bims-nenemi 2024-06-23 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2024–06–23
eightteen papers selected by
Marco Tigano, Thomas Jefferson University

The regulation of the apoptotic pore-An immunological tightrope walk.
hnRNPH1 maintains mitochondrial homeostasis by establishing NRF1/DRP1 retrograde signaling under mitochondrial stress.
Mitochondria and cell death.
Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation.
DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
The emerging role of mtDNA release in sepsis: Current evidence and potential therapeutic targets.
MITOCHONDRIAL ANTIVIRAL PATHWAYS CONTROL ANTI-HIV RESPONSES AND ISCHEMIC STROKE OUTCOMES VIA THE RIG-1 SIGNALING AND INNATE IMMUNITY MECHANISMS.
Olfaction regulates peripheral mitophagy and mitochondrial function.
Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy.
Exposure of negative-sense viral RNA in the cytoplasm initiates innate immunity to West Nile virus.
Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.
Proofreading mechanisms of the innate immune receptor RIG-I: distinguishing self and viral RNA.
STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.
STING1-accelerated vascular smooth muscle cell senescence-associated vascular calcification in diabetes is ameliorated by oleoylethanolamide via improved mitochondrial DNA oxidative damage.
MALSU1-mediated regulation of mitochondrial function governs proliferation and doxorubicin resistance in triple-negative breast cancer cells.
Tissue-specific roles of mitochondrial unfolded protein response during obesity.
A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism.

Adv Immunol. 2024 ;pii: S0065-2776(24)00029-4. [Epub ahead of print]162 59-108

The regulation of the apoptotic pore-An immunological tightrope walk.

Andreas Jenner, Ana J Garcia-Saez.

  Apoptotic pore formation in mitochondria is the pivotal point for cell death during mitochondrial apoptosis. It is regulated by BCL-2 family proteins in response to various cellular stress triggers and mediates mitochondrial outer membrane permeabilization (MOMP). This allows the release of mitochondrial contents into the cytosol, which triggers rapid cell death and clearance through the activation of caspases. However, under conditions of low caspase activity, the mitochondrial contents released into the cytosol through apoptotic pores serve as inflammatory signals and activate various inflammatory responses. In this chapter, we discuss how the formation of the apoptotic pore is regulated by BCL-2 proteins as well as other cellular or mitochondrial proteins and membrane lipids. Moreover, we highlight the importance of sublethal MOMP in the regulation of mitochondrial-activated inflammation and discuss its physiological consequences in the context of pathogen infection and disease and how it can potentially be exploited therapeutically, for example to improve cancer treatment.

Keywords:  Apoptosis; BCL-2 proteins; MOMP; Mitochondria-associated inflammation; MtDNA

DOI:  https://doi.org/10.1016/bs.ai.2024.02.004
Cell Death Differ. 2024 Jun 19.

hnRNPH1 maintains mitochondrial homeostasis by establishing NRF1/DRP1 retrograde signaling under mitochondrial stress.

Lili Zhao, Xiaotian Zou, Jiaqiang Deng, Bin Sun, Yan Li, Li Zhao, Hong Zhao, Xiao Zhang, Xieyong Yuan, Xudong Zhao, Fangdong Zou.

Mitochondrial homeostasis is coordinated through communication between mitochondria and the nucleus. In response to stress, mitochondria generate retrograde signals to protect against their dysfunction by activating the expression of nuclear genes involved in metabolic reprogramming. However, the mediators associated with mitochondria-to-nucleus communication pathways remain to be clarified. Here, we identified that hnRNPH1 functions as a pivotal mediator of mitochondrial retrograde signaling to maintain mitochondrial homeostasis. hnRNPH1 accumulates in the nucleus following mitochondrial stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Accordingly, hnRNPH1 interacts with the transcription factor NRF1 and binds to the DRP1 promoter, enhancing the transcription of DRP1. Furthermore, in the cytoplasm, hnRNPH1 directly interacts with DRP1 and enhances DRP1 Ser616 phosphorylation, thereby increasing DRP1 translocation to mitochondrial outer membranes and triggering mitochondrial fission. Collectively, our findings reveal a novel role for hnRNPH1 in the mitochondrial-nuclear communication pathway to maintain mitochondrial homeostasis under stress and suggest that it may be a potential target for mitochondrial dysfunction diseases.

DOI: https://doi.org/10.1038/s41418-024-01331-4
Nat Cell Biol. 2024 Jun 20.

Mitochondria and cell death.

Hannah L Glover, Annabell Schreiner, Grant Dewson, Stephen W G Tait.

Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.

DOI: https://doi.org/10.1038/s41556-024-01429-4
Int J Biol Sci. 2024 ;20(8): 2860-2880

Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation.

Kristina Xiao Liang, Anbin Chen, Atefeh Kianian, Cecilie Katrin Kristiansen, Tsering Yangzom, Jessica Furriol, Lena Elise Høyland, Mathias Ziegler, Torbjørn Kråkenes, Charalampos Tzoulis, Evandro Fei Fang, Gareth John Sullivan, Laurence A Bindoff.

Mitochondrial diseases are associated with neuronal death and mtDNA depletion. Astrocytes respond to injury or stimuli and damage to the central nervous system. Neurodegeneration can cause astrocytes to activate and acquire toxic functions that induce neuronal death. However, astrocyte activation and its impact on neuronal homeostasis in mitochondrial disease remain to be explored. Using patient cells carrying POLG mutations, we generated iPSCs and then differentiated these into astrocytes. POLG astrocytes exhibited mitochondrial dysfunction including loss of mitochondrial membrane potential, energy failure, loss of complex I and IV, disturbed NAD+/NADH metabolism, and mtDNA depletion. Further, POLG derived astrocytes presented an A1-like reactive phenotype with increased proliferation, invasion, upregulation of pathways involved in response to stimulus, immune system process, cell proliferation and cell killing. Under direct and indirect co-culture with neurons, POLG astrocytes manifested a toxic effect leading to the death of neurons. We demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astrocytes. These findings reveal a novel role for dysfunctional astrocytes that contribute to the pathogenesis of POLG diseases.

DOI: https://doi.org/10.7150/ijbs.93445
Nat Commun. 2024 Jun 20. 15(1): 5265

DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.

Adinarayana Marada, Corvin Walter, Tamara Suhm, Sahana Shankar, Arpita Nandy, Tilman Brummer, Ines Dhaouadi, F-Nora Vögtle, Chris Meisinger.

Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.

DOI: https://doi.org/10.1038/s41467-024-49611-4
J Cell Physiol. 2024 Jun 18.

The emerging role of mtDNA release in sepsis: Current evidence and potential therapeutic targets.

Qianya Hong, Shuainan Zhu, Ying Yu, Yun Ren, Lin Jin, Huilin Wang, Hao Zhang, Kefang Guo.

  Sepsis is a systemic inflammatory reaction caused by infection, and severe sepsis can develop into septic shock, eventually leading to multiorgan dysfunction and even death. In recent years, studies have shown that mitochondrial damage is closely related to the occurrence and development of sepsis. Recent years have seen a surge in concern over mitochondrial DNA (mtDNA), as anomalies in this material can lead to cellular dysfunction, disruption of aerobic respiration, and even death of the cell. In this review, we discuss the latest findings on the mechanisms of mitochondrial damage and the molecular mechanisms controlling mitochondrial mtDNA release. We also explored the connection between mtDNA misplacement and inflammatory activation. Additionally, we propose potential therapeutic targets of mtDNA for sepsis treatment.

Keywords:  inflammation; mitochondrial dysfunction; mtDNA; sepsis; therapeutic targets

DOI:  https://doi.org/10.1002/jcp.31331
bioRxiv. 2024 Jun 08. pii: 2024.06.07.598027. [Epub ahead of print]

MITOCHONDRIAL ANTIVIRAL PATHWAYS CONTROL ANTI-HIV RESPONSES AND ISCHEMIC STROKE OUTCOMES VIA THE RIG-1 SIGNALING AND INNATE IMMUNITY MECHANISMS.

Silvia Torices, Thaidy Moreno, Sita Ramaswamy, Oandy Naranjo, Timea Teglas, Olivia M Osborne, Minseon Park, Enze Sun, Michal Toborek.

Occludin (ocln) is one of the main regulatory cells of the blood-brain barrier (BBB). Ocln silencing resulted in alterations of the gene expression signatures of a variety of genes of the innate immunity system, including IFN-stimulated genes (ISGs) and the antiviral retinoic acid-inducible gene-1 (RIG-1) signaling pathway, which functions as a regulator of the cytoplasmic sensors upstream of the mitochondrial antiviral signaling protein (MAVS). Indeed, we observed dysfunctional mitochondrial bioenergetics, dynamics, and autophagy in our system. Alterations of mitochondrial bioenergetics and innate immune protection translated into worsened ischemic stroke outcomes in EcoHIV-infected ocln deficient mice. Overall, these results allow for a better understanding of the molecular mechanisms of viral infection in the brain and describe a previously unrecognized role of ocln as a key factor in the control of innate immune responses and mitochondrial dynamics, which affect cerebral vascular diseases such as ischemic stroke.

DOI: https://doi.org/10.1101/2024.06.07.598027
Sci Adv. 2024 Jun 21. 10(25): eadn0014

Olfaction regulates peripheral mitophagy and mitochondrial function.

Julian G Dishart, Corinne L Pender, Koning Shen, Hanlin Zhang, Megan Ly, Madison B Webb, Andrew Dillin.

The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPRMT); however, the contexts for which this regulatory capability evolved are unknown. UPRMT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPRMT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPRMT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin-mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPRMT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.

DOI: https://doi.org/10.1126/sciadv.adn0014
Dev Cell. 2024 May 20. pii: S1534-5807(24)00295-8. [Epub ahead of print]

Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.

George Kelly, Tetsushi Kataura, Johan Panek, Gailing Ma, Hanna Salmonowicz, Ashley Davis, Hannah Kendall, Charlotte Brookes, Daniel Moscoh Ayine-Tora, Peter Banks, Glyn Nelson, Laura Dobby, Patricia R Pitrez, Laura Booth, Lydia Costello, Gavin D Richardson, Penny Lovat, Stefan Przyborski, Lino Ferreira, Laura Greaves, Karolina Szczepanowska, Thomas von Zglinicki, Satomi Miwa, Max Brown, Michael Flagler, John E Oblong, Charles C Bascom, Bernadette Carroll, Jóhannes Reynisson, Viktor I Korolchuk.

  Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.

Keywords:  PINK1; Parkin; aging; autophagy; mitophagy; nicotinamide; nicotinamide riboside; p62; rapamycin; redox; senescence

DOI:  https://doi.org/10.1016/j.devcel.2024.04.020
bioRxiv. 2024 Apr 05. pii: 2024.04.04.588079. [Epub ahead of print]

Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy.

Pinakin Pandya, Frank P Vendetti, Joseph El-Ghoubaira, Sudipta Pathak, Joshua J Deppas, Reyna Jones, Anthony V Columbus, Yunqi Zhang, Daniel Ivanov, Ziyu Huang, Kate M MacDonald, Shane M Harding, Raquel Buj, Katherine M Aird, Jan H Beumer, Robert W Sobol, Christopher J Bakkenist.

DNA damage and cytoplasmic DNA induce type-1 interferon (IFN-1) and potentiate responses to immune checkpoint inhibitors. Our prior work found that inhibitors of the DNA damage response kinase ATR (ATRi) induce IFN-1 and deoxyuridine (dU) incorporation by DNA polymerases, akin to antimetabolites. Whether and how dU incorporation is required for ATRi-induced IFN-1 signaling is not known. Here, we show that ATRi-dependent IFN-1 responses require uracil DNA glycosylase (UNG)-initiated base excision repair and STING. Quantitative analyses of nine distinct nucleosides reveals that ATRi induce dU incorporation more rapidly in UNG wild-type than knockout cells, and that induction of IFN-1 is associated with futile cycles of repair. While ATRi induce similar numbers of micronuclei in UNG wild-type and knockout cells, dU containing micronuclei and cytoplasmic DNA are increased in knockout cells. Surprisingly, DNA fragments containing dU block STING-dependent induction of IFN-1, MHC-1, and PD-L1. Furthermore, UNG knockout sensitizes cells to IFN-γ in vitro , and potentiates responses to anti-PD-L1 in resistant tumors in vivo . These data demonstrate an unexpected and specific role for dU-rich DNA in suppressing STING-dependent IFN-1 responses, and show that UNG-deficient tumors have a heightened response to immune checkpoint inhibitors.
STATEMENT OF SIGNIFICANCE: Antimetabolites disrupt nucleotide pools and increase dU incorporation by DNA polymerases. We show that unrepaired dU potentiates responses to checkpoint inhibitors in mouse models of cancer. Patients with low tumor UNG may respond to antimetabolites combined with checkpoint inhibitors, and patients with high tumor UNG may respond to UNG inhibitors combined with checkpoint inhibitors.

DOI: https://doi.org/10.1101/2024.04.04.588079
bioRxiv. 2024 Jun 07. pii: 2024.06.07.597966. [Epub ahead of print]

Exposure of negative-sense viral RNA in the cytoplasm initiates innate immunity to West Nile virus.

Emmanuelle Genoyer, Jonathan Wilson, Joshua M Ames, Caleb Stokes, Dante Moreno, Noa Etzyon, Andrew Oberst, Michael Gale.

For many RNA viruses, immunity is triggered when RIG-I-like receptors (RLRs) detect viral RNA. However, only a minority of infected cells undergo innate immune activation. By examining these "first responder" cells during West Nile virus infection, we found that specific accumulation of anti- genomic negative-sense viral RNA (-vRNA) underlies innate immune activation and that RIG-I preferentially interacts with -vRNA. However, flaviviruses sequester -vRNA into membrane-bound replication compartments away from cytosolic sensors. We found that single-stranded -vRNA accumulates outside of replication compartments in "first responder" cells, rendering it accessible to RLRs. Exposure of this -vRNA occurs at late timepoints of infection, is linked to viral assembly, and depends on the expression of viral structural proteins. These findings reveal that while most infected cells replicate high levels of vRNA, release of -vRNA from replication compartments during assembly occurs at low frequency and is critical for initiation of innate immunity during flavivirus infection.

DOI: https://doi.org/10.1101/2024.06.07.597966
Nat Commun. 2024 Jun 18. 15(1): 5199

Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.

Jia-Rui Zhang, Shi-Yu Shen, Meng-Ying Zhai, Zu-Qi Shen, Wei Li, Ling-Feng Liang, Shu-Yuan Yin, Qiu-Qin Han, Bing Li, Yu-Qiu Zhang, Jin Yu.

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.

DOI: https://doi.org/10.1038/s41467-024-49597-z
Biochem Soc Trans. 2024 Jun 17. pii: BST20230724. [Epub ahead of print]

Proofreading mechanisms of the innate immune receptor RIG-I: distinguishing self and viral RNA.

Mihai Solotchi, Smita S Patel.

  The RIG-I-like receptors (RLRs), comprising retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), are pattern recognition receptors belonging to the DExD/H-box RNA helicase family of proteins. RLRs detect viral RNAs in the cytoplasm and respond by initiating a robust antiviral response that up-regulates interferon and cytokine production. RIG-I and MDA5 complement each other by recognizing different RNA features, and LGP2 regulates their activation. RIG-I's multilayered RNA recognition and proofreading mechanisms ensure accurate viral RNA detection while averting harmful responses to host RNAs. RIG-I's C-terminal domain targets 5'-triphosphate double-stranded RNA (dsRNA) blunt ends, while an intrinsic gating mechanism prevents the helicase domains from non-specifically engaging with host RNAs. The ATPase and RNA translocation activity of RIG-I adds another layer of selectivity by minimizing the lifetime of RIG-I on non-specific RNAs, preventing off-target activation. The versatility of RIG-I's ATPase function also amplifies downstream signaling by enhancing the signaling domain (CARDs) exposure on 5'-triphosphate dsRNA and promoting oligomerization. In this review, we offer an in-depth understanding of the mechanisms RIG-I uses to facilitate viral RNA sensing and regulate downstream activation of the immune system.

Keywords:  RIG-I like receptors; helicase; nucleic acid receptors

DOI:  https://doi.org/10.1042/BST20230724
Cell. 2024 Jun 07. pii: S0092-8674(24)00576-2. [Epub ahead of print]

STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.

Marcel S Woo, Christina Mayer, Lars Binkle-Ladisch, Jana K Sonner, Sina C Rosenkranz, Artem Shaposhnykov, Nicola Rothammer, Volodymyr Tsvilovskyy, Svenja M Lorenz, Lukas Raich, Lukas C Bal, Vanessa Vieira, Ingrid Wagner, Simone Bauer, Markus Glatzel, Marcus Conrad, Doron Merkler, Marc Freichel, Manuel A Friese.

  Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS.

Keywords:  STING; calcium signaling; cell death; excitotoxicity; ferroptosis; multiple sclerosis; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.1016/j.cell.2024.05.031
Free Radic Biol Med. 2024 Jun 16. pii: S0891-5849(24)00527-6. [Epub ahead of print]

STING1-accelerated vascular smooth muscle cell senescence-associated vascular calcification in diabetes is ameliorated by oleoylethanolamide via improved mitochondrial DNA oxidative damage.

Zhengdong Chen, Xiaoxue Li, Xuejiao Sun, Shengjue Xiao, Tian Chen, Liqun Ren, Naifeng Liu.

  Vascular calcification is a prevalent hallmark of cardiovascular risk in elderly and diabetic individuals. Senescent vascular smooth muscle cells (VSMCs) participate in calcification; however, the associated underlying mechanisms remain unknown. Aberrant activation of the cytosolic DNA sensing adaptor stimulator of interferon gene 1 (STING1) caused by cytosolic DNA, particularly that leaked from damaged mitochondria, is a catalyst for aging-related diseases. Although oleoylethanolamide (OEA) is an endogenous bioactive lipid mediator with lipid overload-associated vasoprotective effects, its benefit in diabetic vascular calcification remains uncharacterized. This study focused on the role of STING1 in mitochondrial dysfunction-mediated calcification and premature VMSC senescence in diabetes and the effects of OEA on these pathological processes. In diabetic in vivo rat/mouse aorta calcification models and an in vitro VSMC calcification model induced by Nε-carboxymethyl-lysine (CML), senescence levels, STING1 signaling activation, and mitochondrial damage markers were significantly augmented; however, these alterations were markedly alleviated by OEA, partially in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner, and similar anti-calcification and senescence effects were observed in STING1-knockout mice and STING1-knockdown VSMCs. Mechanistically, mitochondrial DNA (mtDNA) damage was aggravated by CML in a reactive oxygen species-dependent manner, followed by mtDNA leakage into the cytosol, contributing to VSMC senescence-associated calcification via STING1 pathway activation. OEA treatment significantly attenuated the aforementioned cytotoxic effects of CML by enhancing cellular antioxidant capacity through the maintenance of Nrf2 translocation to the nucleus. Collectively, targeting STING1, a newly defined VSMC senescence regulator, contributes to anti-vascular calcification effects.

Keywords:  Oleoylethanolamide; Osteogenic differentiation; Oxidative stress; STING1; Senescence; Vascular calcification; mtDNA damage

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.010
Mol Cell Biochem. 2024 Jun 19.

MALSU1-mediated regulation of mitochondrial function governs proliferation and doxorubicin resistance in triple-negative breast cancer cells.

Feifei Zhuang, Shaoyan Huang, Lei Liu.

  Triple-negative breast cancer (TNBC) poses a formidable challenge in oncology due to its aggressive nature and limited treatment options. Although doxorubicin, a widely used chemotherapeutic agent, shows efficacy in TNBC treatment, acquired resistance remains a significant obstacle. Our study explores the role of MALSU1, a regulator of mitochondrial translation, in TNBC and its impact on cell proliferation and doxorubicin resistance. We observed increased MALSU1 expression in TNBC, correlating with poor patient prognosis. MALSU1 knockdown in TNBC cells significantly reduced proliferation, indicating its pivotal role in sustaining cell growth. Mechanistically, MALSU1 depletion resulted in decreased activities of mitochondrial respiratory chain complexes, cellular ATP levels, and mitochondrial respiration. Notably, exogenous addition of normal mitochondria restored proliferation and mitochondrial respiration in MALSU1-depleted TNBC cells. Importantly, MALSU1 knockdown enhanced the sensitivity of doxorubicin-resistant TNBC cells to doxorubicin treatment. Furthermore, pharmacological inhibition of mitochondrial translation using tigecycline and chloramphenicol mimicked the effects of MALSU1 knockdown, suggesting mitochondrial translation as a potential therapeutic target. Taken together, our findings not only elucidate the intricate role of MALSU1 in TNBC biology and doxorubicin resistance but also lay the groundwork for future investigations targeting MALSU1 and/or mitochondrial translation as a promising avenue for developing innovative therapeutic strategies against TNBC.

Keywords:  Doxorubicin resistance; Doxorubicin sensitivity; Mitochondrial respiration; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s11010-024-05053-6
Obes Rev. 2024 Jun 16. e13791

Tissue-specific roles of mitochondrial unfolded protein response during obesity.

Fernanda S Carneiro, Carlos K Katashima, Joshua D Dodge, Dennys E Cintra, José Rodrigo Pauli, Adelino S R Da Silva, Eduardo R Ropelle.

  Obesity is a worldwide multifactorial disease caused by an imbalance in energy metabolism, increasing adiposity, weight gain, and promoting related diseases such as diabetes, cardiovascular diseases, neurodegeneration, and cancer. Recent findings have reported that metabolic stress related to obesity induces a mitochondrial stress response called mitochondrial unfolded protein response (UPRmt), a quality control pathway that occurs in a nuclear DNA-mitochondria crosstalk, causing transduction of chaperones and proteases under stress conditions. The duality of UPRmt signaling, with both beneficial and detrimental effects, acts in different contexts depending on the tissue, cell type, and physiological states, affecting the mitochondrial function and efficiency and the metabolism homeostasis during obesity, which remains not fully clarified. Therefore, this review discusses the most recent findings regarding UPRmt signaling during obesity, bringing an overview of UPRmt across different metabolic tissues.

Keywords:  metabolism; mitochondria; mitochondrial unfolded protein response; obesity

DOI:  https://doi.org/10.1111/obr.13791
Nat Commun. 2024 Jun 15. 15(1): 5119

A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism.

Deborah Mesa, Elisa Barbieri, Andrea Raimondi, Stefano Freddi, Giorgia Miloro, Gorana Jendrisek, Giusi Caldieri, Micaela Quarto, Irene Schiano Lomoriello, Maria Grazia Malabarba, Arianna Bresci, Francesco Manetti, Federico Vernuccio, Hind Abdo, Giorgio Scita, Letizia Lanzetti, Dario Polli, Carlo Tacchetti, Paolo Pinton, Massimo Bonora, Pier Paolo Di Fiore, Sara Sigismund.

One open question in the biology of growth factor receptors is how a quantitative input (i.e., ligand concentration) is decoded by the cell to produce specific response(s). Here, we show that an EGFR endocytic mechanism, non-clathrin endocytosis (NCE), which is activated only at high ligand concentrations and targets receptor to degradation, requires a tripartite organelle platform involving the plasma membrane (PM), endoplasmic reticulum (ER) and mitochondria. At these contact sites, EGFR-dependent, ER-generated Ca2+ oscillations are sensed by mitochondria, leading to increased metabolism and ATP production. Locally released ATP is required for cortical actin remodeling and EGFR-NCE vesicle fission. The same biochemical circuitry is also needed for an effector function of EGFR, i.e., collective motility. The multiorganelle signaling platform herein described mediates direct communication between EGFR signaling and mitochondrial metabolism, and is predicted to have a broad impact on cell physiology as it is activated by another growth factor receptor, HGFR/MET.

DOI: https://doi.org/10.1038/s41467-024-49543-z