bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2022‒11‒27
twelve papers selected by
Bradley Irizarry
Thomas Jefferson University

  1. J Mol Cell Cardiol. 2022 Nov 18. pii: S0022-2828(22)00563-6. [Epub ahead of print]
      Mitochondrial permeability transition pore (mPTP)-dependent necrotic cell death is a form of necrotic cell death that is driven by mitochondrial dysfunction by the opening of the mPTP and is triggered by increases in matrix levels of Ca2+ and reactive oxygen species. This form of cell death has been implicated in ischemic injuries of the heart and brain as well as numerous degenerative diseases in the brain and skeletal muscle. This review focuses on the molecular triggers and regulators of mPTP-dependent necrosis in the context of myocardial ischemia reperfusion injury. Research over the past 50 years has led to the identity of regulators and putative pore-forming components of the mPTP. Finally, downstream consequences of activation of the mPTP as well as ongoing questions and areas of research are discussed. These questions pose a particular interest as targeting the mPTP could potentially represent an efficacious therapeutic strategy to reduce infarct size following an ischemic event.
    Keywords:  ANT; ATP synthase; BAK; BAX; Calcium; CypD; Ischemia reperfusion; MPTP; Mitochondria; Mitochondrial dysfunction; Necrosis; Permeability transition; ROS
  2. Enzymes. 2022 ;pii: S1874-6047(22)00010-5. [Epub ahead of print]52 1-10
      DNA damage and breaks are events that happen to DNA which exert a variety of influence on cell physiology including inhibition of DNA synthesis, repair response, cell cycle effect and cell death. Thus, it is important to deepened understanding of these events. In volume 51, we discussed topics including (1) assays to detect double-strand breaks, (2) conditions leading to double-strand breaks, (3) effects of irradiation, (4) DNA structure and chromatins, and (5) direct and indirect effect on DNA. Contributing authors and a table of contents for volume 51 are mentioned. We also discuss further issues and topics that need to be featured in future volumes. These include DNA damage sensors, DNA damage response proteins, and double-strand break repair pathways.
    Keywords:  DNA breaks; DNA damage; Direct and indirect effects; Future perspective; Volume 51
  3. Elife. 2022 Nov 21. pii: e82244. [Epub ahead of print]11
      To mount a protective response to infection while preventing hyperinflammation, gene expression in innate immune cells must be tightly regulated. Despite the importance of pre-mRNA splicing in shaping the proteome, its role in balancing immune outcomes remains understudied. Transcriptomic analysis of murine macrophage cell lines identified Serine/Arginine Rich Splicing factor 6 (SRSF6) as a gatekeeper of mitochondrial homeostasis. SRSF6-dependent orchestration of mitochondrial health is directed in large part by alternative splicing of the pro-apoptosis pore-forming protein BAX. Loss of SRSF6 promotes accumulation of BAX-k, a variant that sensitizes macrophages to undergo cell death and triggers upregulation of interferon stimulated genes through cGAS sensing of cytosolic mitochondrial DNA. Upon pathogen sensing, macrophages regulate SRSF6 expression to control the liberation of immunogenic mtDNA and adjust the threshold for entry into programmed cell death. This work defines BAX alternative splicing by SRSF6 as a critical node not only in mitochondrial homeostasis, but also in the macrophage's response to pathogens.
    Keywords:  chromosomes; gene expression; immunology; inflammation; mouse
  4. Int J Mol Sci. 2022 Nov 16. pii: 14149. [Epub ahead of print]23(22):
      Dieckol is a natural brown algal-derived polyphenol and its cytotoxic potential against various types of cancer cells has been studied. However, the effects of dieckol on autophagy in cancer cells remain unknown. Here, we show that dieckol inhibits the growth of A375 human melanoma cells by inducing apoptotic cell death, which is associated with lysosomal dysfunction and the inhibition of autophagic flux. Dieckol induces autophagosome accumulation by inhibiting autophagosome-lysosome fusion. Moreover, dieckol not only triggers lysosomal membrane permeabilization, followed by an increase in lysosomal pH and the inactivation of cathepsin B and D, but also causes the loss of mitochondrial membrane potential. Importantly, a cathepsin D inhibitor partially relieved dieckol-induced mitochondrial membrane impairment and caspase-mediated apoptosis. Collectively, our findings indicate that dieckol is a novel autophagy inhibitor that induces apoptosis-mediated cell death via lysosomal dysfunction and mitochondrial membrane impairment in A375 human melanoma cells. This suggests the novel potential value of dieckol as a chemotherapeutic drug candidate for melanoma treatment.
    Keywords:  antitumor activity; apoptosis; autophagy; cell death; dieckol; melanoma
  5. Nanoscale. 2022 Nov 22.
      LL-37, the only human host cathelicidin peptide, is proposed to be able to induce host cell apoptosis through mitochondrial membrane permeabilization (MMP). Detailed pathways of the LL-37-triggered MMP are however still disputed. It is generally believed that cationic peptides permeate a membrane mostly in conditions of micromolar peptide concentrations and negatively charged membranes, which are not usually satisfied in the mitochondrial circumstance. Herein, using a variety of single-molecule techniques, we show that nanomolar LL-37 specifically induces permeability of a phosphoethanolamine (PE)-rich biomimetic mitochondrial membrane in a protein-independent manner. The insertion dynamics of single LL-37 molecules exhibit different metastable states in bilayers composed of different lipids. Moreover, the PE lipids significantly facilitate adsorption and accumulation of LL-37 on the PE-rich bilayer, and produce deeper insertion of peptide oligomers, especially tetramers, into the bilayer. This work offers an alternative pathway of the LL-37-triggered MMP and apoptosis.
  6. Adv Immunol. 2022 ;pii: S0065-2776(22)00029-3. [Epub ahead of print]156 55-102
      The cGAS-STING pathway is responsible for cytoplasmic double-stranded DNA (dsDNA) -triggered innate immunity and involved in the pathology of various diseases including infection, autoimmune diseases, neurodegeneration and cancer. Understanding the activation and regulatory mechanisms of this pathway is critical to develop therapeutic strategies toward these diseases. Here, we review the signal transduction, cellular functions and regulations of cGAS and STING, particularly highlighting the latest understandings on the activation of cGAS by dsDNA and/or Manganese (Mn2+), STING trafficking, sulfated glycosaminoglycans (sGAGs)-induced STING polymerization and activation, and also regulation of the cGAS-STING pathway by different biocondensates formed via phase separation of proteins from host cells and viruses.
    Keywords:  Apoptosis; Biomolecular condensate; Cancer immunotherapy; Caspase; Cyclic-dinucleotides (CDNs); DAMPs; Double-stranded DNA (dsDNA); Infection; Inflammasome; Innate immunity; Manganese (Mn(2+)); PAMPs; Phase separation; STING; STING phase-separator; STING trafficking; Sulfated glycosaminoglycans (sGAGs); TBK1; Type I-IFNs; cGAMP; cGAS
  7. Fish Shellfish Immunol Rep. 2021 Dec;2 100019
      Mitochondria are organelles commonly associated with adenosine triphosphate (ATP) formation through the oxidative phosphorylation (OXPHOS) process. However, mitochondria are also responsible for functions such as calcium homeostasis, apoptosis, autophagy, and production of reactive oxygen species (ROS) that, in conjunction, can lead to different cell fate decisions. Mitochondrial morphology changes rely on nutrients' availability and the bioenergetics demands of the cells, in a process known as mitochondrial dynamics, which includes both fusion and fission. This organelle senses the microenvironment and can modify the cells to either a pro or anti-inflammatory profile. The zebrafish has been increasingly used to research mitochondrial dynamics and its connection with the immune system since the pathways and molecules involved in these processes are conserved on this fish. Several genetic tools and technologies are currently available to analyze the behavior of mitochondria in zebrafish. However, even though zebrafish presents several similar processes known in mammals, the effect of the mitochondria in the immune system has not been so broadly studied in this model. In this review, we summarize the current knowledge in zebrafish studies regarding mitochondrial function and immuno metabolism.
    Keywords:  Fish; Immuno metabolism; Immunology; Metabolism; Mitochondria; Mitochondrial functions
  8. Front Aging Neurosci. 2022 ;14 1013943
      Mitochondrial dysfunction plays a key role in the pathogenesis of Alzheimer's disease (AD). The translocase of the outer membrane (TOM) complex controls the input of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions. However, its role in AD development remains unclear. TOM70 is an important translocase present in the TOM complex. In the current study, we found that TOM70 levels were reduced in the peripheral blood and hippocampus of the APP/PS1 mice. In addition, we examined the whole-blood mRNA levels of TOM70 in patients with AD, dementia with Lewy bodies (DLB), and post-stroke dementia (PSD). Our study revealed that the mRNA level of TOM70 was decreased in the blood samples of patients with AD, which was also correlated with the progression of clinical stages. Therefore, we proposed that the expression of TOM70 could be a promising biomarker for AD diagnosis and monitoring of disease progression.
    Keywords:  Alzheimer's disease; TOM70; biomarker; gene expression; progression
  9. Clin Exp Immunol. 2022 Nov 24. pii: uxac107. [Epub ahead of print]
      Mitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system towards immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference.
    Keywords:  T cells; autoimmunity; macrophages; mitochondria; rheumatoid arthritis; tumor necrosis factor
  10. Mol Ther Nucleic Acids. 2022 Dec 13. 30 359-377
      Mitochondrial diseases are one of the largest groups of neurological genetic disorders. Despite continuous efforts of the scientific community, no cure has been developed, and most treatment strategies rely on managing the symptoms. After the success of coronavirus disease 2019 (COVID-19) mRNA vaccines and accelerated US Food and Drug Administration (FDA) approval of four new RNAi drugs, we sought to investigate the potential of mitochondrion-targeting RNA-based therapeutic agents for treatment of mitochondrial diseases. Here we describe the causes and existing therapies for mitochondrial diseases. We then detail potential RNA-based therapeutic strategies for treatment of mitochondrial diseases, including use of antisense oligonucleotides (ASOs) and RNAi drugs, allotopic therapies, and RNA-based antigenomic therapies that aim to decrease the level of deleterious heteroplasmy in affected tissues. Finally, we review different mechanisms by which RNA-based therapeutic agents can be delivered to the mitochondrial matrix, including mitochondrion-targeted nanocarriers and endogenous mitochondrial RNA import pathways.
    Keywords:  MT: Oligonucleotides, Therapies and Applications; RNA therapeutics; RNA therapy; mitochondrial DNA; mitochondrial RNA import; mitochondrial disease; mitochondrial therapy; mitochondrion-targeted nanocarrier
  11. EMBO Rep. 2022 Nov 23. e54006
      While previous studies have identified cancer stem-like cells (CSCs) as a crucial driver for chemoresistance and tumor recurrence, the underlying mechanisms for populating the CSC pool remain unclear. Here, we identify hypermitophagy as a feature of human lung CSCs, promoting metabolic adaption via the Notch1-AMPK axis to drive CSC expansion. Specifically, mitophagy is highly active in CSCs, resulting in increased mitochondrial DNA (mtDNA) content in the lysosome. Lysosomal mtDNA acts as an endogenous ligand for Toll-like receptor 9 (TLR9) that promotes Notch1 activity. Notch1 interacts with AMPK to drive lysosomal AMPK activation by inducing metabolic stress and LKB1 phosphorylation. This TLR9-Notch1-AMPK axis supports mitochondrial metabolism to fuel CSC expansion. In patient-derived xenograft chimeras, targeting mitophagy and TLR9-dependent Notch1-AMPK pathway restricts tumor growth and CSC expansion. Taken together, mitochondrial hemostasis is interlinked with innate immune sensing and Notch1-AMPK activity to increase the CSC pool of human lung cancer.
    Keywords:  AMPK; Notch1; TLR9; cancer stem-like cell; mitophagy
  12. Hum Mol Genet. 2022 Nov 26. pii: ddac292. [Epub ahead of print]
      The mitochondrial DNA mutation m.9032 T > C was previously identified in patients presenting with NARP (Neuropathy Ataxia Retinitis Pigmentosa). Their clinical features had a maternal transmission and patient's cells showed a reduced oxidative phosphorylation capacity, elevated reactive oxygen species (ROS) production and hyperpolarization of the mitochondrial inner membrane, providing evidence that m.9032 T > C is truly pathogenic. This mutation leads to replacement of a highly conserved leucine residue with proline at position 169 of ATP synthase subunit a (L169P). This protein and a ring of identical c-subunits (c-ring) move protons through the mitochondrial inner membrane coupled to ATP synthesis. We herein investigated the consequences of m.9032 T > C on ATP synthase in a strain of Saccharomyces cerevisiae with an equivalent mutation (L186P). The mutant enzyme assembled correctly but was mostly inactive as evidenced by a > 95% drop in the rate of mitochondrial ATP synthesis and absence of significant ATP-driven proton pumping across the mitochondrial membrane. Intragenic suppressors selected from L186P yeast restoring ATP synthase function to varying degrees (30-70%) were identified at the original mutation site (L186S) or in another position of the subunit a (H114Q, I118T). In light of atomic structures of yeast ATP synthase recently described, we conclude from these results that m.9032 T > C disrupts proton conduction between the external side of the membrane and the c-ring, and that H114Q and I118T enable protons to access the c-ring through a modified pathway.
    Keywords:  mitochondrial diseasesNARP syndromemitochondrial DNAATP synthase subunit ayeastsuppressor genetics