bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024‒01‒21
twenty papers selected by
Marco Tigano, Thomas Jefferson University
  1. Genetically encoded tool for manipulation of ΔΨm identifies the latter as the driver of integrative stress response induced by ATP Synthase dysfunction.
  2. Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.
  3. In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
  4. Cytosolic mtDNA-cGAS-STING axis contributes to sepsis-induced acute kidney injury via activating the NLRP3 inflammasome.
  5. NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
  6. Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis.
  7. Gasdermin D triggers cardiolipin-driven mitochondrial damage and pyroptosis.
  8. STIM1 translocation to the nucleus protects cells from DNA damage.
  9. LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins.
  10. Mitochondrial reactive oxygen species initiate gasdermin D-mediated pyroptosis and contribute to paraquat-induced nephrotoxicity.
  11. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1.
  12. Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
  13. Mitochondrial DNA Sensing Pathogen Recognition Receptors in Systemic Sclerosis Associated Interstitial Lung Disease: A Review.
  14. Covalent inhibition of pro-apoptotic BAX.
  15. MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response.
  16. Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.
  17. USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
  18. Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
  19. Regulation of mitochondrial metabolism by autophagy supports leptin-induced cell migration.
  20. Mitophagy plays a "double-edged sword" role in the radiosensitivity of cancer cells.
  1. bioRxiv. 2023 Dec 27. pii: 2023.12.27.573435. [Epub ahead of print]
    Genetically encoded tool for manipulation of ΔΨm identifies the latter as the driver of integrative stress response induced by ATP Synthase dysfunction.
    Mangyu Choe, Denis V Titov.
      Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the Integrated Stress Response induced by ATP synthase inhibition in mammalian cells.
    DOI:  https://doi.org/10.1101/2023.12.27.573435
  2. Cell Death Dis. 2024 Jan 15. 15(1): 51
    Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.
    Ari Kwon, Na Young Lee, Jae-Hyun Yu, Myeung Gi Choi, Jeongwoo Park, Ja Hyun Koo.
      Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ) are the main effectors of the Hippo pathway and their dysregulation contributes to diseases in tissues including the liver. Although mitochondria are capable of transmitting signals to change transcriptomic landscape of diseased hepatocytes, such retrograde signaling and the related nuclear machinery are largely unknown. Here, we show that increased YAP activity is associated with mitochondrial stress during liver injury; and this is required for secondary inflammation, promoting hepatocyte death. Mitochondrial stress inducers robustly promoted YAP/TAZ dephosphorylation, nuclear accumulation, and target gene transcription. RNA sequencing revealed that the majority of mitochondrial stress transcripts required YAP/TAZ. Mechanistically, direct oxidation of RhoA by mitochondrial superoxide was responsible for PP2A-mediated YAP/TAZ dephosphorylation providing a novel physiological input for the Hippo pathway. Hepatocyte-specific Yap/Taz ablation suppressed acetaminophen-induced liver injury and blunted transcriptomic changes associated with the pathology. Our observations uncover unappreciated pathway of mitochondrial stress signaling and reveal YAP/TAZ activation as the mechanistic basis for liver injury progression.
    DOI:  https://doi.org/10.1038/s41419-024-06448-5
  3. EMBO J. 2024 Jan 15.
    In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
    Michelle Y Fry, Paula P Navarro, Pusparanee Hakim, Virly Y Ananda, Xingping Qin, Juan C Landoni, Sneha Rath, Zintis Inde, Camila Makhlouta Lugo, Bridget E Luce, Yifan Ge, Julie L McDonald, Ilzat Ali, Leillani L Ha, Benjamin P Kleinstiver, David C Chan, Kristopher A Sarosiek, Luke H Chao.
      Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.
    Keywords:  Cristae Remodeling; Cryo-Electron Tomography; Cryo-Focused Ion Beam Milling; Mitochondrial Biology
    DOI:  https://doi.org/10.1038/s44318-024-00027-2
  4. Clin Exp Nephrol. 2024 Jan 19.
    Cytosolic mtDNA-cGAS-STING axis contributes to sepsis-induced acute kidney injury via activating the NLRP3 inflammasome.
    Xi Luo, Yang Zhao, Yunpeng Luo, Jian Lai, Jiemei Ji, Jiao Huang, Yuanyuan Chen, Ziru Liu, Jingchen Liu.
      BACKGROUND: NLRP3 inflammasome activation is significantly associated with sepsis-induced acute kidney injury (S-AKI). Cytosolic DNA derived from damaged mitochondria has been reported to activate NLRP3 inflammasome via upregulating the cyclic GMP-AMP synthase (cGAS)-the stimulator of interferon genes (STING) axis in nucleus pulposus cell and cardiomyocytes. However, the regulatory effect of mitochondria DNA (mtDNA)-cGAS-STING axis on the NLRP3 inflammasome in S-AKI remains unclear.METHODS: In the current study, we established an in vivo model of S-AKI by intraperitoneally injecting male C57BL/6 J mice with lipopolysaccharide (LPS). Next, selective cGAS inhibitor RU.521, and STING agonist DMXAA were intraperitoneally injected in the mice; then, blood urea nitrogen (BUN), serum creatinine (CRE), urinary kidney injury molecular-1 (KIM-1), pathological changes, and infiltrated neutrophils were detected to assess kidney injury. We also performed western blot and immunofluorescence assays to evaluate STING, cGAS, TBK-1, p-TBK-1, IRF3, p-IRF3, NF-kB, p-NF-kB, NLRP3, cleaved caspase-1, caspase-1, GSDMD-N, and GSDMD expression levels in kidney tissues. IL-18 and IL-1β in renal tissue were identified by ELISA. In vitro, we treated HK-2 cells with LPS to establish a cell model of S-AKI. Furthermore, ethidium bromide (EtBr) was administered to deplete mitochondria DNA (mtDNA). LPS-induced cytotoxicity was evaluated by LDH release assay. Protein expression of cGAS, STING, and NLRP3 in was quantified by western blot. Cytosolic mtDNA was detected by immunofluorescence and q-PCR. Released IL-1β and IL-18 in HK-2 supernatants were detected by ELISA.
    RESULTS: LPS injection induced S-AKI in mice, as evidenced by neutrophil infiltration, tubular vacuolation, and increased levels of serum creatinine (CRE), blood urea nitrogen (BUN), and urinary KIM-1. In addition, LPS activated the cGAS-STING axis and NLRP3 inflammasome in vivo, illustrated by increased phosphorylation levels of TBK-1, IRF3, and NF-kB protein, increased ratio of cleaved caspase-1 to caspase-1 and GSDMD-N to GSDMD, and increased IL-1β and IL-18 levels. Moreover, the cGAS inhibitor RU.521 effectively attenuated NLRP3 inflammasome and S-AKI; however, these effects were abolished by treatment with the STING agonist DMXAA. Furthermore, cytosolic release of mtDNA and activation of the cGAS-STING-NLRP3 axis were observed in LPS-treated HK-2 cells. Inhibiting mtDNA replication by Ethidium Bromide (EtBr) treatment reduced cytosolic mtDNA accumulation and downregulated the cGAS-STING-NLRP3 axis, ameliorating the cytotoxicity induced by LPS.
    CONCLUSION: This study demonstrated that the cGAS-STING axis was triggered by cytosolic mtDNA and participated in the development of S-AKI by activating NLRP3 inflammasome. Reducing cytosolic mtDNA accumulation or inhibiting the cGAS-STING axis may be potential therapeutic targets for S-AKI.
    Keywords:  Acute kidney injury; Mitochondrial DNA release; NLRP3 inflammasome; Sepsis; cGAS–STING
    DOI:  https://doi.org/10.1007/s10157-023-02448-5
  5. Nat Commun. 2024 Jan 16. 15(1): 546
    NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
    Liang Yang, Zifeng Ruan, Xiaobing Lin, Hao Wang, Yanmin Xin, Haite Tang, Zhijuan Hu, Yunhao Zhou, Yi Wu, Junwei Wang, Dajiang Qin, Gang Lu, Kerry M Loomes, Wai-Yee Chan, Xingguo Liu.
      Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.
    DOI:  https://doi.org/10.1038/s41467-024-44808-z
  6. J Neuroinflammation. 2024 Jan 20. 21(1): 28
    Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis.
    Peng-Fei Wang, Fei Jiang, Qiu-Ming Zeng, Wei-Fan Yin, Yue-Zi Hu, Qiao Li, Zhao-Lan Hu.
      Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction has been implicated in the pathogenesis of MS, as studies have shown abnormalities in mitochondrial activities, metabolism, mitochondrial DNA (mtDNA) levels, and mitochondrial morphology in immune cells of individuals with MS. The presence of mitochondrial dysfunctions in immune cells contributes to immunological dysregulation and neurodegeneration in MS. This review provided a comprehensive overview of mitochondrial dysfunction in immune cells associated with MS, focusing on the potential consequences of mitochondrial metabolic reprogramming on immune function. Current challenges and future directions in the field of immune-metabolic MS and its potential as a therapeutic target were also discussed.
    Keywords:  Immune cells; Immune-metabolic; MS; Mitochondrion
    DOI:  https://doi.org/10.1186/s12974-024-03016-8
  7. Trends Immunol. 2024 Jan 18. pii: S1471-4906(24)00001-2. [Epub ahead of print]
    Gasdermin D triggers cardiolipin-driven mitochondrial damage and pyroptosis.
    Qiang Cai, Quazi T H Shubhra.
      In a remarkable recent study, Miao et al. reveal that gasdermin D N-terminal (GSDMD-NT) instigates mitochondrial damage in pyroptosis by forming pores in inner and outer mitochondrial membranes (OMMs). The authors highlight the key role of mitochondrial cardiolipin in the action of GSDMD-NT, and significantly advance our understanding of this inflammatory cell death mechanism.
    Keywords:  cardiolipin; gasdermin D; mitochondria; pyroptosis; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.it.2024.01.001
  8. Nucleic Acids Res. 2024 Jan 15. pii: gkae001. [Epub ahead of print]
    STIM1 translocation to the nucleus protects cells from DNA damage.
    Irene Sanchez-Lopez, Yolanda Orantos-Aguilera, Eulalia Pozo-Guisado, Alberto Alvarez-Barientos, Sergio Lilla, Sara Zanivan, Christophe Lachaud, Francisco Javier Martin-Romero.
      DNA damage represents a challenge for cells, as this damage must be eliminated to preserve cell viability and the transmission of genetic information. To reduce or eliminate unscheduled chemical modifications in genomic DNA, an extensive signaling network, known as the DNA damage response (DDR) pathway, ensures this repair. In this work, and by means of a proteomic analysis aimed at studying the STIM1 protein interactome, we have found that STIM1 is closely related to the protection from endogenous DNA damage, replicative stress, as well as to the response to interstrand crosslinks (ICLs). Here we show that STIM1 has a nuclear localization signal that mediates its translocation to the nucleus, and that this translocation and the association of STIM1 to chromatin increases in response to mitomycin-C (MMC), an ICL-inducing agent. Consequently, STIM1-deficient cell lines show higher levels of basal DNA damage, replicative stress, and increased sensitivity to MMC. We show that STIM1 normalizes FANCD2 protein levels in the nucleus, which explains the increased sensitivity of STIM1-KO cells to MMC. This study not only unveils a previously unknown nuclear function for the endoplasmic reticulum protein STIM1 but also expands our understanding of the genes involved in DNA repair.
    DOI:  https://doi.org/10.1093/nar/gkae001
  9. Cell Death Discov. 2024 Jan 15. 10(1): 29
    LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins.
    Liora Lindenboim, Hila Zohar, Gregg G Gundersen, Howard J Worman, Reuven Stein.
      The apoptotic intrinsic pathway is initiated by perforation of the mitochondrial outer membrane by the effector pro-apoptotic proteins of the Bcl-2 family, Bax and Bak. Bax and Bak need to be activated, a process facilitated by the action of BH3-only pro-apoptotic members of the Bcl-2 family. The latter either directly activates the effector proteins or antagonizes the action of pro-survival Bcl-2 family members such as Bcl-xL. The nuclear envelope is a known target of the apoptotic machinery; however, it may also act as mediator of apoptosis. We showed previously that the nuclear envelope protein nesprin-2, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, can bind to Bax in close proximity to the mitochondria and that the binding increases in apoptotic cells. We now show that depleting nesprin-2 inhibits the apoptotic mitochondrial pathway as measured by Bax and Bak activation and cytochrome c release. This survival effect was Bcl-xL-dependent. Nesprin-2 depletion also inhibited spontaneous exposure of the N-terminus of Bak in cells lacking Bcl-xL and increased the presence of Bcl-xL and Bax in the mitochondria. These results indicate that nesprin-2 promotes Bak activation and regulates mitochondrial translocation/retrotranslocation of Bcl-2 family proteins. Our findings demonstrate a new apoptotic pathway whereby the nuclear envelope, via nesprin-2, regulates apoptosis.
    DOI:  https://doi.org/10.1038/s41420-023-01763-w
  10. Chem Biol Interact. 2024 Jan 16. pii: S0009-2797(24)00019-X. [Epub ahead of print] 110873
    Mitochondrial reactive oxygen species initiate gasdermin D-mediated pyroptosis and contribute to paraquat-induced nephrotoxicity.
    Kaiyuan Chen, Mengxuan Li, Yahui Tang, Zhongqiu Lu.
      Paraquat (PQ)-induced acute kidney injury (AKI) progresses rapidly and is associated with high mortality rates; however, no specific antidote for PQ has been identified. Poor understanding of toxicological mechanisms underlying PQ has hindered the development of suitable treatments to combat PQ exposure. Gasdermin D (GSDMD), a key executor of pyroptosis, has recently been shown to enhance nephrotoxicity in drug-induced AKI. To explore the role of pyroptosis in PQ-induced AKI, the plasma membrane damage of the cells was detected by LDH release assay. Western blot was performed to detect the cleavage of GSDMD. RNA sequencing analysis was performed to explore the mechanism of PQ induced nephrotoxicity. Herein, we demonstrated that PQ could induce pyroptosis in HK-2 cells and nephridial tissues. Mechanistically, PQ initiated GSDMD cleavage, and GSDMD knockout attenuated PQ-induced nephrotoxicity in vivo. Further analysis revealed that the accumulation of mitochondrial reactive oxygen species (ROS) induced p38 activation, contributing to PQ-induced pyroptosis. Furthermore, mitoquinone, a mitochondria-targeted antioxidant, reduced mitochondrial ROS levels and inhibited pyroptosis. Collectively, these findings provide insights into the role of GSDMD-dependent pyroptosis as a novel mechanism of PQ-induced AKI.
    Keywords:  Gasdermin D; Kidney injury; Mitochondrial ROS; Paraquat; Poisoning
    DOI:  https://doi.org/10.1016/j.cbi.2024.110873
  11. bioRxiv. 2023 Dec 29. pii: 2023.12.29.573615. [Epub ahead of print]
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1.
    Sivakumar Boopathy, Camila Makhlouta Lugo, Bridget E Luce, Julie L McDonald, Pusparanee Hakim, Jackeline Ponce, Beatrix Ueberheide, Luke H Chao.
      Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46-Opa1-Mfn1/2 complex. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and the helical repeat 1 region of Mfn2 interacts with the SLC25A46 N-terminus. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    DOI:  https://doi.org/10.1101/2023.12.29.573615
  12. Cell Rep. 2024 Jan 17. pii: S2211-1247(24)00009-3. [Epub ahead of print]43(2): 113681
    Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
    Madeleine J Twyning, Roberta Tufi, Thomas P Gleeson, Kinga M Kolodziej, Susanna Campesan, Ana Terriente-Felix, Lewis Collins, Federica De Lazzari, Flaviano Giorgini, Alexander J Whitworth.
      Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.
    Keywords:  Alzheimer's disease; CP: Neuroscience; Drosophila; Huntington's disease; MCU; NCLX; Parkinson's disease; calcium overload; frontotemporal dementia; mitochondrial calcium; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2024.113681
  13. Curr Treatm Opt Rheumatol. 2023 Dec;9(4): 204-220
    Mitochondrial DNA Sensing Pathogen Recognition Receptors in Systemic Sclerosis Associated Interstitial Lung Disease: A Review.
    Alexander Ghincea, Samuel Woo, Yu Sheeline, Taylor Pivarnik, Vitoria Fiorini, Erica L Herzog, Changwan Ryu.
      Purpose of the review: Systemic sclerosis (SSc) is a condition of dermal and visceral scar formation characterized by immune dysregulation and inflammatory fibrosis. Approximately 90% of SSc patients develop interstitial lung disease (ILD), and it is the leading cause of morbidity and mortality. Further understanding of immune-mediated fibroproliferative mechanisms has the potential to catalyze novel treatment approaches in this difficult to treat disease.Recent findings: Recent advances have demonstrated the critical role of aberrant innate immune activation mediated by mitochondrial DNA (mtDNA) through interactions with toll-like receptor 9 (TLR9) and cytosolic cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS).
    Summary: In this review, we will discuss how the nature of the mtDNA, whether oxidized or mutated, and its mechanism of release, either intracellularly or extracellularly, can amplify fibrogenesis by activating TLR9 and cGAS, and the novel insights gained by interrogating these signaling pathways. Because the scope of this review is intended to generate hypotheses for future research, we conclude our discussion with several important unanswered questions.
    Keywords:  Interstitial lung disease; Systemic Sclerosis; TLR9; cGAS-STING; mitochondial DNA
    DOI:  https://doi.org/10.1007/s40674-023-00211-1
  14. Nat Chem Biol. 2024 Jan 17.
    Covalent inhibition of pro-apoptotic BAX.
    Matthew W McHenry, Peiwen Shi, Christina M Camara, Daniel T Cohen, T Justin Rettenmaier, Utsarga Adhikary, Micah A Gygi, Ka Yang, Steven P Gygi, Thomas E Wales, John R Engen, James A Wells, Loren D Walensky.
      BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). In this study, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by triggering ligands or point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. These data inform a pharmacologic strategy for suppressing apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.
    DOI:  https://doi.org/10.1038/s41589-023-01537-6
  15. EMBO J. 2024 Jan 18.
    MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response.
    Wenjuan Ma, Shah Adil Ishtiyaq Ahmad, Michihiro Hashimoto, Ahad Khalilnezhad, Miho Kataoka, Yuichiro Arima, Yosuke Tanaka, Shigeru Yanagi, Terumasa Umemoto, Toshio Suda.
      Hematopoietic stem cell (HSC) divisional fate and function are determined by cellular metabolism, yet the contribution of specific cellular organelles and metabolic pathways to blood maintenance and stress-induced responses in the bone marrow remains poorly understood. The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 (encoded by the Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and to promote cell survival. Here, we investigated the functional involvement of MITOL in HSC maintenance by generating MX1-cre inducible Mitol knockout mice. MITOL deletion in the bone marrow resulted in HSC exhaustion and impairment of bone marrow reconstitution capability in vivo. Interestingly, MITOL loss did not induce major mitochondrial dysfunction in hematopoietic stem and progenitor cells. In contrast, MITOL deletion induced prolonged ER stress in HSCs, which triggered cellular apoptosis regulated by IRE1α. In line, dampening of ER stress signaling by IRE1α inihibitor KIRA6 partially rescued apoptosis of long-term-reconstituting HSC. In summary, our observations indicate that MITOL is a principal regulator of hematopoietic homeostasis and protects blood stem cells from cell death through its function in ER stress signaling.
    Keywords:  Apoptosis; Cell Cycle; ER Stress Response; IRE1; MITOL
    DOI:  https://doi.org/10.1038/s44318-024-00029-0
  16. Mol Neurobiol. 2024 Jan 15.
    Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.
    Mazyar Yazdani.
      Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder. It is caused by mitochondrial DNA (mtDNA) rearrangements, mostly large-scale deletions of 1.1-10 kb. These deletions primarily affect energy supply through impaired oxidative phosphorylation and reduced ATP production. This impairment gives rise to dysfunction of several tissues, in particular those with high energy demand like brain and muscles. Over the past decades, changes in respiratory chain complexes and energy metabolism have been emphasized, whereas little attention has been paid to other reports on ROS overproduction, protein synthesis inhibition, myelin vacuolation, demyelination, autophagy, apoptosis, and involvement of lipid raft and oligodendrocytes in KSS. Therefore, this paper draws attention towards these relatively underemphasized findings that might further clarify the pathologic cascades following deletions in the mtDNA.
    Keywords:  Apoptosis; Autophagy; Lipid raft; Myelin Vacuolation; Oligodendrocyte; Reactive Oxygen Species (ROS)
    DOI:  https://doi.org/10.1007/s12035-024-03938-7
  17. Cell Death Dis. 2024 Jan 15. 15(1): 52
    USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
    Justyna Okarmus, Jette Bach Agergaard, Tina C Stummann, Henriette Haukedal, Malene Ambjørn, Kristine K Freude, Karina Fog, Morten Meyer.
      Ubiquitination of mitochondrial proteins plays an important role in the cellular regulation of mitophagy. The E3 ubiquitin ligase parkin (encoded by PARK2) and the ubiquitin-specific protease 30 (USP30) have both been reported to regulate the ubiquitination of outer mitochondrial proteins and thereby mitophagy. Loss of E3 ligase activity is thought to be pathogenic in both sporadic and inherited Parkinson's disease (PD), with loss-of-function mutations in PARK2 being the most frequent cause of autosomal recessive PD. The aim of the present study was to evaluate whether mitophagy induced by USP30 inhibition provides a functional rescue in isogenic human induced pluripotent stem cell-derived dopaminergic neurons with and without PARK2 knockout (KO). Our data show that healthy neurons responded to CCCP-induced mitochondrial damage by clearing the impaired mitochondria and that this process was accelerated by USP30 inhibition. Parkin-deficient neurons showed an impaired mitophagic response to the CCCP challenge, although mitochondrial ubiquitination was enhanced. USP30 inhibition promoted mitophagy in PARK2 KO neurons, independently of whether left in basal conditions or treated with CCCP. In PARK2 KO, as in control neurons, USP30 inhibition balanced oxidative stress levels by reducing excessive production of reactive oxygen species. Interestingly, non-dopaminergic neurons were the main driver of the beneficial effects of USP30 inhibition. Our findings demonstrate that USP30 inhibition is a promising approach to boost mitophagy and improve cellular health, also in parkin-deficient cells, and support the potential relevance of USP30 inhibitors as a novel therapeutic approach in diseases with a need to combat neuronal stress mediated by impaired mitochondria.
    DOI:  https://doi.org/10.1038/s41419-024-06439-6
  18. Cell Death Differ. 2024 Jan 18.
    Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
    Elena Marchesan, Alice Nardin, Sofia Mauri, Greta Bernardo, Vivek Chander, Simone Di Paola, Monica Chinellato, Sophia von Stockum, Joy Chakraborty, Stephanie Herkenne, Valentina Basso, Emilie Schrepfer, Oriano Marin, Laura Cendron, Diego L Medina, Luca Scorrano, Elena Ziviani.
      Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.
    DOI:  https://doi.org/10.1038/s41418-023-01251-9
  19. Sci Rep. 2024 01 16. 14(1): 1408
    Regulation of mitochondrial metabolism by autophagy supports leptin-induced cell migration.
    Alin García-Miranda, José Benito Montes-Alvarado, Fabiola Lilí Sarmiento-Salinas, Verónica Vallejo-Ruiz, Eduardo Castañeda-Saucedo, Napoleón Navarro-Tito, Paola Maycotte.
      Leptin is an adipokine secreted by adipose tissue, which promotes tumor progression by activating canonical signaling pathways such as MAPK/ERK. Recent studies have shown that leptin induces autophagy, and this process is involved in leptin-induced characteristics of malignancy. Autophagy is an intracellular degradation process associated with different hallmarks of cancer, such as cell survival, migration, and metabolic reprogramming. However, its relationship with metabolic reprogramming has not been clearly described. The purpose of this study was to determine the role of leptin-induced autophagy in cancer cell metabolism and its association with cellular proliferation and migration in breast cancer cells. We used ER+/PR+ and triple-negative breast cancer cell lines treated with leptin, autophagy inhibition, or mitochondrial metabolism inhibitors. Our results show that leptin induces autophagy, increases proliferation, mitochondrial ATP production and mitochondrial function in ER+/PR+ cells. Importantly, autophagy was required to maintain metabolic changes and cell proliferation driven by leptin. In triple-negative cells, leptin did not induce autophagy or cell proliferation but increased glycolytic and mitochondrial ATP production, mitochondrial function, and cell migration. In triple negative cells, autophagy was required to support metabolic changes and cell migration, and autophagy inhibition decreased cellular migration similar to mitochondrial inhibitors. In conclusion, leptin-induced autophagy supports mitochondrial metabolism in breast cancer cells as well as glycolysis in triple negative cells. Importantly, leptin-induced mitochondrial metabolism promoted cancer cell migration.
    DOI:  https://doi.org/10.1038/s41598-024-51406-y
  20. J Cancer Res Clin Oncol. 2024 Jan 18. 150(1): 14
    Mitophagy plays a "double-edged sword" role in the radiosensitivity of cancer cells.
    Qian Wang, Chengxin Liu.
      Mitochondria are organelles with double-membrane structure of inner and outer membrane, which provides main energy support for cell growth and metabolism. Reactive oxygen species (ROS) mainly comes from mitochondrial and can cause irreversible damage to cells under oxidative stress. Thus, mitochondrial homeostasis is the basis for maintaining the normal physiological function of cells and mitophagy plays a pivotal role in the maintenance of mitochondrial homeostasis. At present, to enhance the sensitivity of cancer cells to radiotherapy and chemotherapy by regulating mitochondria has increasingly become a hot spot of cancer therapy. It is particularly important to study the effect of ionizing radiation (IR) on mitochondria and the role of mitophagy in the radiosensitivity of cancer cells. Most of the existing reviews have focused on mitophagy-related molecules or pathways and the impact of mitophagy on diseases. In this review, we mainly focus on discussing the relationship between mitophagy and radiosensitivity of cancer cells around mitochondria and IR.
    Keywords:  Cancer; Ionizing radiation; Mitophagy; Radiosensitivity
    DOI:  https://doi.org/10.1007/s00432-023-05515-2
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