bims-mitper 2022-10-09 papers

bims-mitper

Biomed News

on Mitochondrial Permeabilization

Issue of 2022–10–09
nine papers selected by
Bradley Irizarry, Thomas Jefferson University

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis.
Roles of mitochondrial fusion and fission in breast cancer progression: a systematic review.
Activating Innate Immunity by a STING Signal Amplifier for Local and Systemic Immunotherapy.
RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.
Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation.
Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression.
Structural basis of Ca2+ uptake by mitochondrial calcium uniporter in mitochondria: a brief review.
Cell-Free Mitochondrial DNA in Acute Brain Injury.
Pathogenic mtDNA variants, in particular single large-scale mtDNA deletions, are strongly associated with post-lingual onset sensorineural hearing loss in primary mitochondrial disease.

J Neuroinflammation. 2022 Oct 04. 19(1): 242

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis.

Xinli Hu, Haojie Zhang, Qianxin Zhang, Xue Yao, Wenfei Ni, Kailiang Zhou.

  Stimulator of interferons genes (STING), which is crucial for the secretion of type I interferons and proinflammatory cytokines in response to cytosolic nucleic acids, plays a key role in the innate immune system. Studies have revealed the participation of the STING pathway in unregulated inflammatory processes, traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid haemorrhage (SAH) and hypoxic-ischaemic encephalopathy (HIE). STING signalling is markedly increased in CNS injury, and STING agonists might facilitate the pathogenesis of CNS injury. However, the effects of STING-regulated signalling activation in CNS injury are not well understood. Aberrant activation of STING increases inflammatory events, type I interferon responses, and cell death. cGAS is the primary pathway that induces STING activation. Herein, we provide a comprehensive review of the latest findings related to STING signalling and the cGAS-STING pathway and highlight the control mechanisms and their functions in CNS injury. Furthermore, we summarize and explore the most recent advances toward obtaining an understanding of the involvement of STING signalling in programmed cell death (autophagy, necroptosis, ferroptosis and pyroptosis) during CNS injury. We also review potential therapeutic agents that are capable of regulating the cGAS-STING signalling pathway, which facilitates our understanding of cGAS-STING signalling functions in CNS injury and the potential value of this signalling pathway as a treatment target.

Keywords:  Cell death; Central nervous system injury; Inflammation; STING; cGAS

DOI:  https://doi.org/10.1186/s12974-022-02602-y
World J Surg Oncol. 2022 Oct 03. 20(1): 331

Roles of mitochondrial fusion and fission in breast cancer progression: a systematic review.

Jixiang Xing, Luyao Qi, Xiaofei Liu, Guangxi Shi, Xiaohui Sun, Yi Yang.

   BACKGROUND: Mitochondria play critical roles in cellular physiological activity as cellular organelles. Under extracellular stimulation, mitochondria undergo constant fusion and fission to meet different cellular demands. Mitochondrial dynamics, which are involved in mitochondrial fusion and fission, are regulated by specialized proteins and lipids, and their dysregulation causes human diseases, such as cancer. The advanced literature about the crucial role of mitochondrial dynamics in breast cancer is performed.
METHODS: All related studies were systematically searched through online databases (PubMed, Web of Science, and EMBASE) using keywords (e.g., breast cancer, mitochondrial, fission, and fusion), and these studies were then screened through the preset inclusion and exclusion criteria.
RESULTS: Eligible studies (n = 19) were evaluated and discussed in the systematic review. These advanced studies established the roles of mitochondrial fission and fusion of breast cancer in the metabolism, proliferation, survival, and metastasis. Importantly, the manipulating of mitochondrial dynamic is significant for the progresses of breast cancer.
CONCLUSION: Understanding the mechanisms underlying mitochondrial fission and fusion during tumorigenesis is important for improving breast cancer treatments.

Keywords:  Breast cancer; Fission; Fusion; Mitochondria

DOI:  https://doi.org/10.1186/s12957-022-02799-5
ACS Nano. 2022 Oct 03.

Activating Innate Immunity by a STING Signal Amplifier for Local and Systemic Immunotherapy.

Wen Song, Shu-Jun Song, Jing Kuang, Hang Yang, Tao Yu, Fan Yang, Tao Wan, Yi Xu, Si-Tian Wei, Mu-Xuan Li, Yuan Xiong, Ying Zhou, Wen-Xiu Qiu.

  The number of patients who benefit from acquired immunotherapy is limited. Stimulator of interferon genes (STING) signal activation is a significant component to enhance innate immunity, which has been used to realize broad-spectrum immunotherapy. Here, M@P@HA nanoparticles, as a STING signal amplifier, are constructed to enhance innate immunotherapy. Briefly, when M@P@HA was targeted into tumor cells, the nanoparticles decomposed with Mn2+ and activated the release of protoporphyrin (PpIX). Under light irradiation, the generated reactive oxygen species disrupt the cellular redox homeostasis to lead cytoplasm leakage of damaged mitochondrial double-stranded (ds) DNA, which is the initiator of the STING signal. Simultaneously, Mn2+ as the immunoregulator could significantly increase the activity of related protein of a STING signal, such as cyclic GMP-AMP synthase (cGAS) and STING, to further amplify the STING signal of tumor cells. Subsequently, the STING signal of tumor-associated macrophages (TAM) is also activated by capturing dsDNA and Mn2+ that escaped from tumor cells, so as to enhance innate immunity. It is found that, by amplifying the STING signal of tumor tissue, M@P@HA could not only activate innate immunity but also cascade to activate CD8+ T cell infiltration even in a tumor with low immunogenicity.

Keywords:  STING; aPD-L1; immunotherapy; innate immunity; mitochondria damage

DOI:  https://doi.org/10.1021/acsnano.2c03509
Autophagy. 2022 Oct 06.

RHOA, a small G-protein, signals to mitophagy through regulation of PINK1 protein stability and protects cardiomyocytes against ischemia.

Michelle Tu, Shigeki Miyamoto.

  RHOA (ras homolog family member A) is a small G-protein that regulates a range of cellular processes including cell growth and survival. RHOA is a proximal downstream effector of G protein-coupled receptor coupling to GNA12/Gα12-GNA13/Gα13 proteins, and is activated in response to stretch and oxidative stress, functioning as a stress-response molecule. It has been demonstrated that RHOA signaling provides cardioprotection through inhibition of mitochondrial death pathways. Mitochondrial integrity is preserved not only by inhibition of mitochondrial death pathways but also by mitochondrial quality control mechanisms including mitophagy. One of the most well-established mechanisms of mitophagy is the mitochondrial membrane depolarization-dependent PINK1-PRKN/Parkin pathway. However, depolarization of the mitochondrial membrane potential is a late-stage event that occurs just before cell death, and additional intracellular mechanisms that enhance the PINK1-PRKN pathway have not been fully determined. We recently discovered that RHOA activation engages a unique mechanism to regulate PINK1 protein stability without inducing mitochondrial membrane depolarization, leading to increased mitophagy and protection against ischemia in cardiomyocytes. Our results suggest regulation of RHOA signaling as a potential strategy to enhance protective mitophagy against stress without compromising mitochondrial functions.

Keywords:  Cardiomyocytes; PINK1, RHOA; ischemia; mitophagy, Parkin

DOI:  https://doi.org/10.1080/15548627.2022.2132707
Cell Rep. 2022 Oct 04. pii: S2211-1247(22)01275-X. [Epub ahead of print]41(1): 111434

Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation.

Yaqiu Wang, Rajendra Karki, Raghvendra Mall, Bhesh Raj Sharma, Ravi C Kalathur, SangJoon Lee, Balabhaskararao Kancharana, Matthew So, Katie L Combs, Thirumala-Devi Kanneganti.

  Type I interferons (IFNs) are essential innate immune proteins that maintain tissue homeostasis through tonic expression and can be upregulated to drive antiviral resistance and inflammation upon stimulation. However, the mechanisms that inhibit aberrant IFN upregulation in homeostasis and the impacts of tonic IFN production on health and disease remain enigmatic. Here, we report that caspase-8 negatively regulates type I IFN production by inhibiting the RIPK1-TBK1 axis during homeostasis across multiple cell types and tissues. When caspase-8 is deleted or inhibited, RIPK1 interacts with TBK1 to drive elevated IFN production, leading to heightened resistance to norovirus infection in macrophages but also early onset lymphadenopathy in mice. Combined deletion of caspase-8 and RIPK1 reduces the type I IFN signaling and lymphadenopathy, highlighting the critical role of RIPK1 in this process. Overall, our study identifies a mechanism to constrain tonic type I IFN during homeostasis which could be targeted for infectious and inflammatory diseases.

Keywords:  CP: Immunology; PANoptosis; RIPK1; TBK1; apoptosis; caspase-8; cell death; inflammasome; inflammation; pyroptosis; type I interferon

DOI:  https://doi.org/10.1016/j.celrep.2022.111434
Front Oncol. 2022 ;12 992260

Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression.

Swaroop Kumar Pandey, Anna Shteinfer-Kuzmine, Vered Chalifa-Caspi, Varda Shoshan-Barmatz.

  Mitochondrial SMAC/Diablo induces apoptosis by binding the inhibitor of apoptosis proteins (IAPs), thereby activating caspases and, subsequently, apoptosis. Previously, we found that despite its pro-apoptotic activity, SMAC/Diablo is overexpressed in cancer, and demonstrated that in cancer it possesses new essential and non-apoptotic functions that are associated with regulating phospholipid synthesis including modulating mitochondrial phosphatidylserine decarboxylase activity. Here, we demonstrate additional functions for SMAC/Diablo associated with inflammation and immunity. CRISPR/Cas9 SMAC/Diablo-depleted A549 lung cancer cells displayed inhibited cell proliferation and migration. Proteomics analysis of these cells revealed altered expression of proteins associated with lipids synthesis and signaling, vesicular transport and trafficking, metabolism, epigenetics, the extracellular matrix, cell signaling, and neutrophil-mediated immunity. SMAC-KO A549 cell-showed inhibited tumor growth and proliferation and activated apoptosis. The small SMAC-depleted "tumor" showed a morphology of alveoli-like structures, reversed epithelial-mesenchymal transition, and altered tumor microenvironment. The SMAC-lacking tumor showed reduced expression of inflammation-related proteins such as NF-kB and TNF-α, and of the PD-L1, associated with immune system suppression. These results suggest that SMAC is involved in multiple processes that are essential for tumor growth and progression. Thus, targeting SMAC's non-canonical function is a potential strategy to treat cancer.

Keywords:  SMAC; cell proliferation; immunosuppression; inflammation; lung cancer

DOI:  https://doi.org/10.3389/fonc.2022.992260
BMB Rep. 2022 Oct 05. pii: 5705. [Epub ahead of print]

Structural basis of Ca2+ uptake by mitochondrial calcium uniporter in mitochondria: a brief review.

Jiho Yoo.

Mitochondria are cellular organelles that perform various functions within cells. They are responsible for ATP production, cell-signal regulation, autophagy, and cell apoptosis. Because the mitochondrial proteins that perform these functions need Ca2+ ions for their activity, mitochondria have ion channels to selectively uptake Ca2+ ions from the cytoplasm. The ion channel known to play the most important role in the Ca2+ uptake in mitochondria is the mitochondrial calcium uniporter (MCU) holo-complex located in the inner mitochondrial membrane (IMM). This ion channel complex exists in the form of a complex consisting of the pore-forming protein through which the Ca2+ ions are transported into the mitochondrial matrix, and the auxiliary protein involved in regulating the activity of the Ca2+ uptake by the MCU holo-complex. Studies of this MCU holocomplex have long been conducted, but we didn't know in detail how mitochondria uptake Ca2+ ions through this ion channel complex or how the activity of this ion channel complex is regulated. Recently, the protein structure of the MCU holo-complex was identified, enabling the mechanism of Ca2+ uptake and its regulation by the MCU holo-complex to be confirmed. In this review, I will introduce the mechanism of action of the MCU holo-complex at the molecular level based on the Cryo-EM structure of the MCU holo-complex to help understand how mitochondria uptake the necessary Ca2+ ions through the MCU holo-complex and how these Ca2+ uptake mechanisms are regulated.
Neurotrauma Rep. 2022 ;3(1): 415-420

Cell-Free Mitochondrial DNA in Acute Brain Injury.

Saeed Kayhanian, Angelos Glynos, Richard Mair, Andras Lakatos, Peter J A Hutchinson, Adel E Helmy, Patrick F Chinnery.

  Traumatic brain injury and aneurysmal subarachnoid haemorrhage are a major cause of morbidity and mortality worldwide. Treatment options remain limited and are hampered by our understanding of the cellular and molecular mechanisms, including the inflammatory response observed in the brain. Mitochondrial DNA (mtDNA) has been shown to activate an innate inflammatory response by acting as a damage-associated molecular pattern (DAMP). Here, we show raised circulating cell-free (ccf) mtDNA levels in both cerebrospinal fluid (CSF) and serum within 48 h of brain injury. CSF ccf-mtDNA levels correlated with clinical severity and the interleukin-6 cytokine response. These findings support the use of ccf-mtDNA as a biomarker after acute brain injury linked to the inflammatory disease mechanism.

Keywords:  DAMP; acute brain injury; brain inflammation; mitochondrial DNA; subarachnoid hemorrhage; traumatic brain injury

DOI:  https://doi.org/10.1089/neur.2022.0032
Mol Genet Metab. 2022 Sep 19. pii: S1096-7192(22)00398-5. [Epub ahead of print]137(3): 230-238

Pathogenic mtDNA variants, in particular single large-scale mtDNA deletions, are strongly associated with post-lingual onset sensorineural hearing loss in primary mitochondrial disease.

Johanna Elander, Elizabeth M McCormick, Maria Värendh, Karin Stenfeldt, Rebecca D Ganetzky, Amy Goldstein, Zarazuela Zolkipli-Cunningham, Laura E MacMullen, Rui Xiao, Marni J Falk, Johannes K Ehinger.

  In this retrospective cohort study of 193 consecutive subjects with primary mitochondrial disease (PMD) seen at the Children's Hospital of Philadelphia Mitochondrial Medicine Frontier Program, we assessed prevalence, severity, and time of onset of sensorineural hearing loss (SNHL) for PMD cases with different genetic etiologies. Subjects were grouped by genetic diagnosis: mitochondrial DNA (mtDNA) pathogenic variants, single large-scale mtDNA deletions (SLSMD), or nuclear DNA (nDNA) pathogenic variants. SNHL was audiometrically confirmed in 27% of PMD subjects (20% in mtDNA pathogenic variants, 58% in SLSMD and 25% in nDNA pathogenic variants). SLSMD had the highest odds ratio for SNHL. SNHL onset was post-lingual in 79% of PMD cases, interestingly including all cases with mtDNA pathogenic variants and SLSMD, which was significantly different from PMD cases caused by nDNA pathogenic variants. SNHL onset during school age was predominant in this patient population. Regular audiologic assessment is important for PMD patients, and PMD of mtDNA etiology should be considered as a differential diagnosis in pediatric patients and young adults with post-lingual SNHL onset, particularly in the setting of multi-system clinical involvement. Pathogenic mtDNA variants and SLSMD are less likely etiologies in subjects with congenital, pre-lingual onset SNHL.

Keywords:  Audiology; Mitochondria; Mitochondrial DNA; Mitochondrial disease; Primary mitochondrial disease; Sensorineural hearing loss

DOI:  https://doi.org/10.1016/j.ymgme.2022.09.002