bims-mitper 2022-12-18 papers

bims-mitper

Biomed News

on Mitochondrial Permeabilization

Issue of 2022–12–18
twelve papers selected by
Bradley Irizarry, Thomas Jefferson University

Mitochondrial Permeability Transition.
The cGAS-STING pathway and cancer.
Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker.
Mitochondrial dynamics proteins as emerging drug targets.
Implications of p53 in mitochondrial dysfunction and Parkinson's disease.
An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration.
The Relationship between Reactive Oxygen Species and the cGAS/STING Signaling Pathway in the Inflammaging Process.
Simultaneous extraction and quantification of circulating mitochondrial and nuclear DNA using a single plasma sample to predict specific molecular diagnostic implications.
A rapid RIG-I signaling relay mediates efficient antiviral response.
Progress in Research on TLR4-Mediated Inflammatory Response Mechanisms in Brain Injury after Subarachnoid Hemorrhage.
Trophoblastic mitochondrial DNA induces endothelial dysfunction and NLRP3 inflammasome activation: Implications for preeclampsia.
Cardiopulmonary bypass-derived plasma exosomal HMGB1 contributes to alveolar epithelial cell necroptosis via mtDNA/cGAS/STING pathway.

Cells. 2022 Nov 30. pii: 3866. [Epub ahead of print]11(23):

Mitochondrial Permeability Transition.

Paolo Bernardi, Evgeny Pavlov.

The mitochondrial permeability transition (PT) is a phenomenon that can be broadly defined as an increase in the permeability of the mitochondrial inner membrane [...].

DOI: https://doi.org/10.3390/cells11233866
Nat Cancer. 2022 Dec 12.

The cGAS-STING pathway and cancer.

Natasha Samson, Andrea Ablasser.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a critical innate immune pathway that, following engagement by DNA, promotes distinct immune effector responses that can impact virtually all aspects of tumorigenesis, from malignant cell transformation to metastasis. Here we address how natural tumor-associated processes and traditional cancer therapies are shaped by cGAS-STING signaling, and how this contributes to beneficial or detrimental outcomes of cancer. We consider current efforts to target the cGAS-STING axis in tumors and highlight new frontiers in cGAS-STING biology to inspire thinking about their connection to cancer.

DOI: https://doi.org/10.1038/s43018-022-00468-w
Int J Mol Sci. 2022 Dec 02. pii: 15166. [Epub ahead of print]23(23):

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker.

Jun Feng, Zhaowei Chen, Wei Liang, Zhongping Wei, Guohua Ding.

  The kidney is a mitochondria-rich organ, and kidney diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal mitochondrial function. Mitochondrial dysfunction caused by mtDNA damage, including impaired mtDNA replication, mtDNA mutation, mtDNA leakage, and mtDNA methylation, is involved in the progression of kidney diseases. Herein, we review the roles of mtDNA damage in different setting of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). In a variety of kidney diseases, mtDNA damage is closely associated with loss of kidney function. The level of mtDNA in peripheral serum and urine also reflects the status of kidney injury. Alleviating mtDNA damage can promote the recovery of mitochondrial function by exogenous drug treatment and thus reduce kidney injury. In short, we conclude that mtDNA damage may serve as a novel biomarker for assessing kidney injury in different causes of renal dysfunction, which provides a new theoretical basis for mtDNA-targeted intervention as a therapeutic option for kidney diseases.

Keywords:  kidney diseases; mitochondrial DNA; mtDNA leakage; mtDNA methylation; mtDNA mutation; mtDNA replication

DOI:  https://doi.org/10.3390/ijms232315166
Trends Pharmacol Sci. 2022 Dec 07. pii: S0165-6147(22)00254-1. [Epub ahead of print]

Mitochondrial dynamics proteins as emerging drug targets.

Emmanouil Zacharioudakis, Evripidis Gavathiotis.

  The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure-function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.

Keywords:  activators; fission; fusion; inhibitors; mitochondria; mitochondrial dynamics; mitochondrial structure

DOI:  https://doi.org/10.1016/j.tips.2022.11.004
Int J Neurosci. 2022 Dec 14. 1-22

Implications of p53 in mitochondrial dysfunction and Parkinson's disease.

Yi-Fang Wang, Ying-Di Wang, Song Gao, Wei Sun.

  Mitochondria are vital subcellular organelles for that maintain cellular function, and mitochondrial defect and impairment are primary causes of dopaminergic neuron degeneration in Parkinson's disease (PD). P53 is a multifunctional protein implicated in the regulation of diverse cellular processes via transcription-dependent and transcription-independent mechanisms. Increasing evidence has revealed that mitochondrial dysfunction-associated dopaminergic neuron degeneration is tightly regulated by p53 in PD pathogenesis. Neurodegenerative stress triggers p53 activation, which induces mitochondrial changes, including transmembrane permeability, reactive oxygen species production, Ca2+ overload, electron transport chain defects and other dynamic alterations, and these changes contribute to neurodegeneration and are linked closely with PD occurrence and development. P53 inhibition has been shown to attenuate mitochondrial dysfunction and protect dopaminergic neurons from degeneration under conditions of neurodegenerative stress, and thus, p53 appears to be a potential target for neuroprotective therapy. We review the contributions of p53 to mitochondrial changes leading to apoptosis and the subsequent degeneration of dopaminergic neurons to advance the understanding of the underlying molecular mechanisms and provide a potential therapeutic target for PD treatment.

Keywords:  P53; Parkinson’s disease; mitochondrial dysfunction; neurodegeneration

DOI:  https://doi.org/10.1080/00207454.2022.2158824
Sci Rep. 2022 Dec 14. 12(1): 21634

An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration.

Agalya Periasamy, Naomi Mitchell, Olga Zaytseva, Arjun S Chahal, Jiamin Zhao, Peter M Colman, Leonie M Quinn, Jacqueline M Gulbis.

Intronic polymorphic TOMM40 variants increasing TOMM40 mRNA expression are strongly correlated to late onset Alzheimer's Disease. The gene product, hTomm40, encoded in the APOE gene cluster, is a core component of TOM, the translocase that imports nascent proteins across the mitochondrial outer membrane. We used Drosophila melanogaster eyes as an in vivo model to investigate the relationship between elevated Tom40 (the Drosophila homologue of hTomm40) expression and neurodegeneration. Here we provide evidence that an overabundance of Tom40 in mitochondria invokes caspase-dependent cell death in a dose-dependent manner, leading to degeneration of the primarily neuronal eye tissue. Degeneration is contingent on the availability of co-assembling TOM components, indicating that an increase in assembled TOM is the factor that triggers apoptosis and degeneration in a neural setting. Eye death is not contingent on inner membrane translocase components, suggesting it is unlikely to be a direct consequence of impaired import. Another effect of heightened Tom40 expression is upregulation and co-association of a mitochondrial oxidative stress biomarker, DmHsp22, implicated in extension of lifespan, providing new insight into the balance between cell survival and death. Activation of regulated death pathways, culminating in eye degeneration, suggests a possible causal route from TOMM40 polymorphisms to neurodegenerative disease.

DOI: https://doi.org/10.1038/s41598-022-23280-z
Int J Mol Sci. 2022 Dec 02. pii: 15182. [Epub ahead of print]23(23):

The Relationship between Reactive Oxygen Species and the cGAS/STING Signaling Pathway in the Inflammaging Process.

Bárbara Andrade, Carlos Jara-Gutiérrez, Marilyn Paz-Araos, Mary Carmen Vázquez, Pablo Díaz, Paola Murgas.

  During Inflammaging, a dysregulation of the immune cell functions is generated, and these cells acquire a senescent phenotype with an increase in pro-inflammatory cytokines and ROS. This increase in pro-inflammatory molecules contributes to the chronic inflammation and oxidative damage of biomolecules, classically observed in the Inflammaging process. One of the most critical oxidative damages is generated to the host DNA. Damaged DNA is located out of the natural compartments, such as the nucleus and mitochondria, and is present in the cell's cytoplasm. This DNA localization activates some DNA sensors, such as the cGAS/STING signaling pathway, that induce transcriptional factors involved in increasing inflammatory molecules. Some of the targets of this signaling pathway are the SASPs. SASPs are secreted pro-inflammatory molecules characteristic of the senescent cells and inducers of ROS production. It has been suggested that oxidative damage to nuclear and mitochondrial DNA generates activation of the cGAS/STING pathway, increasing ROS levels induced by SASPs. These additional ROS increase oxidative DNA damage, causing a loop during the Inflammaging. However, the relationship between the cGAS/STING pathway and the increase in ROS during Inflammaging has not been clarified. This review attempt to describe the potential connection between the cGAS/STING pathway and ROS during the Inflammaging process, based on the current literature, as a contribution to the knowledge of the molecular mechanisms that occur and contribute to the development of the considered adaptative Inflammaging process during aging.

Keywords:  DNA damage; ROS; SASPs; STING; aging; cGAS; cGAS/STING pathway; immunosenescence; inflammaging; macrophage; senescence

DOI:  https://doi.org/10.3390/ijms232315182
Mitochondrion. 2022 Dec 09. pii: S1567-7249(22)00107-6. [Epub ahead of print]68 114-124

Simultaneous extraction and quantification of circulating mitochondrial and nuclear DNA using a single plasma sample to predict specific molecular diagnostic implications.

Sandeep Kumar Vishwakarma, Nusrath Fathima, Santosh K Tiwari, Aleem Ahmed Khan.

  The magnitude of variations in the level of circulating mitochondrial (cir-mtDNA) and nuclear DNA (cir-ncDNA) in different diseases has indicated the need for investigating a discriminative approach for evaluating their diagnostic significance. This study reports a typical in-house process for extracting both types of cir-DNAs from a single plasma sample and assessed their usefulness in discriminating type 2 diabetes mellitus patients from healthy individuals to eliminate the prevailing dispute about their discriminative role and improve their diagnostic value. This approach offers a more precise and valuable tool for distinguishing the impact of cir-mtDNA from cir-ncDNA in diagnostic implications.

Keywords:  Circulating DNA (cir-DNA); DNA extraction; DNA quantification; Mitochondrial DNA (mtDNA); Nuclear DNA (ncDNA)

DOI:  https://doi.org/10.1016/j.mito.2022.12.003
Mol Cell. 2022 Dec 06. pii: S1097-2765(22)01131-5. [Epub ahead of print]

A rapid RIG-I signaling relay mediates efficient antiviral response.

Daniel T Thoresen, Drew Galls, Benjamin Götte, Wenshuai Wang, Anna M Pyle.

  RIG-I is essential for host defense against viral pathogens, as it triggers the release of type I interferons upon encounter with viral RNA molecules. In this study, we show that RIG-I is rapidly and efficiently activated by small quantities of incoming viral RNA and that it relies exclusively on the constitutively expressed resident pool of RIG-I receptors for a strong antiviral response. Live-cell imaging of RIG-I following stimulation with viral or synthetic dsRNA reveals that RIG-I signaling occurs without mass aggregation at the mitochondrial membrane. By contrast, interferon-induced RIG-I protein becomes embedded in cytosolic aggregates that are functionally unrelated to signaling. These findings suggest that endogenous RIG-I efficiently recognizes viral RNA and rapidly relays an antiviral signal to MAVS via a transient signaling complex and that cellular aggregates of RIG-I have a function that is distinct from signaling.

Keywords:  RIG-I; antiviral response; innate immunity; type I interferon response

DOI:  https://doi.org/10.1016/j.molcel.2022.11.018
Cells. 2022 Nov 26. pii: 3781. [Epub ahead of print]11(23):

Progress in Research on TLR4-Mediated Inflammatory Response Mechanisms in Brain Injury after Subarachnoid Hemorrhage.

Lintao Wang, Guangping Geng, Tao Zhu, Wenwu Chen, Xiaohui Li, Jianjun Gu, Enshe Jiang.

  Subarachnoid hemorrhage (SAH) is one of the common clinical neurological emergencies. Its incidence accounts for about 5-9% of cerebral stroke patients. Even surviving patients often suffer from severe adverse prognoses such as hemiplegia, aphasia, cognitive dysfunction and even death. Inflammatory response plays an important role during early nerve injury in SAH. Toll-like receptors (TLRs), pattern recognition receptors, are important components of the body's innate immune system, and they are usually activated by damage-associated molecular pattern molecules. Studies have shown that with TLR 4 as an essential member of the TLRs family, the inflammatory transduction pathway mediated by it plays a vital role in brain injury after SAH. After SAH occurrence, large amounts of blood enter the subarachnoid space. This can produce massive damage-associated molecular pattern molecules that bind to TLR4, which activates inflammatory response and causes early brain injury, thus resulting in serious adverse prognoses. In this paper, the process in research on TLR4-mediated inflammatory response mechanism in brain injury after SAH was reviewed to provide a new thought for clinical treatment.

Keywords:  TLR4; brain injury; cerebrospinal fluid; inflammatory response; subarachnoid hemorrhage

DOI:  https://doi.org/10.3390/cells11233781
Int Immunopharmacol. 2022 Dec 09. pii: S1567-5769(22)01008-6. [Epub ahead of print]114 109523

Trophoblastic mitochondrial DNA induces endothelial dysfunction and NLRP3 inflammasome activation: Implications for preeclampsia.

Zi Lv, Ding-Yi Lv, Jia-Yu Meng, Xiao-Yan Sha, Xue-Ya Qian, Yun-Shan Chen, Xiu-Yu Pan, Guang-Yuan Yu, Hui-Shu Liu.

   AIMS: Preeclampsia (PE) is characterised by systemic vascular endothelium dysfunction. Circulating trophoblastic secretions contribute to endothelial dysfunction, resulting in PE; however, the underlying mechanisms remain unclear. Herein, we aimed to determine the potential correlation between the release of trophoblastic mitochondrial deoxyribonucleic acid (DNA) (mtDNA) and endothelium damage in PE.
MATERIALS AND METHODS: Umbilical cord sera and tissues from patients with PE were investigated for inflammasome activation. Following this, trophoblastic mitochondria were isolated from HTR-8/SVneo trophoblasts under 21 % oxygen (O2) or hypoxic conditions (1 % O2 for 48 h) for subsequent treatments. Primary human umbilical veinendothelial cells (HUVECs) were isolated from the human umbilical cord and then exposed to a vehicle (phosphate-buffered saline [PBS]), mtDNA, hypo-mtDNA, or hypo-mtDNA with INF39 (nucleotide oligomerisation domain-like receptor family pyrin domain containing 3 [NLRP3]-specific inhibitor) for 12 h before flow cytometry and immunoblotting. The effects of trophoblastic mtDNA on the endothelium were further analysed in vivo using enzyme-linked immunosorbent assay (ELISA) and vascular reactivity assay. The effects of mtDNA on vascular phenotypes were also tested on NLRP3 knockout mice.
RESULTS: Elevated interleukin (IL)-1β in PE sera was accompanied by NLRP3 inflammasome activation in cord tissues. In vitro and in vivo experiments revealed that the release of trophoblastic mtDNA could damage the endothelium via NLRP3 activation, resulting in the overexpression of NLRP3, caspase-1 p20, IL-1β p17, and gasdermin D (GSDMD); reduced endothelial nitric oxide synthase (eNOS) levels; and impaired vascular relaxation. Flow cytometric analysis confirmed that extensive cell death was induced by mtDNA, and simultaneously, a more pronounced pro-apoptotic effect was caused by hypoxia-treated trophoblastic mtDNA. The NLRP3 knockout or pharmacologic NLRP3 inhibition partially reversed tumour necrosis factor-α (TNF-α) and IL-1β levels and endothelium-dependent vasodilation in mice.
CONCLUSION: These findings demonstrate that trophoblastic mtDNA induced NLRP3/caspase-1/IL-1β signalling activation, eNOS-related endothelial injury, and vasodilation dysfunction in PE.

Keywords:  Endothelial dysfunction; Inflammation; Mitochondrial DNA; NLRP3 inflammasome; Preeclampsia

DOI:  https://doi.org/10.1016/j.intimp.2022.109523
Shock. 2022 Dec 16.

Cardiopulmonary bypass-derived plasma exosomal HMGB1 contributes to alveolar epithelial cell necroptosis via mtDNA/cGAS/STING pathway.

Yupeng Zhao, Jinyuan Zhang, Huihong Lu, Yiliang Mao, Jiawen Qin, Yinglin Wang, Xuebin Wang, Zhiguang Dai, Xiangrui Wang, Zhongwei Yang, Lei Hou.

ABSTRACT: Our previous study confirmed that cardiopulmonary bypass (CPB) leads to acute lung injury (ALI) via inducing high-mobility group box 1 (HMGB1) release. Recent research showed HMGB1 promotes pulmonary injury mainly via exosomes transport. Currently, alveolar epithelial cell (AEC) necroptosis has been demonstrated to be involved in ALI. However, it is unknown whether exosomal inflammatory cytokine HMGB1 promotes ALI by inducing AEC necroptosis and its underling mechanisms remain elusive. Here, a prospective cohort study was carried out, in which plasma samples from 21 CPB patients were isolated at 4 specific time points: pre-CPB, 2 h, 12 h, and 24 h after initiation of CPB. Plasma exosomes were extracted via ultra-high-speed centrifugation and co-cultured with AEC cell line-A549 cells at increasing concentrations of 50, 100 and 150 μg/ml. Then, HMGB1 antagonist-Box A and mtDNA deficiency ethidium bromide (EtBr) were applied to explore the underlying role of exosomal HMGB1 and cytoplasm mitochondrial DNA in AEC. Western blot analysis showed that plasma exosomal HMGB1 expression gradually increased and peaked at 24 h after CPB. 24 hours Treatment of CPB-derived exosomes at 150 μg/ml for 24 h could induce necroptosis by promoting mitochondrial fission and further elevating cytoplasm mtDNA levels in A549 cells, which was successfully blocked by Box A or EtBr. Most importantly, EtBr significantly inhibited cytoplasm mtDNA downstream cGAS/STING signal pathway. Collectively, these data demonstrate that CPB-derived plasma exosomal HMGB1 contributes to AEC necroptosis through the mtDNA/cGAS/STING pathway.

DOI: https://doi.org/10.1097/SHK.0000000000002006