bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2023‒05‒21
thirteen papers selected by
Bradley Irizarry
Thomas Jefferson University

  1. J Transl Med. 2023 May 19. 21(1): 331
      BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD.METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways.
    RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction.
    CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.
    Keywords:  Anti-viral signaling; Inflammation; Interferon; Mitochondrial disease; PBMCs
  2. Cells. 2023 04 27. pii: 1273. [Epub ahead of print]12(9):
      The mitochondrial permeability transition pore (MPTP) is a calcium-dependent, ion non-selective membrane pore with a wide range of functions. Although the MPTP has been studied for more than 50 years, its molecular structure remains unclear. Short-term (reversible) opening of the MPTP protects cells from oxidative damage and enables the efflux of Ca2+ ions from the mitochondrial matrix and cell signaling. However, long-term (irreversible) opening induces processes leading to cell death. Ca2+ ions, reactive oxygen species, and changes in mitochondrial membrane potential regulate pore opening. The sensitivity of the pore to Ca2+ ions changes as an organism ages, and MPTP opening plays a key role in the pathogenesis of many diseases. Most studies of the MPTP have focused on elucidating its molecular structure. However, understanding the mechanisms that will inhibit the MPTP may improve the treatment of diseases associated with its opening. To evaluate the functional state of the MPTP and its inhibitors, it is therefore necessary to use appropriate methods that provide reproducible results across laboratories. This review summarizes our current knowledge of the function and regulation of the MPTP. The latter part of the review introduces two optimized methods for evaluating the functional state of the pore under standardized conditions.
    Keywords:  calcium retention capacity; calcium signaling; calcium-induced swelling; mitochondria; mitochondrial permeability transition; mitochondrial permeability transition pore
  3. Int J Mol Sci. 2023 Apr 29. pii: 8076. [Epub ahead of print]24(9):
      Diabetic retinopathy continues to progress even when hyperglycemia is terminated, suggesting a 'metabolic memory' phenomenon. Mitochondrial dysfunction is closely associated with the development of diabetic retinopathy, and mitochondria remain dysfunctional. Quality control of mitochondria requires a fine balance between mitochondrial fission-fusion, removal of the damaged mitochondria (mitophagy) and formation of new mitochondria (biogenesis). In diabetes, while mitochondrial fusion protein (Mfn2) is decreased, fission protein (Drp1) is increased, resulting in fragmented mitochondria. Re-institution of normal glycemia fails to reverse mitochondrial fragmentation, and dysfunctional mitochondria continue to accumulate. Our aim was to investigate the direct effect of regulation of the mitochondrial fusion process during normal glycemia that follows a high glucose insult on mitochondrial quality control in the 'metabolic memory' phenomenon. Human retinal endothelial cells, incubated in 20 mM glucose for four days, followed by 5 mM glucose for four additional days, with or without the Mfn2 activator leflunomide, were analyzed for mitochondrial fission (live cell imaging), mitophagy (flow cytometry and immunofluorescence microscopy), and mitochondrial mass (mitochondrial copy numbers and MitoTracker labeling). Mitochondrial health was determined by quantifying mitochondrial reactive oxygen species (ROS), respiration rate (Seahorse XF96) and mitochondrial DNA (mtDNA) damage. Addition of leflunomide during normal glucose exposure that followed high glucose prevented mitochondrial fission, facilitated mitophagy and increased mitochondrial mass. Glucose-induced decrease in mitochondrial respiration and increase in ROS and mtDNA damage were also prevented. Thus, direct regulation of mitochondrial dynamics can help maintain mitochondrial quality control and interfere with the metabolic memory phenomenon, preventing further progression of diabetic retinopathy.
    Keywords:  diabetic retinopathy; metabolic memory; mitochondria; mitochondrial dynamics; mitophagy
  4. Int J Mol Sci. 2023 May 02. pii: 8151. [Epub ahead of print]24(9):
      There is mounting evidence that the development of Alzheimer's disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP-AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS-STING signaling pathway and the mechanisms underlying the association between cGAS-STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS-STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS-STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs.
    Keywords:  Alzheimer’s disease; STING; cGAS; neuroinflammation; type-I IFN
  5. Biomed Pharmacother. 2023 May 12. pii: S0753-3322(23)00659-5. [Epub ahead of print]163 114869
      Pain is a common clinical condition. However, the mechanisms underlying pain are not yet fully understood. It is known that the neuroimmune system plays a critical role in the pathogenesis of pain. Recent studies indicated that the cyclic-GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can activate the innate immune system by sensing both extrinsic and intrinsic double-stranded DNA in the cytoplasm, which is involved in pain processing. In this review, we summarise (1) the roles of the cGAS-STING pathway in different pain models, (2) the effect of the cGAS-STING pathway in different cells during pain regulation, and (3) the downstream molecular mechanisms of the cGAS-STING pathway in pain regulation. This review provides evidence that the cGAS-STING pathway has pro- and anti-nociceptive effects in pain models. It has different functions in neuron, microglia, macrophage, and T cells. Its downstream molecules include IFN-I, NF-κB, NLRP3, and eIF2α. The bidirectional roles of the cGAS-STING pathway in pain processing are mediated by regulating nociceptive neuronal sensitivity and neuroinflammatory responses. However, their effects in special brain regions, activation of astrocytes, and the different phases of pain require further exploration.
    Keywords:  Astrocyte; Chronic pain; Microglia; Neuroinflammation; Nociceptive neuron; cGAS-STING
  6. Cells. 2023 04 07. pii: 1106. [Epub ahead of print]12(8):
      The RUNX family of transcription factors, including RUNX1, RUNX2, and RUNX3, are key regulators of development and can function as either tumor suppressors or oncogenes in cancer. Emerging evidence suggests that the dysregulation of RUNX genes can promote genomic instability in both leukemia and solid cancers by impairing DNA repair mechanisms. RUNX proteins control the cellular response to DNA damage by regulating the p53, Fanconi anemia, and oxidative stress repair pathways through transcriptional or non-transcriptional mechanisms. This review highlights the importance of RUNX-dependent DNA repair regulation in human cancers.
    Keywords:  DNA damage; DNA repair; Fanconi anemia; RUNX1; RUNX2; RUNX3; TGF-β; leukemia; p53; reactive oxygen species
  7. Int J Mol Sci. 2023 Apr 22. pii: 7693. [Epub ahead of print]24(9):
      Mitochondria are highly dynamic and responsive organelles capable of fission and fusion and are a hub of diverse signaling pathways that are fundamental to cellular homeostasis, energy production, metabolism, survival, and death [...].
  8. Biomedicines. 2023 Apr 13. pii: 1172. [Epub ahead of print]11(4):
      BACKGROUND: The POLG gene encodes the catalytic subunit of DNA polymerase γ, which is crucial for mitochondrial DNA (mtDNA) repair and replication. Gene mutation alters the stability of mtDNA and is associated with several clinical presentations, such as dysarthria and ophthalmoplegia (SANDO), progressive external ophthalmoplegia (PEO), spinocerebellar ataxia and epilepsy (SCAE), Alpers syndrome, and sensory ataxic neuropathy. Recent evidence has also indicated that POLG mutations may be involved in some neurodegenerative disorders, although systematic screening is currently lacking.METHODS: To investigate the frequency of POLG gene mutations in neurodegenerative disorders, we screened a group of 33 patients affected by neurodegenerative diseases, including Parkinson's disease, some atypical parkinsonisms, and dementia of different types.
    RESULTS: Mutational analysis revealed the presence of the heterozygous Y831C mutation in two patients, one with frontotemporal dementia and one with Lewy body dementia. The allele frequency of this mutation reported by the 1000 Genomes Project in the healthy population is 0.22%, while in our group of patients, it was 3.03%, thus showing a statistically significant difference between the two groups.
    CONCLUSIONS: Our results may expand the genotype-phenotype spectrum associated with mutations in the POLG gene and strengthen the hypothesis of a pathogenic role of the Y831C mutation in neurodegeneration.
    Keywords:  POLG; Y831C; dementia; movement disorders; neurodegeneration
  9. Exp Gerontol. 2023 May 10. pii: S0531-5565(23)00124-9. [Epub ahead of print] 112203
      Mitochondrial DNA (mtDNA) is as a multi-copy genome existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. Accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and older adults, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.
    Keywords:  Heteroplasmy; Mitochondrial biogenesis; Mitochondrial diseases; Mitochondrial quality; mtDNA deletions; mtDNA mutations
  10. Nat Struct Mol Biol. 2023 May 18.
      Accurate replication of mitochondrial DNA (mtDNA) by DNA polymerase γ (Polγ) is essential for maintaining cellular energy supplies, metabolism, and cell cycle control. To illustrate the structural mechanism for Polγ coordinating polymerase (pol) and exonuclease (exo) activities to ensure rapid and accurate DNA synthesis, we determined four cryo-EM structures of Polγ captured after accurate or erroneous incorporation to a resolution of 2.4-3.0 Å. The structures show that Polγ employs a dual-checkpoint mechanism to sense nucleotide misincorporation and initiate proofreading. The transition from replication to error editing is accompanied by increased dynamics in both DNA and enzyme, in which the polymerase relaxes its processivity and the primer-template DNA unwinds, rotates, and backtracks to shuttle the mismatch-containing primer terminus 32 Å to the exo site for editing. Our structural and functional studies also provide a foundation for analyses of Polγ mutation-induced human diseases and aging.
  11. Ageing Res Rev. 2023 May 15. pii: S1568-1637(23)00114-9. [Epub ahead of print] 101955
      Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of aging, the role of mitochondrial quality control (MQC) in aging is still poorly understood. A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized by-products through mitochondrial proteases and mitochondrial unfolded protein response (UPRmt). Mitochondrial-derived vesicles (MDVs) are the first line of MQC to dispose of oxidized derivatives. Besides, mitophagy helps remove partially damaged mitochondria to ensure that mitochondria are healthy and functional. Although abundant interventions on MQC have been explored, over-activation or inhibition of any type of MQC may even accelerate abnormal energy metabolism and mitochondrial dysfunction-induced senescence. This review summarizes mechanisms essential for maintaining mitochondrial homeostasis and emphasizes that imbalanced MQC may accelerate cellular senescence and aging. Thus, appropriate interventions on MQC may delay the aging process and extend lifespan.
    Keywords:  Aging; mitochondrial dysfunction; mitochondrial quality control; reactive oxygen species
  12. Int J Mol Sci. 2023 May 03. pii: 8181. [Epub ahead of print]24(9):
      Mitochondria are organelles present in almost all eukaryotic cells, where they represent the main site of energy production. Mitochondria are involved in several important cell processes, such as calcium homeostasis, OXPHOS, autophagy, and apoptosis. Moreover, they play a pivotal role also in inflammation through the inter-organelle and inter-cellular communications, mediated by the release of mitochondrial damage-associated molecular patterns (mtDAMPs). It is currently well-documented that in addition to traditional endocrine and paracrine communication, the cells converse via extracellular vesicles (EVs). These small membrane-bound particles are released from cells in the extracellular milieu under physio-pathological conditions. Importantly, EVs have gained much attention for their crucial role in inter-cellular communication, translating inflammatory signals into recipient cells. EVs cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Studies have shown that EVs may transport mitochondrial portions, proteins, and/or mtDAMPs to modulate the metabolic and inflammatory responses of recipient cells. Overall, the relationship between EVs and mitochondria in inflammation is an active area of research, although further studies are needed to fully understand the mechanisms involved and how they may be targeted for therapeutic purposes. Here, we have reported and discussed the latest studies focused on this fascinating and recent area of research, discussing of tricky connection between mitochondria and EVs in inflammatory-related diseases.
    Keywords:  extracellular vesicles; inflammation; inflammatory diseases; intercellular communication; mitochondria; mitochondria-derived vesicles; mitovesicles