bims-miptne 2024-07-14 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2024–07–14
eleven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

The C-terminal sequences of Bcl-2 family proteins mediate interactions that regulate cell death.
Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role.
Coptisine exerts anti-tumour effects in triple-negative breast cancer by targeting mitochondrial complex I.
Emergence of large-scale cell death through ferroptotic trigger waves.
Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.
Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.
ADP-ribosylome analysis reveals homogeneous DNA-damage-induced serine ADP-ribosylation across wild-type and BRCA-mutant breast cancer cell lines.
Differentiation activates mitochondrial OPA1 processing in myoblast cell lines.
Cyclophilin D induces necrotic core formation by mediating mitochondria-associated macrophage death in advanced atherosclerotic lesions.
Exploring cell death mechanisms in spheroid cultures using a novel application of the RIP3-caspase3-assay.
The Role of PGC-1α in Aging Skin Barrier Function.

Biochem J. 2024 Jul 17. 481(14): 903-922

The C-terminal sequences of Bcl-2 family proteins mediate interactions that regulate cell death.

Dang Nguyen, Elizabeth Osterlund, Justin Kale, David W Andrews.

  Programmed cell death via the both intrinsic and extrinsic pathways is regulated by interactions of the Bcl-2 family protein members that determine whether the cell commits to apoptosis via mitochondrial outer membrane permeabilization (MOMP). Recently the conserved C-terminal sequences (CTSs) that mediate localization of Bcl-2 family proteins to intracellular membranes, have been shown to have additional protein-protein binding functions that contribute to the functions of these proteins in regulating MOMP. Here we review the pivotal role of CTSs in Bcl-2 family interactions including: (1) homotypic interactions between the pro-apoptotic executioner proteins that cause MOMP, (2) heterotypic interactions between pro-apoptotic and anti-apoptotic proteins that prevent MOMP, and (3) heterotypic interactions between the pro-apoptotic executioner proteins and the pro-apoptotic direct activator proteins that promote MOMP.

Keywords:  BH3-only proteins; Bax; Bcl-2; apoptosis; protein–protein interactions; transmembrane domain

DOI:  https://doi.org/10.1042/BCJ20210352
Biochemistry (Mosc). 2024 Jun;89(6): 1061-1078

Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role.

Natalia V Belosludtseva, Mikhail V Dubinin, Konstantin N Belosludtsev.

  Voltage-dependent anion channels (VDAC1-3) of the outer mitochondrial membrane are a family of pore-forming β-barrel proteins that carry out controlled "filtration" of small molecules and ions between the cytoplasm and mitochondria. Due to the conformational transitions between the closed and open states and interaction with cytoplasmic and mitochondrial proteins, VDACs not only regulate the mitochondrial membrane permeability for major metabolites and ions, but also participate in the control of essential intracellular processes and pathological conditions. This review discusses novel data on the molecular structure, regulatory mechanisms, and pathophysiological role of VDAC proteins, as well as future directions in this area of research.

Keywords:  VDAC; cancer; cell death; diabetes mellitus; membrane transport; mitochondria; neurodegenerative diseases

DOI:  https://doi.org/10.1134/S0006297924060075
Br J Pharmacol. 2024 Jul 09.

Coptisine exerts anti-tumour effects in triple-negative breast cancer by targeting mitochondrial complex I.

Yunfu Shen, You Yang, Zi Wang, Wanjun Lin, Na Feng, Meina Shi, Jiachen Liu, Wenzhe Ma.

   BACKGROUND AND PURPOSE: Triple-negative breast cancer (TNBC) has a poor prognosis due to limited therapeutic options. Recent studies have shown that TNBC is highly dependent on mitochondrial oxidative phosphorylation. The aim of this study was to investigate the potential of coptisine, a novel compound that inhibits the complex I of the mitochondrial electron transport chain (ETC), as a treatment for TNBC.
EXPERIMENTAL APPROACH: In this study, mitochondrial metabolism in TNBC was analysed by bioinformatics. In vitro and in vivo experiments (in mice) were conducted to evaluate the potential of coptisine as an ETC complex I-targeting therapeutic agent and to investigate the molecular mechanisms underlying coptisine-induced mitochondrial dysfunction. The therapeutic effect of coptisine was assessed in TNBC cells and xenograft mouse model.
KEY RESULTS: We demonstrated that mitochondrial ETC I was responsible for this metabolic vulnerability in TNBC. Furthermore, a naturally occurring compound, coptisine, exhibited specific inhibitory activity against this complex I. Treatment with coptisine significantly inhibited mitochondrial functions, reprogrammed cellular metabolism, induced apoptosis and ultimately inhibited the proliferation of TNBC cells. Additionally, coptisine administration induced prominent growth inhibition that was dependent on the presence of a functional complex I in xenograft mouse models.
CONCLUSION AND IMPLICATIONS: Altogether, these findings suggest the promising potential of coptisine as a potent ETC complex I inhibitor to target the metabolic vulnerability of TNBC.

Keywords:  coptisine; mitochondrial electron transport chain complex I; oxidative phosphorylation; triple‐negative breast cancer

DOI:  https://doi.org/10.1111/bph.16489
Nature. 2024 Jul 10.

Emergence of large-scale cell death through ferroptotic trigger waves.

Hannah K C Co, Chia-Chou Wu, Yi-Chen Lee, Sheng-Hong Chen.

Large-scale cell death is commonly observed during organismal development and in human pathologies1-5. These cell death events extend over great distances to eliminate large populations of cells, raising the question of how cell death can be coordinated in space and time. One mechanism that enables long-range signal transmission is trigger waves6, but how this mechanism might be used for death events in cell populations remains unclear. Here we demonstrate that ferroptosis, an iron- and lipid-peroxidation-dependent form of cell death, can propagate across human cells over long distances (≥5 mm) at constant speeds (around 5.5 μm min-1) through trigger waves of reactive oxygen species (ROS). Chemical and genetic perturbations indicate a primary role of ROS feedback loops (Fenton reaction, NADPH oxidase signalling and glutathione synthesis) in controlling the progression of ferroptotic trigger waves. We show that introducing ferroptotic stress through suppression of cystine uptake activates these ROS feedback loops, converting cellular redox systems from being monostable to being bistable and thereby priming cell populations to become bistable media over which ROS propagate. Furthermore, we demonstrate that ferroptosis and its propagation accompany the massive, yet spatially restricted, cell death events during muscle remodelling of the embryonic avian limb, substantiating its use as a tissue-sculpting strategy during embryogenesis. Our findings highlight the role of ferroptosis in coordinating global cell death events, providing a paradigm for investigating large-scale cell death in embryonic development and human pathologies.

DOI: https://doi.org/10.1038/s41586-024-07623-6
Am J Physiol Cell Physiol. 2024 Jul 09.

Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.

Soi-Yi Park, Su-Ryun Jung, Jong-Yeon Kim, Yong-Woon Kim, Hoon-Ki Sung, So-Young Park, Kyung-Oh Doh, Jin-Ho Koh.

  Lower oxidative capacity in skeletal muscles (SKMs) is a prevailing cause of metabolic diseases. Exercise not only enhances the fatty acid oxidation (FAO) capacity of SKMs but also increases lactate levels. Given that lactate may contribute to tricarboxylic acid cycle (TCA) flux and impact monocarboxylate transporter 1 in the SKMs, we hypothesize that lactate can influence glucose and fatty acid (FA) metabolism. To test this hypothesis, we investigated the mechanism underlying lactate-driven FAO regulation in the SKM of mice with diet-induced obesity (DIO). Lactate was administered to DIO mice immediately after exercise over three weeks. We found that increased lactate levels enhanced energy expenditure mediated by fat metabolism during exercise recovery and decreased triglyceride levels in DIO mice SKMs. To determine the lactate-specific effects without exercise, we administered lactate to mice on a high-fat diet (HFD) for eight weeks. Similar to our exercise conditions, lactate increased FAO, TCA cycle activity, and mitochondrial respiration in the SKMs of HFD-fed mice. Additionally, under sufficient FA conditions, lactate increased uncoupling protein-3 abundance via the NADH/NAD+ shuttle. Conversely ATP synthase abundance decreased in the SKMs of HFD mice. Taken together, our results suggest that lactate amplifies the adaptive increase in FAO capacity mediated by the TCA cycle and mitochondrial respiration in SKMs under sufficient FA abundance.

Keywords:  Exercise; Fatty acid oxidation; Lactate; Mitochondrial respiration; TCA cycle

DOI:  https://doi.org/10.1152/ajpcell.00060.2024
Int J Mol Sci. 2024 Jul 03. pii: 7305. [Epub ahead of print]25(13):

Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.

Emanuele Marzetti, Riccardo Calvani, Francesco Landi, Helio José Coelho-Júnior, Anna Picca.

  Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This is accompanied by complex cellular changes that enable the development of a senescence-associated secretory phenotype (SASP). Mitochondria, organelles involved in energy provision and activities essential for regulating cell survival and death, are negatively impacted by aging. The age-associated decline in mitochondrial function is also accompanied by the development of chronic low-grade sterile inflammation. The latter shares some features and mediators with the SASP. Indeed, the unloading of damage-associated molecular patterns (DAMPs) at the extracellular level can trigger sterile inflammatory responses and mitochondria can contribute to the generation of DAMPs with pro-inflammatory properties. The extrusion of mitochondrial DNA (mtDNA) via mitochondrial outer membrane permeabilization under an apoptotic stress triggers senescence programs. Additional pathways can contribute to sterile inflammation. For instance, pyroptosis is a caspase-dependent inducer of systemic inflammation, which is also elicited by mtDNA release and contributes to aging. Herein, we overview the molecular mechanisms that may link mitochondrial dyshomeostasis, pyroptosis, sterile inflammation, and senescence and discuss how these contribute to aging and could be exploited as molecular targets for alleviating the cell damage burden and achieving healthy longevity.

Keywords:  DAMPs; SASP; cell death; extracellular vesicles; inflammaging; interleukin; mitochondrial quality control; mitochondrial-derived vesicles; mtDNA; pyroptosis

DOI:  https://doi.org/10.3390/ijms25137305
Cell Rep. 2024 Jul 09. pii: S2211-1247(24)00762-9. [Epub ahead of print]43(7): 114433

ADP-ribosylome analysis reveals homogeneous DNA-damage-induced serine ADP-ribosylation across wild-type and BRCA-mutant breast cancer cell lines.

Holda Awah Anagho, Meeli Mullari, Aurél György Prósz, Sara Charlotte Buch-Larsen, Hayoung Cho, Marie Locard-Paulet, Zoltan Szallasi, Michael Lund Nielsen.

  ADP-ribosylation (ADPr) signaling plays a crucial role in DNA damage response. Inhibitors against the main enzyme catalyzing ADPr after DNA damage, poly(ADP-ribose) polymerase 1 (PARP1), are used to treat patients with breast cancer harboring BRCA1/2 mutations. However, resistance to PARP inhibitors (PARPi) is a major obstacle in treating patients. To understand the role of ADPr in PARPi sensitivity, we use liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze ADPr in six breast cancer cell lines exhibiting different PARPi sensitivities. We identify 1,632 sites on 777 proteins across all cell lines, primarily on serine residues, with site-specific overlap of targeted residues across DNA-damage-related proteins across all cell lines, demonstrating high conservation of serine ADPr-signaling networks upon DNA damage. Furthermore, we observe site-specific differences in ADPr intensities in PARPi-sensitive BRCA mutants and unique ADPr sites in PARPi-resistant BRCA-mutant HCC1937 cells, which have low poly(ADP-ribose) glycohydrolase (PARG) levels and longer ADPr chains on PARP1.

Keywords:  ADP-ribosylation; ADP-ribosylome; Af1521 macrodomain; CP: Cancer; CP: Molecular biology; EThcD; PARG; PARP; PARP inhibitor sensitivity; mass spectrometry; proteomics

DOI:  https://doi.org/10.1016/j.celrep.2024.114433
Mitochondrion. 2024 Jul 08. pii: S1567-7249(24)00091-6. [Epub ahead of print]78 101933

Differentiation activates mitochondrial OPA1 processing in myoblast cell lines.

Harpreet Kaur, Omar Carrillo, Iraselia Garcia, Isaiah Ramos, Shaynah St Vallier, Patrick De La Torre, Alma Lopez, Megan Keniry, Daniel Bazan, Jorge Elizondo, K C Grishma, Lee Ann MacMillan-Crow, Robert Gilkerson.

  Mitochondrial optic atrophy-1 (OPA1) plays key roles in adapting mitochondrial structure to bioenergetic function. When transmembrane potential across the inner membrane (Δψm) is intact, long (L-OPA1) isoforms shape the inner membrane through membrane fusion and the formation of cristal junctions. When Δψm is lost, however, OPA1 is cleaved to short, inactive S-OPA1 isoforms by the OMA1 metalloprotease, disrupting mitochondrial structure and priming cellular stress responses such as apoptosis. Previously, we demonstrated that L-OPA1 of H9c2 cardiomyoblasts is insensitive to loss of Δψm via challenge with the protonophore carbonyl cyanide chlorophenyl hydrazone (CCCP), but that CCCP-induced OPA1 processing is activated upon differentiation in media with low serum supplemented with all-trans retinoic acid (ATRA). Here, we show that this developmental induction of OPA1 processing in H9c2 cells is independent of ATRA; moreover, pretreatment of undifferentiated H9c2s with chloramphenicol (CAP), an inhibitor of mitochondrial protein synthesis, recapitulates the Δψm-sensitive OPA1 processing observed in differentiated H9c2s. L6.C11 and C2C12 myoblast lines display the same developmental and CAP-sensitive induction of OPA1 processing, demonstrating a general mechanism of OPA1 regulation in mammalian myoblast cell settings. Restoration of CCCP-induced OPA1 processing correlates with increased apoptotic sensitivity. Moreover, OPA1 knockdown indicates that intact OPA1 is necessary for effective myoblast differentiation. Taken together, our results indicate that a novel developmental mechanism acts to regulate OMA1-mediated OPA1 processing in myoblast cell lines, in which differentiation engages mitochondrial stress sensing.

Keywords:  Differentiation; Mitochondria; OMA1; OPA1; Transmembrane potential

DOI:  https://doi.org/10.1016/j.mito.2024.101933
Atherosclerosis. 2024 Jun 20. pii: S0021-9150(24)01092-X. [Epub ahead of print]396 118524

Cyclophilin D induces necrotic core formation by mediating mitochondria-associated macrophage death in advanced atherosclerotic lesions.

Jun-Ichiro Koga, Ryuta Umezu, Yuki Kondo, Tomohiro Shirouzu, Nasanbadrakh Orkhonselenge, Hiromichi Ueno, Shunsuke Katsuki, Tetsuya Matoba, Yosuke Nishimura, Masaharu Kataoka.

   BACKGROUND AND AIMS: In advanced atherosclerotic lesions, macrophage deaths result in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. Therefore, this experiment aims to clarify the role of CypD in necrotic core formation.
METHODS: To clarify the specific role of CypD, encoded by Ppif in mice, apolipoprotein-E/CypD-double knockout (Apoe-/-Ppif-/-) mice were generated. These mice were fed a high-fat diet containing 0.15 % cholesterol for 24 weeks to accelerate atherosclerotic lesion development.
RESULTS: Deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control Apoe-/- mice. In RAW264.7 cells, siRNA-mediated knockdown of CypD attenuated the release of cytochrome c from the mitochondria to the cytosol induced by endoplasmic reticulum stress inducer thapsigargin. In addition, necroptosis, induced by TNF-α and caspase inhibitor, was attenuated by knockdown of CypD. Ly-6Chigh inflammatory monocytes in peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-γ, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage.
CONCLUSIONS: These results indicate that CypD induces macrophage death and mediates necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.

Keywords:  Apoptosis; Atherosclerosis; Cyclophilin D; Macrophages; Necrotic core

DOI:  https://doi.org/10.1016/j.atherosclerosis.2024.118524
Sci Rep. 2024 Jul 11. 14(1): 16032

Exploring cell death mechanisms in spheroid cultures using a novel application of the RIP3-caspase3-assay.

C I Philippi, J Hagens, K M Heuer, H C Schmidt, P Schuppert, L Pagerols Raluy, M Trochimiuk, Z Li, M J Bunders, K Reinshagen, C Tomuschat.

  This study explores the application of the RIP3-caspase3-assay in heterogeneous spheroid cultures to analyze cell death pathways, emphasizing the nuanced roles of apoptosis and necroptosis. By employing directly conjugated monoclonal antibodies, we provide detailed insights into the complex mechanisms of cell death. Our findings demonstrate the assay's capability to differentiate between RIP1-independent apoptosis, necroptosis, and RIP1-dependent apoptosis, marking a significant advancement in organoid research. Additionally, we investigate the effects of TNFα on isolated intestinal epithelial cells, revealing a concentration-dependent response and an adaptive or threshold reaction to TNFα-induced stress. The results indicate a preference for RIP1-independent cell death pathways upon TNFα stimulation, with a notable increase in apoptosis and a secondary role of necroptosis. Our research underscores the importance of the RIP3-caspase3-assay in understanding cell death mechanisms in organoid cultures, offering valuable insights for disease modeling and the development of targeted therapies. The assay's adaptability and robustness in spheroid cultures enhances its potential as a tool in personalized medicine and translational research.

Keywords:  Apoptosis and necroptosis; Cell death mechanisms; Organoids; RIP3-caspase3 assay; TNFα -induced stress

DOI:  https://doi.org/10.1038/s41598-024-66805-4
Cells. 2024 Jul 02. pii: 1135. [Epub ahead of print]13(13):

The Role of PGC-1α in Aging Skin Barrier Function.

Yonghong Luo, Wendy B Bollag.

  Skin provides a physical and immune barrier to protect the body from foreign substances, microbial invasion, and desiccation. Aging reduces the barrier function of skin and its rate of repair. Aged skin exhibits decreased mitochondrial function and prolonged low-level inflammation that can be seen in other organs with aging. Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), an important transcriptional coactivator, plays a central role in modulating mitochondrial function and antioxidant production. Mitochondrial function and inflammation have been linked to epidermal function, but the mechanisms are unclear. The aim of this review is to discuss the mechanisms by which PGC-1α might exert a positive effect on aged skin barrier function. Initially, we provide an overview of the function of skin under physiological and aging conditions, focusing on the epidermis. We then discuss mitochondrial function, oxidative stress, cellular senescence, and inflamm-aging, the chronic low-level inflammation observed in aging individuals. Finally, we discuss the effects of PGC-1α on mitochondrial function, as well as the regulation and role of PGC-1α in the aging epidermis.

Keywords:  aging; antioxidant defense; coactivator; epidermis; keratinocytes; melanocytes; mitochondria; permeability barrier; skin; wound healing

DOI:  https://doi.org/10.3390/cells13131135