bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2023‒05‒14
eleven papers selected by
Bradley Irizarry
Thomas Jefferson University

  1. J Indian Soc Periodontol. 2023 Mar-Apr;27(2):27(2): 126-130
      Periodontitis is a chronic oral inflammatory disease that is caused by dental plaque pathogens. Periodontal disease development and evolution are based on the host immune system, humoral and cellular immunity, the integrity of the tissues, and certain endocrine and nutritional factors. Mitochondria are significantly involved in periodontal infections and inflammation, which play a role in the inflammatory response in a variety of ways. In general, oxidative stress causes a stressful environment that subsequently leads to tissue damage and chronic inflammation. Several mutations and alterations in mitochondrial DNA lead the disease to an aggressive condition, by causing dysregulated mitochondrial function. Such mutations are significantly associated with various diseases. Numerous studies indicate chronic periodontitis patients have a decreased level of mitochondrial membrane potential, as well as adenosine triphosphate, and an increased level of reactive oxygen species production, which causes cell death in the periodontium and affects tissue growth. Further studies into the association between mitochondria and periodontitis might be helpful for the treatment and prevention of the diseases.
    Keywords:  Mitochondrial dysfunction; mitochondrial mutation; periodontitis; reactive oxygen species production
  2. Neurotox Res. 2023 May 10.
      Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.
    Keywords:  Fission; Fusion; Mitochondrial dysfunction; Mitochondrial medicine; Mitochondrial quality control; Oxidative stress
  3. Methods Mol Biol. 2023 ;2661 3-5
      In this introductory chapter, I will briefly describe how I came to discover the mammalian mitoribosome and will add a few notes on my contribution to the field.
    Keywords:  Human MRP genes; Human ribosome purification; Mitochondrial disease; Mitochondrial ribosomal proteins; Mitochondrial translation
  4. Exp Gerontol. 2023 May 09. pii: S0531-5565(23)00125-0. [Epub ahead of print] 112204
      The maintenance of functional health is pivotal for achieving independent life in older age. The aged muscle is characterized by ultrastructural changes, including loss of type I and type II myofibers and a greater proportion of cytochrome c oxidase deficient and succinate dehydrogenase positive fibers. Both intrinsic (e.g., altered proteostasis, DNA damage, and mitochondrial dysfunction) and extrinsic factors (e.g., denervation, altered metabolic regulation, declines in satellite cells, and inflammation) contribute to muscle aging. Being a hub for several cellular activities, mitochondria are key to myocyte viability and mitochondrial dysfunction has been implicated in age-associated physical decline. The maintenance of functional organelles via mitochondrial quality control (MQC) processes is, therefore, crucial to skeletal myofiber viability. The autophagy-lysosome pathway has emerged as a critical step of MQC in muscle by disposing organelles and proteins via their tagging for autophagosome incorporation and delivery to the lysosome for clearance. This pathway has been reported to be altered in muscle of physically inactive older people. A relationship between this pathway and muscle tissue composition of the lower extremities as well as physical performance has been identified. Therefore, integrating muscle structure and myocyte quality control measures in the evaluation of muscle health may be a promising strategy for devising interventions fostering muscle health.
    Keywords:  Cytokine; Extracellular matrix; Mitochondrial quality; Physical performance; Sarcopenia; Satellite cells
  5. Mem Inst Oswaldo Cruz. 2023 ;pii: S0074-02762023000100201. [Epub ahead of print]118 e230023
      Innate immunity refers to the mechanisms responsible for the first line of defense against pathogens, cancer cells and toxins. The innate immune system is also responsible for the initial activation of the body's specific immune response (adaptive immunity). Innate immunity was studied and further developed in parallel with adaptive immunity beginning in the first half of the 19th century and has been gaining increasing importance to our understanding of health and disease. In the present overview, we describe the main findings and ideas that contributed to the development of innate immunity as a continually expanding branch of modern immunology. We start with the toxicological studies by Von Haller and Magendie, in the late 18th and early 19th centuries, and continue with the discoveries in invertebrate immunity that supported the discovery and characterization of lipopolysaccharide (LPS) and pattern recognition receptors that led to the development of the pattern recognition and danger theory.
  6. World J Emerg Med. 2023 ;14(3): 209-216
      BACKGROUND: Pulmonary fibrosis (PF) is one of the main causes of death in patients with paraquat (PQ) poisoning. This study aimed to evaluate the relationship between mitochondrial fission and oxidative stress in PQ-induced epithelial-mesenchymal transition (EMT) and PF.METHODS: C57BL/6 mice and MLE-12 cells were exposed to PQ to construct a PF model in vivo and in vitro. Histological changes in the lungs were examined by hematoxylin and eosin (H&E) staining. Mitochondrial morphology was detected by MitoTracker® Deep Red FM or transmission electron microscopy (TEM). Western blotting and immunofluorescence were used to determine the expression of protein. The migration ability of the cells was detected by the cell scratch test. Mitochondrial DNA (mtDNA) levels were assessed by real-time polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was applied to detect cytokine levels. Superoxide dismutase (SOD) activity and the levels of glutathione (GSH) and malondialdehyde (MDA) were detected by chemichromatometry.
    RESULTS: PQ exposure caused EMT and PF in vivo and in vitro. PQ destroyed mitochondrial structure and enhanced the expression of dynamin-related protein 1 (Drp1), which were accompanied by oxidative stress. Inhibiting mitochondrial fission using mitochondrial division inhibitor-1 (Mdivi-1), a selective inhibitor of Drp1, attenuated PQ-induced EMT and oxidative damage. Treatment with N-acetyl-L-cysteine (NAC), an antioxidant, reduced Drp1 expression, attenuated mitochondrial structure damage and inhibited PQ-induced EMT and PF. Both Mdivi-1 and NAC treatment markedly suppressed mtDNA release, the expression of Toll-like receptor 9 (TLR9) and phosphorylation (P)-NF-κB p65 as well as cytokines (interleukin 6 [IL-6], interleukin-1β [IL-1β], and tumor necrosis factor-α [TNF-α]) production.
    CONCLUSION: Mutual promotion of mitochondrial fission and oxidative stress contributes to EMT in PQ-induced PF, which is associated with the mtDNA/TLR9/NF-κB pathway.
    Keywords:  Epithelial-mesenchymal transition; Mitochondrial DNA; Mitochondrial fission; Oxidative stress; Paraquat
  7. Exp Eye Res. 2023 May 09. pii: S0014-4835(23)00120-3. [Epub ahead of print] 109499
      Fuchs Endothelial Corneal Dystrophy (FECD), a late-onset oxidative stress disorder, is the most common cause of corneal endothelial degeneration and is genetically associated with CTG repeat expansion in TCF4. We previously reported accumulation of nuclear (nDNA) and mitochondrial (mtDNA) damage in FECD. Specifically, mitochondrial DNA damage was a prominent finding in development of disease in the ultraviolet-A (UVA) induced FECD mouse model. We hypothesize that an aberrant DNA repair may contribute to the increased DNA damage seen in FECD. We analyzed differential expression profiles of 84 DNA repair genes by real-time PCR arrays using Human DNA Repair RT-Profiler plates using cDNA extracted from Descemet's membrane-corneal endothelium (DM-CE) obtained from FECD patients with expanded (>40) or non-expanded (<40) intronic CTG repeats in Transcription Factor 4 (TCF4) gene and from age-matched normal donors. Change in mRNA expression of <0.5- or >2.0-fold in FECD relative to normal was set as cutoff for down- or upregulation. Downregulated mitochondrial genes were further validated using the UVA-based mouse model of FECD. FECD specimens exhibited downregulation of 9 genes and upregulation of 8 genes belonging to the four major DNA repair pathways, namely, base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double strand break (DSB) repair, compared to normal donors. MMR gene MSH2 and BER gene POLB were preferentially upregulated in expanded FECD. BER genes LIG3 and NEIL2, DSB repair genes PARP3 and TOP3A, NER gene XPC, and unclassified pathway gene TREX1, were downregulated in both expanded and non-expanded FECD. MtDNA repair genes, Lig3, Neil2, and Top3a, were also downregulated in the UVA-based mouse model of FECD. Our findings identify impaired DNA repair pathways that may play an important role in DNA damage due to oxidative stress as well as genetic predisposition noted in FECD.
    Keywords:  CTG repeat Expansion; DNA repair; Fuchs endothelial corneal dystrophy; Mitochondrial DNA damage; Oxidative stress; TCF4
  8. ACS Chem Neurosci. 2023 May 10.
      Cannabidiol (CBD) is a non-psychoactive constituent of the Cannabis plant that has purported effectiveness in treating an array of stress-related neuropsychiatric disorders. The amygdala is a subcortical brain structure that regulates emotional behavior, and its dysfunction has been linked to numerous disorders including anxiety and posttraumatic stress disorder. Despite this, the direct effects of CBD on synaptic and cellular function in the amygdala are not known. Using electrophysiology and pharmacology, we report that CBD reduces presynaptic neurotransmitter release in the amygdala, and these effects are dependent on subnucleus and cell type. Furthermore, CBD broadly decreases cellular excitability across amygdala subnuclei. These data reveal physiological mechanisms by which CBD modulates amygdala activity and could provide insights into how CBD could affect emotional and stress-related behavioral responses.
    Keywords:  amygdala; anxiety; cannabidiol; cannabinoid; cannabis; stress
  9. BMC Biol. 2023 May 08. 21(1): 103
      BACKGROUND: Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions.RESULTS: By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a "hot spot" where one deletion breakpoint occurred within the region of 6-9 kb and another within 13-16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp (base pair) and a second arm at 13,447-13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging.
    CONCLUSIONS: Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.
    Keywords:  Aging; Contact zone; Deletions; Direct repeats; Global secondary structure; Inverted repeats; Mitochondrial DNA; Single-stranded DNA; mtDNA replication
  10. Front Genet. 2023 ;14 1104732
      Introduction: The function, origin and structural features of circulating nuclear DNA (cir-nDNA) and mitochondrial DNA (cir-mtDNA) are poorly known, even though they have been investigated in numerous clinical studies, and are involved in a number of routine clinical applications. Based on our previous report disproving the conventional plasma isolation used for cirDNA analysis, this work enables a direct topological comparison of the circulating structures associated with nuclear DNA and mitochondrial cell-free DNA. Materials and methods: We used a Q-PCR and low-pass whole genome sequencing (LP-WGS) combination approach of cir-nDNA and cir-mtDNA, extracted using a procedure that eliminates platelet activation during the plasma isolation process to prevent mitochondria release in the extracellular milieu. Various physical procedures, such as filtration and differential centrifugation, were employed to infer their circulating structures. Results: DSP-S cir-mtDNA mean size profiles distributed on a slightly shorter range than SSP-S. SSP-S detected 40-fold more low-sized cir-mtDNA fragments (<90 bp/nt) and three-fold less long-sized fragments (>200 bp/nt) than DSP-S. The ratio of the fragment number below 90 bp over the fragment number above 200 bp was very homogenous among both DSP-S and SSP-S profiles, being 134-fold lower with DSP-S than with SSP-S. Cir-mtDNA and cir-nDNA DSP-S and SSP-S mean size profiles of healthy individuals ranged in different intervals with periodic sub-peaks only detectable with cir-nDNA. The very low amount of cir-mtDNA fragments of short size observed suggested that most of the cir-mtDNA is poorly fragmented and appearing longer than ∼1,000 bp, the readout limit of this LP-WGS method. Data suggested that cir-nDNA is, among DNA extracted in plasma, associated with ∼8.6% of large structures (apoptotic bodies, large extracellular vesicles (EVs), cell debris…), ∼27.7% in chromatin and small EVs and ∼63.7% mainly in oligo- and mono-nucleosomes. By contrast, cir-mtDNA appeared to be preponderantly (75.7%) associated with extracellular mitochondria, either in its free form or with large EVs; to a lesser extent, it was also associated with other structures: small EVs (∼18.4%), and exosomes or protein complexes (∼5.9%). Conclusion: This is the first study to directly compare the structural features of cir-nDNA and cir-mtDNA. The significant differences revealed between both are due to the DNA topological structure contained in the nucleus (chromatin) and in the mitochondria (plasmid) that determine their biological stability in blood. Although cir-nDNA and cir-mtDNA are principally associated with mono-nucleosomes and cell-free mitochondria, our study highlights the diversity of the circulating structures associated with cell-free DNA. They consequently have different pharmacokinetics as well as physiological functions. Thus, any accurate evaluation of their biological or diagnostic individual properties must relies on appropriate pre-analytics, and optimally on the isolation or enrichment of one category of their cirDNA associated structures.
    Keywords:  Q-PCR; circulating DNA; diagnostics; extracellular vesicles; mitochondria; structure; topology; whole genome sequencing
  11. J Cell Biochem. 2023 May 09.
      Mitochondrial calcium (Ca2+ ) dynamics play critical roles in regulating vital physiological conditions in the brain. Importantly, Mitochondria-associated endoplasmic reticulum (ER) membranes serve different cellular functions including Ca2+ signaling, bioenergetics, phospholipid biosynthesis, cholesterol esterification, programmed cell death, and communication between the two organelles. Several Ca2+ -transport systems specialize at the mitochondria, ER, and their contact sites that provide tight control of mitochondrial Ca2+ signaling at the molecular level. The biological function of Ca2+ channels and transporters as well as the role of mitochondrial Ca2+ signaling in cellular homeostasis can open new perspectives for investigation and molecular intervention. Emerging evidence suggests that abnormalities in ER/mitochondrial brain functions and dysregulation of Ca2+ homeostasis are neuropathological hallmarks of neurological disorders like Alzheimer's disease, but little evidence is available to demonstrate their relationship to disease pathogenesis and therapeutic approaches. In recent years, the detection of the molecular mechanism regulating cellular Ca2+ homeostasis and also mitochondrial functions have expanded the number of targeted treatments. The main experimental data identify beneficial effects, whereas some scientific trials did not meet the expectations. Together with an overview of the important function of mitochondria, this review paper introduced the possible tested therapeutic approaches that target mitochondria in the context of neurodegenerative diseases. Since these treatments in neurological disorders have shown different degrees of progress, it is essential to perform a detailed assessment of the significance of mitochondrial deterioration in neurodegenerative diseases and of a pharmacological treatment at this stage.
    Keywords:  Alzheimer's disease; ageing; calcium signaling; cellular homeostasis; mitochondria-associated ER membrane; therapeutic strategy