bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–11–03
ten papers selected by
Marco Tigano, Thomas Jefferson University
  1. The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency.
  2. Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
  3. TFAM as a sensor of UVC-induced mitochondrial DNA damage.
  4. Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype.
  5. Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules.
  6. Engineering mtDNA Deletions by Reconstituting End-Joining in Human Mitochondria.
  7. High mitochondrial DNA levels accelerate lung adenocarcinoma progression.
  8. Arsenic-induced mtDNA release promotes inflammatory responses through cGAS-STING signaling in chicken hepatocytes.
  9. Apoptosis signaling is activated as a transient pulse in neurons.
  10. Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia.
  1. bioRxiv. 2024 Oct 17. pii: 2024.10.16.617214. [Epub ahead of print]
    The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency.
    Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Xiaoyan Guo.
      Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of integrated stress response (ISR) in regulating mitophagy, a key mitochondrial stress pathway. Our findings show that the ISR suppresses mitophagy under non-depolarizing mitochondrial stress by positively regulating mitochondrial protein import, independent of ATF4 activation. Mitochondrial protein import is regulated by the rate of protein synthesis under both depolarizing and non-depolarizing stress. Without ISR, increased protein synthesis overwhelms the mitochondrial import machinery, reducing its efficiency. Under depolarizing stress, mitochondrial import is heavily impaired even with active ISR, leading to significant PINK1 accumulation. In contrast, non-depolarizing stress allows more efficient protein import in the presence of ISR, resulting in lower mitophagy. Without ISR, mitochondrial protein import becomes severely compromised, causing PINK1 accumulation to reach the threshold necessary to trigger mitophagy. These findings reveal a novel link between ISR-regulated protein synthesis, mitochondrial import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1101/2024.10.16.617214
  2. Sci Adv. 2024 Nov;10(44): eadk8801
    Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
    Spencer D Shelton, Sara House, Luiza Martins Nascentes Melo, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Gabriele Allies, Jonathan Krystkiewicz, Jonas Rösler, Sven W Meckelmann, Peihua Zhao, Florian Rambow, Dirk Schadendorf, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra.
      Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.
    DOI:  https://doi.org/10.1126/sciadv.adk8801
  3. bioRxiv. 2024 Oct 24. pii: 2024.10.24.620005. [Epub ahead of print]
    TFAM as a sensor of UVC-induced mitochondrial DNA damage.
    Dillon E King, Emily E Beard, Matthew J Satusky, Ian Ryde, Alex George, Caitlin Johnson, Emma L Dolan, Yuning Zhang, Wei Zhu, Hunter Wilkins, Evan Corden, Susan K Murphy, Dorothy Erie, Raluca Gordân, Joel N Meyer.
      Mitochondria lack nucleotide excision DNA repair; however, mitochondrial DNA (mtDNA) is resistant to mutation accumulation following DNA damage. These observations suggest additional damage sensing or protection mechanisms. Transcription Factor A, Mitochondrial (TFAM) compacts mtDNA into nucleoids. As such, TFAM has emerged as a candidate for protecting DNA or sensing damage. To examine these possibilities, we used live-cell imaging, cell-based assays, atomic force microscopy, and high-throughput protein-DNA binding assays to characterize the binding properties of TFAM to UVC-irradiated DNA and cellular consequences of UVC irradiation. Our data indicate an increase in mtDNA degradation and turnover, without a loss in mitochondrial membrane potential that might trigger mitophagy. We identified a reduction in sequence specificity of TFAM associated with UVC irradiation and a redistribution of TFAM binding throughout the mitochondrial genome. Our AFM data show increased compaction of DNA by TFAM in the presence of damage. Despite the TFAM-mediated compaction of mtDNA, we do not observe any protective effect on DNA damage accumulation in cells or in vitro . Taken together, these studies indicate that UVC-induced DNA damage promotes compaction by TFAM, suggesting that TFAM may act as a damage sensor, sequestering damaged genomes to prevent mutagenesis by direct removal or suppression of replication.
    DOI:  https://doi.org/10.1101/2024.10.24.620005
  4. Mol Cell. 2024 Oct 24. pii: S1097-2765(24)00826-8. [Epub ahead of print]
    Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype.
    Matthew J Payea, Showkat A Dar, Carlos Anerillas, Jennifer L Martindale, Cedric Belair, Rachel Munk, Sulochan Malla, Jinshui Fan, Yulan Piao, Xiaoling Yang, Abid Rehman, Nirad Banskota, Kotb Abdelmohsen, Myriam Gorospe, Manolis Maragkakis.
      Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile.
    Keywords:  ATF4; ER stress; ISR; SASP; integrated stress response; nanopore direct RNA sequencing; proteomics; ribosome sequencing; senescence; senescence-associated secretory phenotype; translation
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.003
  5. J Cell Sci. 2024 Oct 28. pii: jcs.263548. [Epub ahead of print]
    Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules.
    Marta Lopez-Nieto, Zhaozhi Sun, Emily Relton, Rahme Safakli, Brian D Freibaum, J Paul Taylor, Alessia Ruggieri, Ioannis Smyrnias, Nicolas Locker.
      To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that SGs and UPRmt pathways are intertwined and communicate. UPRmt induction results in eIF2a phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that may contribute to restoring mitochondrial functions under stressful conditions.
    Keywords:  GADD34; Integrated stress response; Mitochondrial stress response; Stress granules; UPRmt
    DOI:  https://doi.org/10.1242/jcs.263548
  6. bioRxiv. 2024 Oct 17. pii: 2024.10.15.618543. [Epub ahead of print]
    Engineering mtDNA Deletions by Reconstituting End-Joining in Human Mitochondria.
    Yi Fu, Max Land, Ruobing Cui, Tamar Kavlashvili, Minsoo Kim, Toby Lieber, Keun Woo Ryu, Emily DeBitetto, Ignas Masilionis, Rahul Saha, Meril Takizawa, Daphne Baker, Marco Tigano, Ed Reznik, Roshan Sharma, Ronan Chaligne, Craig B Thompson, Dana Pe'er, Agnel Sfeir.
      Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled the precise introduction of base substitutions and the effective removal of genomes carrying harmful mutations. However, the reconstitution of mtDNA deletions responsible for severe mitochondrial myopathies and age-related diseases has not yet been achieved in human cells. Here, we developed a method to engineer specific mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. As a proof-of-concept, we used mito-EJ and mito-ScaI to generate a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion with the full spectrum of heteroplasmy. Investigating these isogenic cells revealed a critical threshold of ∼75% deleted genomes, beyond which cells exhibited depletion of OXPHOS proteins, severe metabolic disruption, and impaired growth in galactose-containing media. Single-cell multiomic analysis revealed two distinct patterns of nuclear gene deregulation in response to mtDNA deletion accumulation; one triggered at the deletion threshold and another progressively responding to increasing heteroplasmy. In summary, the co-expression of mito-EJ and programable nucleases provides a powerful tool to model disease-associated mtDNA deletions in different cell types. Establishing a panel of cell lines with a large-scale deletion at varying levels of heteroplasmy is a valuable resource for understanding the impact of mtDNA deletions on diseases and guiding the development of potential therapeutic strategies.
    Highlights: Combining prokaryotic end-joining with targeted endonucleases generates specific mtDNA deletions in human cellsEngineering a panel of cell lines with a large-scale deletion that spans the full spectrum of heteroplasmy75% heteroplasmy is the threshold that triggers mitochondrial and cellular dysfunctionTwo distinct nuclear transcriptional programs in response to mtDNA deletions: threshold-triggered and heteroplasmy-sensing.
    DOI:  https://doi.org/10.1101/2024.10.15.618543
  7. Sci Adv. 2024 Nov;10(44): eadp3481
    High mitochondrial DNA levels accelerate lung adenocarcinoma progression.
    Mara Mennuni, Stephen E Wilkie, Pauline Michon, David Alsina, Roberta Filograna, Markus Lindberg, David E Sanin, Florian Rosenberger, Alina Schaaf, Erik Larsson, Erika L Pearce, Nils-Göran Larsson.
      Lung adenocarcinoma is a common aggressive cancer and a leading cause of mortality worldwide. Here, we report an important in vivo role for mitochondrial DNA (mtDNA) copy number during lung adenocarcinoma progression in the mouse. We found that lung tumors induced by KRASG12D expression have increased mtDNA levels and enhanced mitochondrial respiration. To experimentally assess a possible causative role in tumor progression, we induced lung cancer in transgenic mice with a general increase in mtDNA copy number and found that they developed a larger tumor burden, whereas mtDNA depletion in tumor cells reduced tumor growth. Immune cell populations in the lung and cytokine levels in plasma were not affected by increased mtDNA levels. Analyses of large cancer databases indicate that mtDNA copy number is also important in human lung cancer. Our study thus reports experimental evidence for a tumor-intrinsic causative role for mtDNA in lung cancer progression, which could be exploited for development of future cancer therapies.
    DOI:  https://doi.org/10.1126/sciadv.adp3481
  8. Pestic Biochem Physiol. 2024 Nov;pii: S0048-3575(24)00362-6. [Epub ahead of print]205 106129
    Arsenic-induced mtDNA release promotes inflammatory responses through cGAS-STING signaling in chicken hepatocytes.
    Hang Pan, Qian Su, Panjing Hong, Yanli You, Limeng Zhou, Junbo Zou, Jingping Sun, Gaolong Zhong, Jianzhao Liao, Hui Zhang, Zhaoxin Tang, Lianmei Hu.
      Arsenic is a toxic element that can cause severe liver damage in humans and animals. Arsenic-based inorganic pesticides, such as lead arsenate, copper arsenate, and calcium arsenate, are widely used for insect control and can eventually affect human health through accumulation in the food chain. However, the relationship between arsenic trioxide (ATO)-induced hepatotoxicity and the cGAS-STING signaling pathway has not been reported. The aim of this study was to investigate the potential role of inflammatory response in ATO-induced hepatotoxicity in chickens. In this study, we found that ATO exposure resulted in mtDNA leakage into the cytoplasm of chicken hepatocytes, which activated the cGAS-STING pathway and significantly increased the cGAS, STING, TBK1, and IRF7 mRNA and protein expression levels. Moreover, type I interferon response was activated. Concurrently, STING triggered the activation of the traditional NF-κB signaling pathway and promoted the expression of pro-inflammatory cytokine genes, including TNF-α, IL-6, and IL-1β. Subsequently, we found that both mtDNA clearance with EtBr and inhibition of the cGAS-STING pathway with H-151 reversed the ATO-induced innate immune and inflammatory responses. In summary, the above findings indicate that chicken hepatocytes can induce innate immune responses and inflammatory responses via mtDNA-cGAS-STING under ATO-exposure conditions, which is of great significance for further studies on the toxicity mechanism of ATO.
    Keywords:  Arsenic; Hepatotoxicity; Inflammatory response; Mitochondrial DNA; cGAS-STING signaling pathway
    DOI:  https://doi.org/10.1016/j.pestbp.2024.106129
  9. Cell Death Differ. 2024 Oct 26.
    Apoptosis signaling is activated as a transient pulse in neurons.
    Keeley L Spiess, Matthew J Geden, Selena E Romero, Emilie Hollville, Elizabeth S Hammond, Rachel L Patterson, Quintin B Girardi, Mohanish Deshmukh.
      Apoptosis is a fundamental process of all mammalian cells but exactly how it is regulated in different primary cells remains less explored. In most contexts, apoptosis is engaged to eliminate cells. However, postmitotic cells such as neurons must efficiently balance the need for developmental apoptosis versus the physiological needs for their long-term survival. Neurons are capable of reversing the commitment to death even after the point of cytochrome c release. This ability of neurons to recover from an apoptotic signal suggests that activation of the apoptotic pathway in neurons could be much more transient than is currently recognized. Here, we investigated whether the apoptotic pathway in neurons is a persistent signal or a transient pulse in continuous presence of apoptotic stimulus. We have examined this at three key steps in apoptotic signaling: phosphorylation of c-Jun, induction of the BH3-only family proteins and Bax activation. Strikingly, we found all three of these events occur as transient signals following Nerve Growth Factor (NGF) deprivation-induced apoptosis in sympathetic neurons. This transient apoptosis signal would effectively allow neurons to reset and permit recovery if the apoptotic stimulus is reversed. Excitingly, we have also discovered that a neuron's ability to recover from an apoptotic signal is dependent on expression of the anti-apoptotic Bcl-2 family protein Bcl-xL. Bcl-xL-deficient neurons lose the ability to recover from NGF deprivation even if NGF is restored. Additionally, we show that recovery from a previous exposure to NGF deprivation is protective against subsequent deprivation. Together, these results define a novel mechanism by which apoptosis is regulated in neurons where the transient pulse of the apoptotic signaling supports neuronal resilience.
    DOI:  https://doi.org/10.1038/s41418-024-01403-5
  10. Cell Rep. 2024 Oct 29. pii: S2211-1247(24)01276-2. [Epub ahead of print]43(11): 114925
    Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia.
    Benjamin R Pryce, Alexander Oles, Erin E Talbert, Martin J Romeo, Silvia Vaena, Sudarshana Sharma, Victoria Spadafora, Lauren Tolliver, David A Mahvi, Katherine A Morgan, William P Lancaster, Eryn Beal, Natlie Koren, Bailey Watts, Morgan Overstreet, Stefano Berto, Suganya Subramanian, Kubra Calisir, Anna Crawford, Brian Neelon, Michael C Ostrowski, Teresa A Zimmers, James G Tidball, David J Wang, Denis C Guttridge.
      Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
    Keywords:  CP: Cancer; CP: Immunology; NF-κB; cancer cachexia; fibro-adipogenic progenitors; macrophages; muscle progenitor cells; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2024.114925
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