bims-mitper 2022-10-02 papers

bims-mitper

Biomed News

on Mitochondrial Permeabilization

Issue of 2022–10–02
ten papers selected by
Bradley Irizarry, Thomas Jefferson University

Expanding role of deoxyribonucleic acid-sensing mechanism in the development of lifestyle-related diseases.
Dynamic features of human mitochondrial DNA maintenance and transcription.
Mitochondrial protein dysfunction in pathogenesis of neurological diseases.
TraB family proteins are components of ER-mitochondrial contact sites and regulate ER-mitochondrial interactions and mitophagy.
ER stress promotes mitochondrial DNA mediated type-1 interferon response in beta-cells and interleukin-8 driven neutrophil chemotaxis.
Control of mitochondrial dynamics and apoptotic pathways by peroxisomes.
Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins.
DNA sensor associated type I Interferon signalling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids.
MicroRNAs as a new target for Alzheimer's disease treatment.
Regulation of innate immunity by Nrf2.

Front Cardiovasc Med. 2022 ;9 881181

Expanding role of deoxyribonucleic acid-sensing mechanism in the development of lifestyle-related diseases.

Sachiko Nishimoto, Masataka Sata, Daiju Fukuda.

  In lifestyle-related diseases, such as cardiovascular, metabolic, respiratory, and kidney diseases, chronic inflammation plays a causal role in their pathogenesis; however, underlying mechanisms of sterile chronic inflammation are not well-understood. Previous studies have confirmed the damage of cells in these organs in the presence of various risk factors such as diabetes, dyslipidemia, and cigarette smoking, releasing various endogenous ligands for pattern recognition receptors. These studies suggested that nucleic acids released from damaged tissues accumulate in these tissues, acting as an endogenous ligand. Undamaged DNA is an integral factor for the sustenance of life, whereas, DNA fragments, especially those from pathogens, are potent activators of the inflammatory response. Recent studies have indicated that inflammatory responses such as the production of type I interferon (IFN) induced by DNA-sensing mechanisms which contributes to self-defense system in innate immunity participates in the progression of inflammatory diseases by the recognition of nucleic acids derived from the host, including mitochondrial DNA (mtDNA). The body possesses several types of DNA sensors. Toll-like receptor 9 (TLR9) recognizes DNA fragments in the endosomes. In addition, the binding of DNA fragments in the cytosol activates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), resulting in the synthesis of the second messenger cyclic GMP-AMP (cGAMP). The binding of cGAMP to stimulator of interferon genes (STING) activates NF-κB and TBK-1 signaling and consequently the production of many inflammatory cytokines including IFNs. Numerous previous studies have demonstrated the role of DNA sensors in self-defense through the recognition of DNA fragments derived from pathogens. Beyond the canonical role of TLR9 and cGAS-STING, this review describes the role of these DNA-sensing mechanism in the inflammatory responses caused by endogenous DNA fragments, and in the pathogenesis of lifestyle-related diseases.

Keywords:  CKD; COPD; DNA-sensing mechanism; STING; TLR9; atherosclerosis; chronic inflammation; metabolic diseases

DOI:  https://doi.org/10.3389/fcvm.2022.881181
Front Cell Dev Biol. 2022 ;10 984245

Dynamic features of human mitochondrial DNA maintenance and transcription.

Mansour Akbari, Hilde Loge Nilsen, Nicola Pietro Montaldo.

  Mitochondria are the primary sites for cellular energy production and are required for many essential cellular processes. Mitochondrial DNA (mtDNA) is a 16.6 kb circular DNA molecule that encodes only 13 gene products of the approximately 90 different proteins of the respiratory chain complexes and an estimated 1,200 mitochondrial proteins. MtDNA is, however, crucial for organismal development, normal function, and survival. MtDNA maintenance requires mitochondrially targeted nuclear DNA repair enzymes, a mtDNA replisome that is unique to mitochondria, and systems that control mitochondrial morphology and quality control. Here, we provide an overview of the current literature on mtDNA repair and transcription machineries and discuss how dynamic functional interactions between the components of these systems regulate mtDNA maintenance and transcription. A profound understanding of the molecular mechanisms that control mtDNA maintenance and transcription is important as loss of mtDNA integrity is implicated in normal process of aging, inflammation, and the etiology and pathogenesis of a number of diseases.

Keywords:  DNA repair; base excision repair (BER); base excision repair (BER)glycosylases; mitochdrial damage; mitochondria; transcription

DOI:  https://doi.org/10.3389/fcell.2022.984245
Front Mol Neurosci. 2022 ;15 974480

Mitochondrial protein dysfunction in pathogenesis of neurological diseases.

Liang Wang, Ziyun Yang, Xiumei He, Shiming Pu, Cheng Yang, Qiong Wu, Zuping Zhou, Xiaobo Cen, Hongxia Zhao.

  Mitochondria are essential organelles for neuronal function and cell survival. Besides the well-known bioenergetics, additional mitochondrial roles in calcium signaling, lipid biogenesis, regulation of reactive oxygen species, and apoptosis are pivotal in diverse cellular processes. The mitochondrial proteome encompasses about 1,500 proteins encoded by both the nuclear DNA and the maternally inherited mitochondrial DNA. Mutations in the nuclear or mitochondrial genome, or combinations of both, can result in mitochondrial protein deficiencies and mitochondrial malfunction. Therefore, mitochondrial quality control by proteins involved in various surveillance mechanisms is critical for neuronal integrity and viability. Abnormal proteins involved in mitochondrial bioenergetics, dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance have been linked to the pathogenesis of a number of neurological diseases. The goal of this review is to give an overview of these pathways and to summarize the interconnections between mitochondrial protein dysfunction and neurological diseases.

Keywords:  mitochondrial bioenergetics; mitochondrial dynamics; mitochondrial import machinery; mitochondrial proteins; mitophagy; mtDNA maintenance; neurological diseases; pathogenesis

DOI:  https://doi.org/10.3389/fnmol.2022.974480
Nat Commun. 2022 Sep 26. 13(1): 5658

TraB family proteins are components of ER-mitochondrial contact sites and regulate ER-mitochondrial interactions and mitophagy.

Chengyang Li, Patrick Duckney, Tong Zhang, Yanshu Fu, Xin Li, Johan Kroon, Geert De Jaeger, Yunjiang Cheng, Patrick J Hussey, Pengwei Wang.

ER-mitochondrial contact sites (EMCSs) are important for mitochondrial function. Here, we have identified a EMCS complex, comprising a family of uncharacterised mitochondrial outer membrane proteins, TRB1, TRB2, and the ER protein, VAP27-1. In Arabidopsis, there are three TraB family isoforms and the trb1/trb2 double mutant exhibits abnormal mitochondrial morphology, strong starch accumulation, and impaired energy metabolism, indicating that these proteins are essential for normal mitochondrial function. Moreover, TRB1 and TRB2 proteins also interact with ATG8 in order to regulate mitochondrial degradation (mitophagy). The turnover of depolarised mitochondria is significantly reduced in both trb1/trb2 and VAP27 mutants (vap27-1,3,4,6) under mitochondrial stress conditions, with an increased population of dysfunctional mitochondria present in the cytoplasm. Consequently, plant recovery after stress is significantly perturbed, suggesting that TRB1-regulated mitophagy and ER-mitochondrial interaction are two closely related processes. Taken together, we ascribe a dual role to TraB family proteins which are component of the EMCS complex in eukaryotes, regulating both interaction of the mitochondria to the ER and mitophagy.

DOI: https://doi.org/10.1038/s41467-022-33402-w
Front Endocrinol (Lausanne). 2022 ;13 991632

ER stress promotes mitochondrial DNA mediated type-1 interferon response in beta-cells and interleukin-8 driven neutrophil chemotaxis.

Saurabh Vig, Joost M Lambooij, Mette C Dekkers, Frank Otto, Françoise Carlotti, Bruno Guigas, Arnaud Zaldumbide.

  Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. Accumulating evidence suggests the engagement of cellular stress during the initial stage of the disease, preceding destruction and triggering immune cell infiltration. While the role of the endoplasmic reticulum (ER) in this process has been largely described, the participation of the other cellular organelles, particularly the mitochondria which are central mediator for beta-cell survival and function, remains poorly investigated. Here, we have explored the contribution of ER stress, in activating type-I interferon signaling and innate immune cell recruitment. Using human beta-cell line EndoC-βH1 exposed to thapsigargin, we demonstrate that induction of cellular stress correlates with mitochondria dysfunction and a significant accumulation of cytosolic mitochondrial DNA (mtDNA) that triggers neutrophils migration by an IL8-dependent mechanism. These results provide a novel mechanistic insight on how ER stress can cause insulitis and may ultimately facilitate the identification of potential targets to protect beta-cells against immune infiltration.

Keywords:  ER stress; innate immunity; mitochondria; neutrophils; type 1 diabetes

DOI:  https://doi.org/10.3389/fendo.2022.991632
Front Cell Dev Biol. 2022 ;10 938177

Control of mitochondrial dynamics and apoptotic pathways by peroxisomes.

Chenxing Jiang, Tomohiko Okazaki.

  Peroxisomes are organelles containing different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of plasmalogens. Peroxisome biogenesis is controlled by a family of proteins called peroxins, which are required for peroxisomal membrane formation, matrix protein transport, and division. Mutations of peroxins cause metabolic disorders called peroxisomal biogenesis disorders, among which Zellweger syndrome (ZS) is the most severe. Although patients with ZS exhibit severe pathology in multiple organs such as the liver, kidney, brain, muscle, and bone, the pathogenesis remains largely unknown. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream fission-fusion processes, disruption of which causes multiple organ dysfunctions reminiscent of ZS. In this review, we summarize recent findings about peroxisome-mediated regulation of mitochondrial morphology and its possible relationship with the pathogenesis of ZS.

Keywords:  Zellweger syndrome; apoptosis; fission-fusion; mitochondria; organelle interaction; peroxisomes; tethering

DOI:  https://doi.org/10.3389/fcell.2022.938177
Cell Death Differ. 2022 Sep 28.

Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins.

Allan Shuai Huang, Hui San Chin, Boris Reljic, Tirta M Djajawi, Iris K L Tan, Jia-Nan Gong, David A Stroud, David C S Huang, Mark F van Delft, Grant Dewson.

Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death by restraining BAK activating conformation change and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.

DOI: https://doi.org/10.1038/s41418-022-01067-z
Am J Physiol Gastrointest Liver Physiol. 2022 Sep 27.

DNA sensor associated type I Interferon signalling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids.

Peter Flood, Aine Fanning, Jerzy A Woznicki, Tadhg Crowley, Andrea Christopher, Alessandra Vaccaro, Aileen Houston, Sheila McSweeney, Sarah Ross, Aileen Hogan, Elizabeth Brint, Agnieszka Skowyra, Milan Bustamante, Monica Ambrose, Gerard M Moloney, John MacSharry, Marie-Louise Hammarström, Margot Hurley, Christine Fitzgibbons, Eamonn M M Quigley, Fergus Shanahan, Syed A Zulquernain, Jane McCarthy, G Steven Dodson, Karim Dabbagh, Bradford L McRae, Silvia Melgar, Ken Nally.

  DNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLRP3, caspase or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes - PYHIN family members (AIM2, IFI16, MNDA, PYHIN1), as well as ZBP1, cGAS and DDX41 were increased in active UC and expressed in a cell type restricted pattern. Inflammasome genes (CASP1, IL1B, IL18), type I IFN inducers (STING, TBK1, IRF3), IFNB1 and type I IFN biomarker genes (OAS2, IFIT2, MX2) were also increased in active UC. Co-treatment of organoids with IFN-β or IFN-γ and TNFα increased expression of IFI16, ZBP1, CASP1, cGAS and STING, induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.

Keywords:  Cell death; Colonic organoids; DNA sensors; Type I IFN; Ulcerative colitis

DOI:  https://doi.org/10.1152/ajpgi.00104.2022
Microrna. 2022 Sep 28.

MicroRNAs as a new target for Alzheimer's disease treatment.

Behrouz Shademan, Cigir Biray Avci, Vahidreza Karamad, Fatma Sogutlu, Alireza Nourazarian.

  Alzheimer's disease (AD) is the most common progressive neurodegenerative disease associated with advanced age. It is characterized by cognitive decline and memory loss and accounts for most cases of dementia in older people. AD can be rooted in genetic, epigenetic, or environmental causes. There are no drugs or other therapeutic agents to prevent or delay AD progression. MicroRNAs (miRNAs) are short and uncoded RNAs that can bind to 200 RNAs approximately. By inhibiting or destroying specific messenger RNAs (mRNAs), they control gene expression and broadly affect cellular functions. MiRNAs play important roles in regulating neuronal growth, neuronal differentiation, dendritic spine morphology, and synaptic flexibility in the nervous system. The expression levels of miRNAs are changed in neurological diseases, including AD, suggesting that they play an essential role in the pathogenesis of the disease. Therefore, targeting disrupted miRNAs may be a novel therapeutic approach against AD and offers multiple solutions, including harnessing the beneficial effects of beta-amyloid, reducing tau protein, reducing neuronal cell death, and protecting synapses in AD.

Keywords:  Alzheimer's disease; MicroRNA; Tau protein; neurodegenerative disease

DOI:  https://doi.org/10.2174/2211536611666220928154015
Curr Opin Immunol. 2022 Sep 26. pii: S0952-7915(22)00094-2. [Epub ahead of print]78 102247

Regulation of innate immunity by Nrf2.

D van der Horst, M E Carter-Timofte, J van Grevenynghe, N Laguette, A T Dinkova-Kostova, D Olagnier.

The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been mainly investigated as a regulator of redox homeostasis. However, research over the past years has implicated Nrf2 as an important regulator of innate immunity. Here, we discuss the role of Nrf2 in the innate immune response, highlighting the interaction between Nrf2 and major components of the innate immune system. Indeed, Nrf2 has been shown to widely control the immune response by interacting directly or indirectly with important innate immune components, including the toll-like receptors-Nuclear factor kappa B (NF-kB) pathway, inflammasome signaling, and the type-I interferon response. This indicates an essential role for Nrf2 in diseases related to microbial infections, inflammation, and cancer. Yet, further studies are required to determine the exact mechanism underpinning the interactions between Nrf2 and innate immune players in order to allow a better understanding of these diseases and leverage new therapeutic strategies.

DOI: https://doi.org/10.1016/j.coi.2022.102247