bims-midhyp Biomed News
on Mitochondrial dysfunction and hypoxia
Issue of 2023–08–27
thirteen papers selected by
Alia Ablieh, Universität Heidelberg
  1. Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression.
  2. Post-translational modifications and protein quality control of mitochondrial channels and transporters.
  3. Structural mechanism of mitochondrial membrane remodelling by human OPA1.
  4. Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor.
  5. Effect of Mesenchymal Stem Cells Overexpressing BMP-9 Primed with Hypoxia on BMP Targets, Osteoblast Differentiation and Bone Repair.
  6. Perspective: mitochondrial STAT3 in cardioprotection.
  7. Mechanisms of Modulation of Mitochondrial Architecture.
  8. Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
  9. Hypoxic State of Cells and Immunosenescence: A Focus on the Role of the HIF Signaling Pathway.
  10. Mitochondrial Metabolism: A New Dimension of Personalized Oncology.
  11. Involvement of Protein Kinase R in Double-Stranded RNA-Induced Proteasomal Degradation of Hypoxia Inducible Factor-1α.
  12. Role of Mitochondria-ER Contact Sites in Mitophagy.
  13. Mitochondrial morphology governs ATP production rate.
  1. Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2208117120
    Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression.
    Sarah J Kierans, Raphael R Fagundes, Mykyta I Malkov, Ríona Sparkes, Eugène T Dillon, Albert Smolenski, Klaas Nico Faber, Cormac T Taylor.
      The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic adenosine triphosphate (ATP) production, an event with consequences for cellular bioenergetics and cell fate. This response is regulated at the transcriptional level by the hypoxia-inducible factor-1(HIF-1)-dependent transcriptional upregulation of glycolytic enzymes (GEs) and glucose transporters. However, this transcriptional upregulation alone is unlikely to account fully for the levels of glycolytic ATP produced during hypoxia. Here, we investigated additional mechanisms regulating glycolysis in hypoxia. We observed that intestinal epithelial cells treated with inhibitors of transcription or translation and human platelets (which lack nuclei and the capacity for canonical transcriptional activity) maintained the capacity for hypoxia-induced glycolysis, a finding which suggests the involvement of a nontranscriptional component to the hypoxia-induced metabolic switch to a highly glycolytic phenotype. In our investigations into potential nontranscriptional mechanisms for glycolytic induction, we identified a hypoxia-sensitive formation of complexes comprising GEs and glucose transporters in intestinal epithelial cells. Surprisingly, the formation of such glycolytic complexes occurs independent of HIF-1-driven transcription. Finally, we provide evidence for the presence of HIF-1α in cytosolic fractions of hypoxic cells which physically interacts with the glucose transporter GLUT1 and the GEs in a hypoxia-sensitive manner. In conclusion, we provide insights into the nontranscriptional regulation of hypoxia-induced glycolysis in intestinal epithelial cells.
    Keywords:  HIF; glycolysis; hypoxia; metabolism
    DOI:  https://doi.org/10.1073/pnas.2208117120
  2. Front Cell Dev Biol. 2023 ;11 1196466
    Post-translational modifications and protein quality control of mitochondrial channels and transporters.
    Ashlesha Kadam, Pooja Jadiya, Dhanendra Tomar.
      Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.
    Keywords:  MCU; MPQC; MPTP; SLCs; VDAC; mitochondrial channels; mitochondrial transporters; posttranslational modifications
    DOI:  https://doi.org/10.3389/fcell.2023.1196466
  3. Nature. 2023 Aug 23.
    Structural mechanism of mitochondrial membrane remodelling by human OPA1.
    Alexander von der Malsburg, Gracie M Sapp, Kelly E Zuccaro, Alexander von Appen, Frank R Moss, Raghav Kalia, Jeremy A Bennett, Luciano A Abriata, Matteo Dal Peraro, Martin van der Laan, Adam Frost, Halil Aydin.
      Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1-3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
    DOI:  https://doi.org/10.1038/s41586-023-06441-6
  4. Elife. 2023 Aug 23. pii: RP85597. [Epub ahead of print]12
    Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor.
    Erin J Ciampa, Padraich Flahardy, Harini Srinivasan, Christopher Jacobs, Linus Tsai, S Ananth Karumanchi, Samir M Parikh.
      Most cases of preterm labor have unknown cause, and the burden of preterm birth is immense. Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. We report findings stemming from unbiased transcriptomic analysis of mouse placenta, which revealed that hypoxia-inducible factor 1 (HIF-1) stabilization is a hallmark of advanced gestational timepoints, accompanied by mitochondrial dysregulation and cellular senescence; we detected similar effects in aging human placenta. In parallel in primary mouse trophoblasts and human choriocarcinoma cells, we modeled HIF-1 induction and demonstrated resultant mitochondrial dysfunction and cellular senescence. Transcriptomic analysis revealed that HIF-1 stabilization recapitulated gene signatures observed in aged placenta. Further, conditioned media from trophoblasts following HIF-1 induction promoted contractility in immortalized uterine myocytes, suggesting a mechanism by which the aging placenta may drive the transition from uterine quiescence to contractility at the onset of labor. Finally, pharmacological induction of HIF-1 via intraperitoneal administration of dimethyloxalyl glycine (DMOG) to pregnant mice caused preterm labor. These results provide clear evidence for placental aging in normal pregnancy, and demonstrate how HIF-1 signaling in late gestation may be a causal determinant of the mitochondrial dysfunction and senescence observed within the trophoblast as well as a trigger for uterine contraction.
    Keywords:  aging; human; immunology; inflammation; medicine; mitochondria; mouse; placenta; pregnancy; preterm labor
    DOI:  https://doi.org/10.7554/eLife.85597
  5. Biology (Basel). 2023 Aug 19. pii: 1147. [Epub ahead of print]12(8):
    Effect of Mesenchymal Stem Cells Overexpressing BMP-9 Primed with Hypoxia on BMP Targets, Osteoblast Differentiation and Bone Repair.
    Jessica Emanuella Rocha Moura Paz, Leticia Faustino Adolpho, Jaqueline Isadora Reis Ramos, Rayana Longo Bighetti-Trevisan, Robson Diego Calixto, Fabiola Singaretti Oliveira, Adriana Luisa Gonçalves Almeida, Marcio Mateus Beloti, Adalberto Luiz Rosa.
      Bone formation is driven by many signaling molecules including bone morphogenetic protein 9 (BMP-9) and hypoxia-inducible factor 1-alpha (HIF-1α). We demonstrated that cell therapy using mesenchymal stem cells (MSCs) overexpressing BMP-9 (MSCs+BMP-9) enhances bone formation in calvarial defects. Here, the effect of hypoxia on BMP components and targets of MSCs+BMP-9 and of these hypoxia-primed cells on osteoblast differentiation and bone repair was evaluated. Hypoxia was induced with cobalt chloride (CoCl2) in MSCs+BMP-9, and the expression of BMP components and targets was evaluated. The paracrine effects of hypoxia-primed MSCs+BMP-9 on cell viability and migration and osteoblast differentiation were evaluated using conditioned medium. The bone formation induced by hypoxia-primed MSCs+BMP-9 directly injected into rat calvarial defects was also evaluated. The results demonstrated that hypoxia regulated BMP components and targets without affecting BMP-9 amount and that the conditioned medium generated under hypoxia favored cell migration and osteoblast differentiation. Hypoxia-primed MSCs+BMP-9 did not increase bone repair compared with control MSCs+BMP-9. Thus, despite the lack of effect of hypoxia on bone formation, the enhancement of cell migration and osteoblast differentiation opens windows for further investigations on approaches to modulate the BMP-9-HIF-1α circuit in the context of cell-based therapies to induce bone regeneration.
    Keywords:  BMP-9; HIF-1α; bone; cell therapy; hypoxia; stem cells
    DOI:  https://doi.org/10.3390/biology12081147
  6. Basic Res Cardiol. 2023 Aug 24. 118(1): 32
    Perspective: mitochondrial STAT3 in cardioprotection.
    Petra Kleinbongard.
      Activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key cardioprotective signal not only in animal studies but also in humans-in animals, STAT3 is causally involved in cardioprotection. In response to late ischemic conditioning, canonical function of STAT3 activation upregulates the expression of cardioprotective and anti-apoptotic proteins. In its non-canonical function, STAT3 is activated during ischemic conditioning and is part of the cardioprotective cytosolic survival activating factor enhancement pathway. Activated STAT3 is imported and localized to the mitochondria. Mitochondrial STAT3 stimulates the activity of mitochondrial electron transport chain complex I, reduces mitochondrial reactive oxygen species production and mitochondrial permeability transition pore opening. Finally, two novel aspects of STAT activation in cardioprotection are discussed: a genetic variance of the STAT encoding region as a potential primordial confounding variable for cardioprotection, and the cardioprotective potential of sodium-glucose cotransporter 2 inhibitors through STAT3 activation.
    Keywords:  Cardioprotection; Ischemia/reperfusion injury; Mitochondria; SAFE pathway; STAT
    DOI:  https://doi.org/10.1007/s00395-023-01003-3
  7. Biomolecules. 2023 Aug 07. pii: 1225. [Epub ahead of print]13(8):
    Mechanisms of Modulation of Mitochondrial Architecture.
    Juan Pablo Muñoz, Fernanda Luisa Basei, María Laura Rojas, David Galvis, Antonio Zorzano.
      Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.
    Keywords:  lipids; membrane contact sites (MCSs); metabolic disease; metabolism; mitochondria; mitochondrial dynamics; pharmacology; post-translational modification; tethers
    DOI:  https://doi.org/10.3390/biom13081225
  8. Nat Commun. 2023 Aug 22. 14(1): 5114
    Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
    Erika M Palmieri, Ronald Holewinski, Christopher L McGinity, Ciro L Pierri, Nunziata Maio, Jonathan M Weiss, Vincenzo Tragni, Katrina M Miranda, Tracey A Rouault, Thorkell Andresson, David A Wink, Daniel W McVicar.
      M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys477 and Cys484, and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring.
    DOI:  https://doi.org/10.1038/s41467-023-40738-4
  9. Biomedicines. 2023 Aug 01. pii: 2163. [Epub ahead of print]11(8):
    Hypoxic State of Cells and Immunosenescence: A Focus on the Role of the HIF Signaling Pathway.
    Dario Troise, Barbara Infante, Silvia Mercuri, Giuseppe Stefano Netti, Elena Ranieri, Loreto Gesualdo, Giovanni Stallone, Paola Pontrelli.
      Hypoxia activates hypoxia-related signaling pathways controlled by hypoxia-inducible factors (HIFs). HIFs represent a quick and effective detection system involved in the cellular response to insufficient oxygen concentration. Activation of HIF signaling pathways is involved in improving the oxygen supply, promoting cell survival through anaerobic ATP generation, and adapting energy metabolism to meet cell demands. Hypoxia can also contribute to the development of the aging process, leading to aging-related degenerative diseases; among these, the aging of the immune system under hypoxic conditions can play a role in many different immune-mediated diseases. Thus, in this review we aim to discuss the role of HIF signaling pathways following cellular hypoxia and their effects on the mechanisms driving immune system senescence.
    Keywords:  cellular aging; cellular energy; hypoxia-inducible factors; immunosenescence
    DOI:  https://doi.org/10.3390/biomedicines11082163
  10. Cancers (Basel). 2023 Aug 11. pii: 4058. [Epub ahead of print]15(16):
    Mitochondrial Metabolism: A New Dimension of Personalized Oncology.
    Babak Behnam, Farzad Taghizadeh-Hesary.
      Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells' biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironments, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The tumors' responses to anticancer treatments vary, ranging from a complete response to even cancer progression during treatment. Therefore, personalized cancer treatment is of crucial importance. So far, personalized cancer treatment has been based on genomic analysis. Evidence shows that tumors with high mitochondrial content are more resistant to treatment. This paper illustrates how mitochondrial metabolism can participate in cancer resistance to chemotherapy, immunotherapy, and radiotherapy. Pretreatment evaluation of mitochondrial metabolism can provide additional information to genomic analysis and can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.
    Keywords:  T cell; cancer stem cell; mitochondria; personalized oncology
    DOI:  https://doi.org/10.3390/cancers15164058
  11. Inflammation. 2023 Aug 24.
    Involvement of Protein Kinase R in Double-Stranded RNA-Induced Proteasomal Degradation of Hypoxia Inducible Factor-1α.
    Takuma Hotani, Kanako Nakagawa, Tomohito Tsukamoto, Hiroyuki Mizuguchi, Fuminori Sakurai.
      Hypoxia inducible factor-1α (HIF-1α) is a crucial therapeutic target in various diseases, including cancer and fibrosis. We previously demonstrated that transfection with double-stranded RNA (dsRNA), including polyI:C and the dsRNA genome of mammalian orthoreovirus, resulted in significant reduction in HIF-1α protein levels in cultured cells; however, it remained to be elucidated how dsRNA induced down-regulation of HIF-1α protein levels. In this study, we examined the mechanism of dsRNA-mediated down-regulation of HIF-1α protein levels. We found that among the various cellular factors involved in dsRNA-mediated innate immunity, knockdown and knockout of protein kinase R (PKR) significantly restored HIF-1α protein levels in dsRNA-transfected cells, indicating that PKR was involved in dsRNA-mediated down-regulation of HIF-1α. Proteasome inhibitors significantly restored the HIF-1α protein levels in dsRNA-transfected cells. Ubiquitination levels of HIF-1α were increased by transfection with dsRNA. These findings indicated that degradation of HIF-1α in a ubiquitin-proteasome pathway was promoted in a PKR-dependent manner following dsRNA transfection. Expression of not only HIF-1α but also several proteins, including CDK4 and HER2, was down-regulated following dsRNA transfection. These data provide important clues for elucidation of the mechanism of dsRNA-mediated cellular toxicity, as well as for therapeutic application of dsRNA.
    Keywords:  Double-stranded RNA; HIF-1α; PKR; Proteasome; Ubiquitin
    DOI:  https://doi.org/10.1007/s10753-023-01881-8
  12. Biomolecules. 2023 Jul 31. pii: 1198. [Epub ahead of print]13(8):
    Role of Mitochondria-ER Contact Sites in Mitophagy.
    Alina Rühmkorf, Angelika Bettina Harbauer.
      Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.
    Keywords:  mitochondria; mitophagy; organellar contact sites
    DOI:  https://doi.org/10.3390/biom13081198
  13. J Gen Physiol. 2023 09 04. pii: e202213263. [Epub ahead of print]155(9):
    Mitochondrial morphology governs ATP production rate.
    Guadalupe C Garcia, Kavya Gupta, Thomas M Bartol, Terrence J Sejnowski, Padmini Rangamani.
      Life is based on energy conversion. In particular, in the nervous system, significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To a large extent, neurons depend on oxidative phosphorylation in mitochondria to meet their high energy demand. For a comprehensive understanding of the metabolic demands in neuronal signaling, accurate models of ATP production in mitochondria are required. Here, we present a thermodynamically consistent model of ATP production in mitochondria based on previous work. The significant improvement of the model is that the reaction rate constants are set such that detailed balance is satisfied. Moreover, using thermodynamic considerations, the dependence of the reaction rate constants on membrane potential, pH, and substrate concentrations are explicitly provided. These constraints assure that the model is physically plausible. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting steps in making ATP available in the cytosol. The outcomes reveal that, under the conditions used in our simulations, ATP production is the limiting step and not its export. Finally, we performed spatial simulations with nine 3-D realistic mitochondrial reconstructions and linked the ATP production rate in the cytosol with morphological features of the organelles.
    DOI:  https://doi.org/10.1085/jgp.202213263
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