bims-mitper 2022-09-25 papers

Membranes (Basel). 2022 Sep 16. pii: 893. [Epub ahead of print]12(9):

Mitochondrial Fission and Fusion: Molecular Mechanisms, Biological Functions, and Related Disorders.

Mode Al Ojaimi, Azza Salah, Ayman W El-Hattab.

Mitochondria are dynamic organelles that undergo fusion and fission. These active processes occur continuously and simultaneously and are mediated by nuclear-DNA-encoded proteins that act on mitochondrial membranes. The balance between fusion and fission determines the mitochondrial morphology and adapts it to the metabolic needs of the cells. Therefore, these two processes are crucial to optimize mitochondrial function and its bioenergetics abilities. Defects in mitochondrial proteins involved in fission and fusion due to pathogenic variants in the genes encoding them result in disruption of the equilibrium between fission and fusion, leading to a group of mitochondrial diseases termed disorders of mitochondrial dynamics. In this review, the molecular mechanisms and biological functions of mitochondrial fusion and fission are first discussed. Then, mitochondrial disorders caused by defects in fission and fusion are summarized, including disorders related to MFN2, MSTO1, OPA1, YME1L1, FBXL4, DNM1L, and MFF genes.

Keywords: mitochondrial diseases; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion

DOI: https://doi.org/10.3390/membranes12090893

Oncoimmunology. 2022 ;11(1): 2117321

Targeting DNA damage response components induces enhanced STING-dependent type-I IFN response in ATM deficient cancer cells and drives dendritic cell activation.

Marta Lopez-Pelaez, Lucy Young, Mercedes Vazquez-Chantada, Nadine Nelson, Steve Durant, Robert W Wilkinson, Edmund Poon, Miguel Gaspar, Viia Valge-Archer, Paul Smith, Simon J Dovedi.

The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory DNA repair pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. DNA damage response (DDR)-deficient cells are also more sensitive to DNA damaging agents like the DNA crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting the DDR pathways, which could operate through the activation of the innate immune system are less well studied. DNA accumulation in the cytosol acts as an immunogenic danger signal, inducing the expression of type-I interferon (IFN) stimulated genes (ISGs) by the activation of the cGAS-STING pathway. Here, we demonstrate that ATM -/- FaDu tumor cells have higher basal expression of ISGs when compared to WT cells and respond to ceralasertib and PBD SG-3199 by inducing higher levels of ISGs in a cGAS-STING-dependent manner. We show that sensitive tumor cells treated with ceralasertib and PBD SG-3199 activate dendritic cells (DCs) via a type-I IFN-dependent mechanism. However, STING deficiency in tumor cells does not prevent DC activation, suggesting that transactivation of the STING pathway occurs within DCs. Furthermore, depletion of the cytosolic DNA exonuclease TREX1 in tumor cells increases DC activation in response to PBD SG-3199-treated tumor cells, indicating that an increase in tumor-derived cytosolic DNA may further enhance DC activation. In summary, in this study, we show that ceralasertib and PBD SG-3199 treatment not only intrinsically target tumor cells but also extrinsically increase tumor cell immunogenicity by inducing DC activation, which is enhanced in ATM-deficient cells.

Keywords: ATM; ATR; DC; DDR; DNA damage repair; Interferon; PBD SG-3199; STING; TREX1; ceralasertib

DOI: https://doi.org/10.1080/2162402X.2022.2117321

Cytokine Growth Factor Rev. 2022 Sep 14. pii: S1359-6101(22)00075-2. [Epub ahead of print]

The cGAS-STING pathway: Post-translational modifications and functional implications in diseases.

Jun Liu, Ke Rui, Na Peng, Hui Luo, Bo Zhu, Xiaoxia Zuo, Liwei Lu, Jixiang Chen, Jie Tian.

Recent studies have illustrated the functional significance of DNA recognition in the activation of innate immune responses among a variety of diseases. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has been found to be modulated by post-translational modifications and can regulate the immune response via type I IFNs. Accumulating evidence indicates a pivotal role of cGAS-STING signaling, being protective or pathogenic, in the development of diseases. Thus, a comprehensive understanding of the post-translational modifications of cGAS-STING pathway and their role in disease development will provide insights in predicting individual disease outcomes and developing appropriate therapies. In this review, we will discuss the regulation of the cGAS-STING pathway and its implications in disease pathologies, as well as pharmacologic strategies to target the cGAS-STING pathway for therapeutic intervention.

Keywords: CGAS; Disease treatment; Post-translational modifications; STING; Signaling pathway

DOI: https://doi.org/10.1016/j.cytogfr.2022.09.003

Cells. 2022 Sep 08. pii: 2812. [Epub ahead of print]11(18):

Regulation of cGAS Activity and Downstream Signaling.

Bhagwati Joshi, Jagdish Chandra Joshi, Dolly Mehta.

Cyclic GMP-AMP synthase (cGAS) is a predominant and ubiquitously expressed cytosolic onfirmedDNA sensor that activates innate immune responses by producing a second messenger, cyclic GMP-AMP (cGAMP), and the stimulator of interferon genes (STING). cGAS contains a highly disordered N-terminus, which can sense genomic/chromatin DNA, while the C terminal of cGAS binds dsDNA liberated from various sources, including mitochondria, pathogens, and dead cells. Furthermore, cGAS cellular localization dictates its response to foreign versus self-DNA. Recent evidence has also highlighted the importance of dsDNA-induced post-translational modifications of cGAS in modulating inflammatory responses. This review summarizes and analyzes cGAS activity regulation based on structure, sub-cellular localization, post-translational mechanisms, and Ca2+ signaling. We also discussed the role of cGAS activation in different diseases and clinical outcomes.

Keywords: STING; autoimmunity; cGAS; calcium; inflammation

DOI: https://doi.org/10.3390/cells11182812

Membranes (Basel). 2022 Sep 16. pii: 890. [Epub ahead of print]12(9):

Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore.

Tatiana Fedotcheva, Nikolai Shimanovsky, Nadezhda Fedotcheva.

The permeability transition pore in mitochondria (MPTP) and the ATP-binding cassette transporters (АВС transporters) in cell membranes provide the efflux of low-molecular compounds across mitochondrial and cell membranes, respectively. The inhibition of ABC transporters, especially of those related to multi drug resistance (MDR) proteins, is an actively explored approach to enhance intracellular drug accumulation and increase thereby the efficiency of anticancer therapy. Although there is evidence showing the simultaneous effect of some inhibitors on both MDR-related proteins and mitochondrial functions, their influence on MPTP has not been previously studied. We examined the participation of verapamil and quinidine, classified now as the first generation of MDR modulators, and avermectin, which has recently been actively studied as an MDR inhibitor, in the regulation of the MPTP opening. In experiments on rat liver mitochondria, we found that quinidine lowered and verapamil increased the threshold concentrations of calcium ions required for MPTP opening, and that they both decreased the rate of calcium-induced swelling of mitochondria. These effects may be associated with the positive charge of the drugs and their aliphatic properties. Avermectin not only decreased the threshold concentration of calcium ions, but also by itself induced the opening of MPTP and the mitochondrial swelling inhibited by ADP and activated by carboxyatractyloside, the substrate and inhibitor of adenine nucleotide translocase (ANT), which suggests the involvement of ANT in the process. Thus, these data indicate an additional opportunity to evaluate the effectiveness of MDR modulators in the context of their influence on the mitochondrial-dependent apoptosis.

Keywords: avermectin; mitochondrial permeability transition pore; multidrug resistance; quinidine; verapamil

DOI: https://doi.org/10.3390/membranes12090890

Int J Mol Sci. 2022 Sep 17. pii: 10878. [Epub ahead of print]23(18):

Mitochondrial Dysfunction in Spinal Muscular Atrophy.

Eleonora Zilio, Valentina Piano, Brunhilde Wirth.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by recessive mutations in the SMN1 gene, globally affecting ~8-14 newborns per 100,000. The severity of the disease depends on the residual levels of functional survival of motor neuron protein, SMN. SMN is a ubiquitously expressed RNA binding protein involved in a plethora of cellular processes. In this review, we discuss the effects of SMN loss on mitochondrial functions in the neuronal and muscular systems that are the most affected in patients with spinal muscular atrophy. Our aim is to highlight how mitochondrial defects may contribute to disease progression and how restoring mitochondrial functionality may be a promising approach to develop new therapies. We also collected from previous studies a list of transcripts encoding mitochondrial proteins affected in various SMA models. Moreover, we speculate that in adulthood, when motor neurons require only very low SMN levels, the natural deterioration of mitochondria associated with aging may be a crucial triggering factor for adult spinal muscular atrophy, and this requires particular attention for therapeutic strategies.

Keywords: SMN1; SMN2; cellular homeostasis; mitochondria; mitochondria biogenesis and dynamics; motor neuron diseases; neurodegeneration; neurodegenerative diseases; oxidative stress; spinal muscular atrophy

DOI: https://doi.org/10.3390/ijms231810878