yi Xue, Yu-Hong Jian, Zi-Wen Deng, Maryam Mazhar, Yuan Zou, Ping Liu, Ming-Tai Chen, Gang Luo, Meng-Nan Liu.

  Myocardial ischemia-reperfusion injury (MIRI) is an injury to cardiomyocytes due to restoration of blood flow after myocardial infarction (MI). It has recently gained much attention in clinical research with special emphasis on the roles of mitochondrial autophagy and inflammation. A mild inflammatory response promotes recovery of post-ischemic cardiomyocyte function and vascular regeneration, but a severe inflammatory response can cause irreversible and substantial cellular damage. Similarly, moderate mitochondrial autophagy can help inhibit excessive inflammation and protect cardiomyocytes. However, MIRI is aggravated when mitochondrial function is disrupted, such as inadequate clearance of damaged mitochondria or excessive activation of mitophagy. How to moderately control mitochondrial autophagy while promoting its balance with nucleotide-binding oligomerization structural domain receptor protein 3 (NLRP3) inflammasome activation is critical. In this paper, we reviewed the molecular mechanisms of mitochondrial autophagy and NLRP3 inflammasome, described the interaction between NLRP3 inflammasome and mitochondrial autophagy, and the effects of different signaling pathways and molecular proteins on MIRI, to provide a reference for future research.

Keywords:  Inflammatory response; Mitochondrial autophagy; Myocardial ischemia-reperfusion injury; Nucleotide-binding oligomerization structural domain receptor protein 3; Signaling pathway

DOI:  https://doi.org/10.1016/j.lfs.2024.122998
Biochem Pharmacol. 2024 Aug 17. pii: S0006-2952(24)00478-7. [Epub ahead of print]229 116495

Mitochondrial elongation confers protection against doxorubicin-induced cardiotoxicity.

Weibin He, Wenlong He, Xiaopan Chen, Lin Zeng, Lihuan Zeng, Yuanhui Liu, Pengcheng He, Zhongchan Sun.

  Doxorubicin (DOX)-induced cardiac damage remains a leading cause of death amongst cancer survivors. DOX-induced cardiotoxicity (DIC) is mediated by disturbed mitochondrial dynamics, but it remains debated that the mechanisms by which DOX disrupted equilibrium between mitochondrial fission and fusion. In the present study, we observed that DOX induced mitochondrial elongation in multiple cardiovascular cell lines. Mechanically, DOX not only downregulated the mitochondrial fusion proteins including Mitofusin 1/2 (MFN1/2) and Optic atrophy 1 (OPA1), but also induced lower motility of dynamin-related protein 1(Drp1) and its phosphorylation on 637 serine, which could inhibit mitochondrial fission. Interestingly, DOX failed to induce mitochondrial elongation in cardiomyocytes co-treated with protein kinase A (PKA) inhibitor H89 or expressing phosphodeficient Drp1-S637A variants. Besides, carbonyl cyanide 3-chlorophenylhydrazone (CCCP) was able to blocked the mitochondrial elongation induced by DOX treatment, which could be phenocopied by OPA1 knockdown. Therefore, we speculated that DOX inhibited mitochondrial fission and fusion simultaneously, yet enabled mitochondrial fusion dominate the mitochondrial dynamics, resulting in mitochondrial elongation as the main manifestation. Notably, blocking mitochondrial elongation by inhibiting Drp1-S637 phosphorylation or OPA1 knockdown aggravated DOX-induced cardiomyocytes death. Based on these results, we propose a novel mechanistic model that DOX-induced mitochondrial elongation is attributed to the equilibrium disturbance of mitochondrial dynamics, which serves as an adaptive response and confers protection against DIC.

Keywords:  Cardiotoxicity; Doxorubicin; Fission; Fusion; Mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.bcp.2024.116495
Hypertension. 2024 Aug 20.

Novel Drp1 GTPase Inhibitor, Drpitor1a: Efficacy in Pulmonary Hypertension.

Danchen Wu, Ross D Jansen-van Vuuren, Asish Dasgupta, Ruaa Al-Qazazi, Kuang-Hueih Chen, Ashley Martin, Jeffrey D Mewburn, Elahe Alizadeh, Patricia D A Lima, Oliver Jones, Pierce Colpman, Rachel E T Bentley, M Martin VandenBroek, Nolan M Breault, Isaac M Emon, V Siddartha Yerramilli, Luka Jedlovčnik, Yuan Zhao, Michael Wells, Gopinath Sutendra, Mark L Ormiston, Stephen L Archer.

   BACKGROUND: Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH). We developed a potent Drp1 GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy in PAH are unknown.
METHODS: Drpitor1a's ability to inhibit recombinant and endogenous Drp1-GTPase was assessed. Drpitor1a's effects on fission were studied in control and PAH human pulmonary artery smooth muscle cells (hPASMC) and blood outgrowth endothelial cells (BOEC). Cell proliferation and apoptosis were studied in hPASMC. Pharmacokinetics and tissue concentrations were measured following intravenous and oral drug administration. Drpitor1a's efficacy in regressing monocrotaline-PAH was assessed in rats. In a pilot study, Drpitor1a reduced PA remodeling only in females. Subsequently, we compared Drpitor1a to vehicles in normal and monocrotaline-PAH females.
RESULTS: Drp1 GTPase activity was increased in PAH hPASMC. Drpitor1a inhibited the GTPase activity of recombinant and endogenous Drp1 and reversed the increased fission, seen in PAH hPASMC and PAH BOEC. Drpitor1a inhibited proliferation and induced apoptosis in PAH hPASMC without affecting electron transport chain activity, respiration, fission/fusion mediator expression, or mitochondrial Drp1 translocation. Drpitor1a did not inhibit proliferation or alter mitochondrial dynamics in normal hPASMC. Drpitor1a regressed monocrotaline-PAH without systemic vascular effects or toxicity.
CONCLUSIONS: Drpitor1a is a specific Drp1-GTPase inhibitor that reduces mitochondrial fission in PAH hPASMC and PAH BOEC. Drpitor1a reduces proliferation and induces apoptosis in PAH-hPASMC and regresses monocrotaline-PAH. Drp1 is a therapeutic target in PAH, and Drpitor1a is a potential therapy with an interesting therapeutic sexual dimorphism.

Keywords:  GTP phosphohydrolases; endothelial cells; familial primary pulmonary hypertension; mitochondrial dynamics; monocrotaline

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.124.22822
Front Cell Dev Biol. 2024 ;12 1468818

Editorial: Mitochondrial plasticity and quality control in health and disease.

Francesca Forini, Elena Levantini, Emilia Bramanti, Filippo Maria Santorelli, Azhar Ali, Vincenzo Lionetti, Milena Rizzo.



Keywords:  mitochondria in development and differentiation; mitochondria quality control; mitochondrial disorders; mitochondrial dysfunction in pathologies; mitochondrial genome

DOI:  https://doi.org/10.3389/fcell.2024.1468818
J Cell Mol Med. 2024 Aug;28(16): e70006

CKIP-1 silencing suppresses OSCC via mitochondrial homeostasis-associated TFAM/cGAS-STING signalling axis.

Ji-Rong Xie, Xiao-Jie Chen, Gang Zhou.

  Limited effective targets have challenged the treatment of oral squamous cell carcinoma (OSCC). Casein kinase 2 interacting protein 1 (CKIP-1) is a scaffold protein involved in various diseases. However, the role of CKIP-1 in OSCC remains unclear. The aim of this study was to explore the regulatory role of CKIP-1 in OSCC, as well as the involved mechanism. First, higher expression of CKIP-1 in OSCC tissues and cell lines were found. Series of gain- and loss-of-function experiments demonstrated suppressed malignant behaviours and enhanced apoptosis of OSCC cells when CKIP-1 was silenced. Also, inhibited tumour growth in CKIP-1-silenced group were proved. Further, mitochondrial transcription factor A (TFAM) downregulation, increased ROS production, decreased mitochondrial membrane potential and cGAS-STING activation in CKIP-1-silenced group were observed. The involvement of mitochondrial homeostasis-related TFAM/cGAS-STING axis in CKIP-1-silenced OSCC cells was finally demonstrated by tetramethylpyrazine (TMP) that inhibits TFAM degradation. Taken together, our study demonstrated that CKIP-1 silencing could significantly antagonize OSCC via TFAM/cGAS-STING axis, which may provide a candidate target for OSCC treatment.

Keywords:  gene therapy; mitochondria; oral squamous cell carcinoma; signal transduction

DOI:  https://doi.org/10.1111/jcmm.70006
Front Aging Neurosci. 2024 ;16 1387931

O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.

Ibtihal M Alghusen, Marisa S Carman, Heather M Wilkins, Taylor A Strope, Caleb Gimore, Halyna Fedosyuk, Jad Shawa, Sophiya John Ephrame, Aspin R Denson, Xiaowan Wang, Russell H Swerdlow, Chad Slawson.

   Background: The accumulation of dysfunctional mitochondria is an early feature of Alzheimer's disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation, leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global post-translational modification β-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a ubiquitous single sugar modification found in the nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), respectively.
Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma cell lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) or OGT deficiency on mitophagy using biochemical analyses.
Results: Here, we established an essential role for O-GlcNAc in regulating mitophagy (mitochondria-selective autophagy). Stimulating mitophagy using urolithin A (UA) decreases cellular O-GlcNAc and elevates mitochondrial O-GlcNAc. Sustained elevation in O-GlcNAcylation via pharmacologically inhibiting OGA using Thiamet-G (TMG) increases the mitochondrial level of mitophagy protein PTEN-induced kinase 1 (PINK1) and autophagy-related protein light chain 3 (LC3). Moreover, we detected O-GlcNAc on PINK1 and TMG increases its O-GlcNAcylation level. Conversely, decreasing cellular O-GlcNAcylation by knocking down OGT decreases both PINK1 protein expression and LC3 protein expression. Mitochondria isolated from CAMKII-OGT-KO mice also had decreased PINK1 and LC3. Moreover, human brain organoids treated with TMG showed significant elevation in LC3 compared to control. However, TMG-treated AD organoids showed no changes in LC3 expression.
Conclusion: Collectively, these data demonstrate that O-GlcNAc plays a crucial role in the activation and progression of mitophagy, and this activation is disrupted in AD.

Keywords:  Alzheimer’s disease; O-GlcNAc; OGT; PTEN-induced kinase-1; mitophagy

DOI:  https://doi.org/10.3389/fnagi.2024.1387931
Neurochem Int. 2024 Aug 16. pii: S0197-0186(24)00159-1. [Epub ahead of print]179 105832

3-Nitrotyrosine shortens axons of non-dopaminergic neurons by inhibiting mitochondrial motility.

Masahiro Hirai, Kohei Suzuki, Yusuke Kassai, Yoshiyuki Konishi.

  3-Nitrotyrosine (3-NT), a byproduct of oxidative and nitrosative stress, is implicated in age-related neurodegenerative disorders. Current literature suggests that free 3-NT becomes integrated into the carboxy-terminal domain of α-tubulin via the tyrosination/detyrosination cycle. Independently of this integration, 3-NT has been associated with the cell death of dopaminergic neurons. Given the critical role of tyrosination/detyrosination in governing axonal morphology and function, the substitution of tyrosine with 3-NT in this process may potentially disrupt axonal homeostasis, although this aspect remains underexplored. In this study, we examined the impact of 3-NT on the axons of cerebellar granule neurons, which is used as a model for non-dopaminergic neurons. Our observations revealed axonal shortening, which correlated with the incorporation of 3-NT into α-tubulin. Importantly, this axonal effect was observed prior to the onset of cellular death. Furthermore, 3-NT was found to diminish mitochondrial motility within the axon, leading to a subsequent reduction in mitochondrial membrane potential. The suppression of syntaphilin, a protein responsible for anchoring mitochondria to microtubules, restored the mitochondrial motility and axonal elongation that were inhibited by 3-NT. These findings underscore the inhibitory role of 3-NT in axonal elongation by impeding mitochondrial movement, suggesting its potential involvement in axonal dysfunction within non-dopaminergic neurons.

Keywords:  3-Nitrotyrosine; Axonal growth; Cerebellar granule neurons; Microtubules; Mitochondria; Tubulin tyrosine ligase

DOI:  https://doi.org/10.1016/j.neuint.2024.105832
Sci Rep. 2024 08 16. 14(1): 19008

hUMSCs restore ovarian function in POI mice by regulating GSK3β-mediated mitochondrial dynamic imbalances in theca cells.

Yanlian Xiong, Yaru Si, Rengui Quan, Xingyu Huo, Juntong Chen, Jinyu Xu, Zhonglin Jiang, Feibo Xu, Ranran Liu, Qiang Fu.

  Premature ovarian insufficiency (POI), a major cause of female infertility, is defined as follicular atresia and a rapid loss of germ cells in women of reproductive age due to ovarian failure. Recently, findings from several studies have indicated that human umbilical cord mesenchymal stem cells (hUMSCs) can alleviate ovarian dysfunction resulting from POI. However, the mechanisms underlying this effect require further clarification. In this study, a mouse model of POI was established as achieved with an intraperitoneal injection of cyclophosphamide (CTX) into female C57BL/6J mice in vivo. These POI mice received a 1-week intervention of hUMACs. In addition, an in vitro POI model was also included. The cultured supernatants of hUMSCs and glycogen synthase kinase 3 beta (GSK3β) inhibitor (SB216763) were used to treat theca cells (TCs) exposed to CTX. Hematoxylin and Eosin (H&E) staining and Enzyme-linked immunosorbent assay (ELISA) were used to assess ovarian structure and morphology, as well as endocrine function in these POI mice. Based on results from the ELISA and JC-1 labeling, CTX exerted significant detrimental effects on testosterone levels and the mitochondrial membrane potential in TCs. Subsequently, Western Blot, Immunofluorescence staining (IF), and Quantitative real-time polymerase chain reaction (qRT-PCR) were used to evaluate various indicators of testosterone synthesis function and mitochondrial dynamics in ovaries and TCs of POI mice. In vivo, dysfunctions in ovarian structure and function in the POI mouse model were effectively restored following hUMSCs treatment, and abnormalities in hormone synthesis were significantly reduced. Furthermore, when the stem cell supernatants of hUMSCs were applied to TCs in vitro we found that GSK3β expression was reduced, the imbalance of mitochondrial dynamics was alleviated, and the ability of mitochondrial testosterone synthesis was increased. Taken together, our results indicate that hUMSCs treatment can restore the imbalance of mitochondrial dynamics and restart testosterone synthesis of TCs by suppressing GSK3β expression, ultimately alleviating POI damage.

Keywords:  GSK3β; Mitochondrial dynamic; POI; Theca cells; hUMSCs

DOI:  https://doi.org/10.1038/s41598-024-69381-9
Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402491121

MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.

Prottoy Hasan, Elena Berezhnaya, Macarena Rodríguez-Prados, David Weaver, Carmen Bekeova, Benjamin Cartes-Saavedra, Erin Birch, Andreas M Beyer, Janine H Santos, Erin L Seifert, John W Elrod, György Hajnóczky.

  Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.

Keywords:  MICU1; MICU2; calcium; cardiomyocyte; mitochondrial calcium uniporter gating

DOI:  https://doi.org/10.1073/pnas.2402491121
Sci Rep. 2024 08 16. 14(1): 18970

Ferulic acid restores mitochondrial dynamics and autophagy via AMPK signaling pathway in a palmitate-induced hepatocyte model of metabolic syndrome.

Yitong Li, Weiyang Zhao, Ali Tahir Sair, Tong Li, Rui Hai Liu.

  Mitochondrial dysfunction, characterized by elevated oxidative stress, impaired energy balance, and dysregulated mitochondrial dynamics, is a hallmark of metabolic syndrome (MetS) and its comorbidities. Ferulic acid (FA), a principal phenolic compound found in whole grains, has demonstrated potential in ameliorating oxidative stress and preserving energy homeostasis. However, the influence of FA on mitochondrial health within the context of MetS remains unexplored. Moreover, the impact of FA on autophagy, which is essential for maintaining energy homeostasis and mitochondrial integrity, is not fully understood. Here, we aimed to study the mechanisms of action of FA in regulating mitochondrial health and autophagy using palmitate-treated HepG2 hepatocytes as a MetS cell model. We found that FA improved mitochondrial health by restoring redox balance and optimizing mitochondrial dynamics, including biogenesis and the fusion/fission ratio. Additionally, FA was shown to recover autophagy and activate AMPK-related cell signaling. Our results provide new insights into the therapeutic potential of FA as a mitochondria-targeting agent for the prevention and treatment of MetS.

Keywords:  Autophagy; Diabetes; Ferulic acid; Metabolic syndrome; Mitochondria; Obesity; Phenolics

DOI:  https://doi.org/10.1038/s41598-024-66362-w
Biochim Biophys Acta Mol Cell Res. 2024 Aug 19. pii: S0167-4889(24)00168-X. [Epub ahead of print] 119825

FTMT-dependent mitophagy is crucial for ferroptosis resistance in cardiac fibroblast.

Cheng-Zhang Xu, Qing-Yuan Gao, Guang-Hao Gao, Zhi-Teng Chen, Mao-Xiong Wu, Guang-Hong Liao, Yang-Wei Cai, Nuo Chen, Jing-Feng Wang, Hai-Feng Zhang.

  Metabolic responses to cellular stress are pivotal in cell ferroptosis, with mitophagy serving as a crucial mechanism in both metabolic processes and ferroptosis. This study aims to elucidate the effects of high glucose on cardiomyocytes (CMs) and cardiac fibroblasts (CFs) regarding ferroptosis and to uncover the underlying mechanisms involved. We examined alterations in glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and mitophagy, which are essential for metabolic adaptations and ferroptosis. High glucose exposure induced ferroptosis specifically in CMs, while CFs exhibited resistance to ferroptosis, increased glycolytic activity, and no change in OXPHOS. Moreover, high glucose treatment enhanced mitophagy and upregulated mitochondrial ferritin (FTMT). Notably, the combination of FTMT and the autophagy-related protein nuclear receptor coactivator 4 (NCOA4) increased under high glucose conditions. Silencing FTMT significantly impeded mitophagy and eliminated ferroptosis resistance in CFs cultured under high glucose conditions. The transcription factor forkhead box A1 (FOXA1) was upregulated in CFs upon high glucose exposure, playing a crucial role in the increased expression of FTMT. Within the 5'-flanking sequence of the FTMT mRNA, approximately -500 nt from the transcription initiation site, three putative FOXA1 binding sites were identified. High glucose augmented the binding affinity between FOXA1 and these sequences, thereby promoting FTMT transcription. In summary, high glucose upregulated FOXA1 expression and stimulated FTMT promoter activity in CFs, thereby promoting FTMT-dependent mitophagy and conferring ferroptosis resistance in CFs.

Keywords:  Cardiac fibroblast; Ferroptosis; Mitochondrial ferritin; Mitophagy; Nuclear receptor coactivator 4

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119825
Heliyon. 2024 Aug 15. 10(15): e35305

Construction of a mitophagy-related prognostic signature for predicting prognosis and tumor microenvironment in lung adenocarcinoma.

Wu-Sheng Liu, Ru-Mei Li, Yong-Hong Le, Zan-Lei Zhu.

   Background: Mitophagy is the selective degradation of mitochondria by autophagy. It becomes increasingly clear that mitophagy pathways are important for cancer cells to adapt to their high-energy needs. However, which genes associated with mitophagy could be used to prognosis cancer is unknown.
Methods: We created a clinical prognostic model using mitophagy-related genes (MRGs) in lung adenocarcinoma (LUAD) patients for the first time, and we employed bioinformatics methods to search for biomarkers that affect the progression and prognosis of LUAD. Transcriptome data for LUAD were obtained from The Cancer Genome Atlas (TCGA) database, and additional expression data from LUAD patients were sourced from the Gene Expression Omnibus (GEO) database. Furthermore, 25 complete MRGs were identified based on annotations from the MSigDB database.
Results: A comparison of the mitophagy scores between the groups with high and low scores was done using receiver operating characteristic (ROC) curves, which also revealed the differential gene expression patterns between the two groups. Using Kaplan-Meier analysis, two prognostic MRGs from the groups with high and low mitophagy scores were identified: TOMM40 and VDAC1. Using univariate and multivariate Cox regression, the relationship between the expression levels of these two genes and prognostic clinical features of LUAD was examined further.The prognosis of LUAD patients was shown to be significantly correlated (P < 0.05) with the expression levels of these two genes.
Conclusions: Our prognostic model would improve the prognosis of LUAD and guide clinical treatments.

Keywords:  Bioinformatics; Gene; Lung adenocarcinoma; Mitophagy; Prognosis

DOI:  https://doi.org/10.1016/j.heliyon.2024.e35305
Elife. 2024 Aug 23. pii: RP87880. [Epub ahead of print]12

Drosophila model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy.

Yohei Nitta, Jiro Osaka, Ryuto Maki, Satoko Hakeda-Suzuki, Emiko Suzuki, Satoshi Ueki, Takashi Suzuki, Atsushi Sugie.

  Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynamin like GTPase (OPA1) gene. OPA1 encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant-negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of the dOPA1 gene in Drosophila can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human OPA1 (hOPA1) gene, indicating that hOPA1 is functionally interchangeable with dOPA1 in the fly system. However, mutations previously identified did not ameliorate the dOPA1 deficiency phenotype. By expressing both WT and DOA plus mutant hOPA1 forms in the optic nerve of dOPA1 mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant-negative mutations in hOPA1. This fly model aids in distinguishing DOA from DOA plus and guides initial hOPA1 mutation treatment strategies.

Keywords:  D. melanogaster; Drosophila; OPA1; axonal degeneration; dominant optic atrophy; medicine

DOI:  https://doi.org/10.7554/eLife.87880