bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒06‒23
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico 
  1. Is mitochondrial morphology important for cellular physiology?
  2. DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
  3. Mitochondrial proteases modulate mitochondrial stress signalling and cellular homeostasis in health and disease.
  4. MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
  5. Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.
  6. Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation.
  7. Harlequin mice exhibit cognitive impairment, severe loss of Purkinje cells and a compromised bioenergetic status due to the absence of Apoptosis Inducing Factor.
  8. Oxidative protein folding in the intermembrane space of human mitochondria.
  9. Psychosocial experiences are associated with human brain mitochondrial biology.
  10. Metabolic regulation of misfolded protein import into mitochondria.
  11. Multiomics analysis reveals serine catabolism as a potential therapeutic target for MELAS.
  12. Progressive degeneration in a new Drosophila model of spinocerebellar ataxia type 7.
  13. Liver gene transfer for metabolite detoxification in inherited metabolic diseases.
  14. Mitochondrial unfolded protein response (UPRmt): what we know thus far.
  15. An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich's Ataxia.
  16. A single-cell atlas of pig gastrulation as a resource for comparative embryology.
  17. An Amino Acid Mixture to Counteract Skeletal Muscle Atrophy: Impact on Mitochondrial Bioenergetics.
  18. Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases.
  19. Spatial proteomics of skeletal muscle using thin cryosections reveals metabolic adaptation at the muscle-tendon transition zone.
  20. AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.
  21. Mitochondria and cell death.
  22. A Mitochondrial Basis for Heart Failure Progression.
  23. Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review.
  1. Trends Endocrinol Metab. 2024 Jun 11. pii: S1043-2760(24)00123-1. [Epub ahead of print]
    Is mitochondrial morphology important for cellular physiology?
    Timothy Wai.
      Mitochondria are double membrane-bound organelles the network morphology of which in cells is shaped by opposing events of fusion and fission executed by dynamin-like GTPases. Mutations in these genes can perturb the form and functions of mitochondria in cell and animal models of mitochondrial diseases. An expanding array of chemical, mechanical, and genetic stressors can converge on mitochondrial-shaping proteins and disrupt mitochondrial morphology. In recent years, studies aimed at disentangling the multiple roles of mitochondrial-shaping proteins beyond fission or fusion have provided insights into the homeostatic relevance of mitochondrial morphology. Here, I review the pleiotropy of mitochondrial fusion and fission proteins with the aim of understanding whether mitochondrial morphology is important for cell and tissue physiology.
    Keywords:  fission and fusion; genetic disease; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology
    DOI:  https://doi.org/10.1016/j.tem.2024.05.005
  2. 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
  3. Biochimie. 2024 Jun 19. pii: S0300-9084(24)00141-X. [Epub ahead of print]
    Mitochondrial proteases modulate mitochondrial stress signalling and cellular homeostasis in health and disease.
    Nicoleta Moisoi.
      Maintenance of mitochondrial homeostasis requires a plethora of coordinated quality control and adaptations' mechanisms in which mitochondrial proteases play a key role. Their activation or loss of function reverberate beyond local mitochondrial biochemical and metabolic remodelling into coordinated cellular pathways and stress responses that feedback onto the mitochondrial functionality and adaptability. Mitochondrial proteolysis modulates molecular and organellar quality control, metabolic adaptations, lipid homeostasis and regulates transcriptional stress responses. Defective mitochondrial proteolysis results in disease conditions most notably, mitochondrial diseases, neurodegeneration and cancer. Here, it will be discussed how mitochondrial proteases and mitochondria stress signalling impact cellular homeostasis and determine the cellular decision to survive or die, how these processes may impact disease etiopathology, and how modulation of proteolysis may offer novel therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.biochi.2024.06.005
  4. iScience. 2024 Jun 21. 27(6): 109994
    MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
    Atul Kumar, Delfina Larrea, Maria Elena Pero, Paola Infante, Marilisa Conenna, Grace J Shin, Vincent Van Elias, Wesley B Grueber, Lucia Di Marcotullio, Estela Area-Gomez, Francesca Bartolini.
      Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion and tethering with the ER. The role of MFN2 in mitochondrial transport has however remained elusive. Like MFN2, acetylated microtubules play key roles in mitochondria dynamics. Nevertheless, it is unknown if the α-tubulin acetylation cycle functionally interacts with MFN2. Here, we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). This activity is critical for MFN2-dependent regulation of mitochondria transport, and axonal degeneration caused by CMT2A MFN2 associated R94W and T105M mutations may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in α-tubulin acetylation and suggest that disruption of this activity plays a role in the onset of MFN2-dependent CMT2A.
    Keywords:  Cell biology; Lipidomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109994
  5. Mitochondrion. 2024 Jun 17. pii: S1567-7249(24)00080-1. [Epub ahead of print]78 101922
    Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.
    Dilpreet Singh.
      Mitochondrial disorders, stemming from mutations in mitochondrial DNA (mtDNA), present a significant therapeutic challenge due to their complex pathophysiology and broad spectrum of clinical manifestations. Traditional gene therapy approaches, primarily reliant on viral vectors, face obstacles such as potential immunogenicity, insertional mutagenesis, and the specificity of targeting mtDNA. This review delves into non-viral methods for mitochondrial gene delivery, emerging as a promising alternative to overcome these limitations. Focusing on lipid-based nanoparticles, polymer-based vectors, and mitochondrial-targeted peptides, the mechanisms of action, advantages, and current applications in treating mitochondrial diseases was well elucidated. Non-viral vectors offer several benefits, including reduced immunogenicity, enhanced safety profiles, and the flexibility to carry a wide range of genetic material. We examine case studies where these methods have been applied, highlighting their potential in correcting pathogenic mtDNA mutations and mitigating disease phenotypes. Despite their promise, challenges such as delivery efficiency, specificity, and long-term expression stability persist. The review underscores the need for ongoing research to refine these delivery systems carry a wide range of genetic material. We examine case studies where these methods settings. As we advance our understanding of mitochondrial biology and gene delivery technologies, non-viral methods hold the potential to revolutionize the treatment of mitochondrial disorders, offering hope for therapies that can precisely target and correct the underlying genetic defects.
    Keywords:  Gene therapy; Lipid-based nanoparticles; Mitochondrial disorders; Mitochondrial gene delivery; Mitochondrial-targeted peptides; Non-viral vectors; Polymer-based vectors; Precision medicine
    DOI:  https://doi.org/10.1016/j.mito.2024.101922
  6. 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
  7. Biochim Biophys Acta Mol Basis Dis. 2024 Jun 17. pii: S0925-4439(24)00261-8. [Epub ahead of print] 167272
    Harlequin mice exhibit cognitive impairment, severe loss of Purkinje cells and a compromised bioenergetic status due to the absence of Apoptosis Inducing Factor.
    Hélène Cwerman-Thibault, Vassilissa Malko-Baverel, Gwendoline Le Guilloux, Isabel Torres-Cuevas, Edward Ratcliffe, Djmila Mouri, Virginie Mignon, Bruno Saubaméa, Odile Boespflug-Tanguy, Pierre Gressens, Marisol Corral-Debrinski.
      The functional integrity of the central nervous system relies on complex mechanisms in which the mitochondria are crucial actors because of their involvement in a multitude of bioenergetics and biosynthetic pathways. Mitochondrial diseases are among the most prevalent groups of inherited neurological disorders, affecting up to 1 in 5000 adults and despite considerable efforts around the world there is still limited curative treatments. Harlequin mice correspond to a relevant model of recessive X-linked mitochondrial disease due to a proviral insertion in the first intron of the Apoptosis-inducing factor gene, resulting in an almost complete depletion of the corresponding protein. These mice exhibit progressive degeneration of the retina, optic nerve, cerebellum, and cortical regions leading to irremediable blindness and ataxia, reminiscent of what is observed in patients suffering from mitochondrial diseases. We evaluated the progression of cerebellar degeneration in Harlequin mice, especially for Purkinje cells and its relationship with bioenergetics failure and behavioral damage. For the first time to our knowledge, we demonstrated that Harlequin mice display cognitive and emotional impairments at early stage of the disease with further deteriorations as ataxia aggravates. These functions, corresponding to higher-order cognitive processing, have been assigned to a complex network of reciprocal connections between the cerebellum and many cortical areas which could be dysfunctional in these mice. Consequently, Harlequin mice become a suitable experimental model to test innovative therapeutics, via the targeting of mitochondria which can become available to a large spectrum of neurological diseases.
    Keywords:  Cerebellar ataxia; Cognitive impairment; Harlequin mice; Mitochondria; Purkinje cells
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167272
  8. FEBS Open Bio. 2024 Jun 12.
    Oxidative protein folding in the intermembrane space of human mitochondria.
    Christine Zarges, Jan Riemer.
      The mitochondrial intermembrane space hosts a machinery for oxidative protein folding, the mitochondrial disulfide relay. This machinery imports a large number of soluble proteins into the compartment, where they are retained through oxidative folding. Additionally, the disulfide relay enhances the stability of many proteins by forming disulfide bonds. In this review, we describe the mitochondrial disulfide relay in human cells, its components, and their coordinated collaboration in mechanistic detail. We also discuss the human pathologies associated with defects in this machinery and its protein substrates, providing a comprehensive overview of its biological importance and implications for health.
    Keywords:  ALR; IMS; MIA40; mitochondria; oxidative protein folding; protein import
    DOI:  https://doi.org/10.1002/2211-5463.13839
  9. Proc Natl Acad Sci U S A. 2024 Jul 02. 121(27): e2317673121
    Psychosocial experiences are associated with human brain mitochondrial biology.
    Caroline Trumpff, Anna S Monzel, Carmen Sandi, Vilas Menon, Hans-Ulrich Klein, Masashi Fujita, Annie Lee, Vladislav A Petyuk, Cheyenne Hurst, Duc M Duong, Nicholas T Seyfried, Aliza P Wingo, Thomas S Wingo, Yanling Wang, Madhav Thambisetty, Luigi Ferrucci, David A Bennett, Philip L De Jager, Martin Picard.
      Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes.
    Keywords:  mitochondria; proteome; psychosocial factors; single cell RNA-seq; transcriptome
    DOI:  https://doi.org/10.1073/pnas.2317673121
  10. Elife. 2024 Jun 20. pii: RP87518. [Epub ahead of print]12
    Metabolic regulation of misfolded protein import into mitochondria.
    Yuhao Wang, Linhao Ruan, Jin Zhu, Xi Zhang, Alexander Chih-Chieh Chang, Alexis Tomaszewski, Rong Li.
      Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
    Keywords:  AMPK; MAGIC; S. cerevisiae; cell biology; human; metabolism; misfolded protein; mitochondria; protein import; proteostasis
    DOI:  https://doi.org/10.7554/eLife.87518
  11. FASEB J. 2024 Jun 30. 38(12): e23742
    Multiomics analysis reveals serine catabolism as a potential therapeutic target for MELAS.
    Tongling Liufu, Xutong Zhao, Meng Yu, Zhiying Xie, Lingchao Meng, He Lv, Wei Zhang, Yun Yuan, Guogang Xing, Jianwen Deng, Zhaoxia Wang.
      Mitochondrial disease is a devastating genetic disorder, with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and m.3243A>G being the most common phenotype and genotype, respectively. The treatment for MELAS patients is still less effective. Here, we performed transcriptomic and proteomic analysis in muscle tissue of MELAS patients, and discovered that the expression of molecules involved in serine catabolism were significantly upregulated, and serine hydroxymethyltransferase 2 (SHMT2) increased significantly in both the mRNA and protein levels. The SHMT2 protein level was also increased in myoblasts with m.3243A>G mutation, which was transdifferentiated from patients derived fibroblasts, accompanying with the decreased nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) ratio and cell viability. After treating with SHMT2 inhibitor (SHIN1), the NAD+/NADH ratio and cell viability in MELAS myoblasts increased significantly. Taken together, our study indicates that enhanced serine catabolism plays an important role in the pathogenesis of MELAS and that SHIN1 can be a potential small molecule for the treatment of this disease.
    Keywords:  M.3243 A>G; MELAS; NADH; SHIN1; SHMT2; multiomics
    DOI:  https://doi.org/10.1096/fj.202302286RRR
  12. Sci Rep. 2024 Jun 21. 14(1): 14332
    Progressive degeneration in a new Drosophila model of spinocerebellar ataxia type 7.
    Alyson Sujkowski, Bedri Ranxhi, Zoya R Bangash, Zachary M Chbihi, Matthew V Prifti, Zaina Qadri, Nadir Alam, Sokol V Todi, Wei-Ling Tsou.
      Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder resulting from abnormal expansion of an uninterrupted polyglutamine (polyQ) repeat in its disease protein, ataxin-7 (ATXN7). ATXN7 is part of Spt-Ada-Gcn5 acetyltransferase (SAGA), an evolutionarily conserved transcriptional coactivation complex with critical roles in chromatin remodeling, cell signaling, neurodifferentiation, mitochondrial health and autophagy. SCA7 is dominantly inherited and characterized by genetic anticipation and high repeat-length instability. Patients with SCA7 experience progressive ataxia, atrophy, spasticity, and blindness. There is currently no cure for SCA7, and therapies are aimed at alleviating symptoms to increase quality of life. Here, we report novel Drosophila lines of SCA7 with polyQ repeats in wild-type and human disease patient range. We find that ATXN7 expression has age- and polyQ repeat length-dependent reduction in fruit fly survival and retinal instability, concomitant with increased ATXN7 protein aggregation. These new lines will provide important insight on disease progression that can be used in the future to identify therapeutic targets for SCA7 patients.
    Keywords:  Aggregation; Polyglutamine; Proteinopathy; Retinal degeneration
    DOI:  https://doi.org/10.1038/s41598-024-65172-4
  13. FEBS Lett. 2024 Jun 17.
    Liver gene transfer for metabolite detoxification in inherited metabolic diseases.
    Alfonso M D'Alessio, Iolanda Boffa, Lucia De Stefano, Leandro R Soria, Nicola Brunetti-Pierri.
      Inherited metabolic disorders (IMDs) are a growing group of genetic diseases caused by defects in enzymes that mediate cellular metabolism, often resulting in the accumulation of toxic substrates. The liver is a highly metabolically active organ that hosts several thousands of chemical reactions. As such, it is an organ frequently affected in IMDs. In this article, we review current approaches for liver-directed gene-based therapy aimed at metabolite detoxification in a variety of IMDs. Moreover, we discuss current unresolved challenges in gene-based therapies for IMDs.
    Keywords:  AAV; gene therapy; inherited metabolic disorders; lipid nanoparticles; liver; metabolite detoxification
    DOI:  https://doi.org/10.1002/1873-3468.14957
  14. Front Cell Dev Biol. 2024 ;12 1405393
    Mitochondrial unfolded protein response (UPRmt): what we know thus far.
    Angie K Torres, Veronika Fleischhart, Nibaldo C Inestrosa.
      Mitochondria are key organelles for the optimal function of the cell. Among their many functions, they maintain protein homeostasis through their own proteostatic machinery, which involves proteases and chaperones that regulate protein import and folding inside mitochondria. In the early 2000s, the mitochondrial unfolded protein response (UPRmt) was first described in mammalian cells. This stress response is activated by the accumulation of unfolded/misfolded proteins within the mitochondrial matrix, which results in the transmission of a signal to the nucleus to increase the expression of proteases and chaperones to address the abnormal mitochondrial protein load. After its discovery, this retrograde signaling pathway has also been described in other organisms of different complexities, suggesting that it is a conserved stress response. Although there are some specific differences among organisms, the mechanism of this stress response is mostly similar and involves the transmission of a signal from mitochondria to the nucleus that induces chromatin remodeling to allow the binding of specific transcription factors to the promoters of chaperones and proteases. In the last decade, proteins and signaling pathways that could be involved in the regulation of the UPRmt, including the Wnt signaling pathway, have been described. This minireview aims to summarize what is known about the mechanism of the UPRmt and its regulation, specifically in mammals and C. elegans.
    Keywords:  Caenorhabditis elegans; UPRmt; misfolded protein; mitochondria; stress; wnt signaling
    DOI:  https://doi.org/10.3389/fcell.2024.1405393
  15. Int J Mol Sci. 2024 May 26. pii: 5796. [Epub ahead of print]25(11):
    An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich's Ataxia.
    Loiane Mendonça Abrantes Da Conceição, Lucio Mendes Cabral, Gabriel Rodrigues Coutinho Pereira, Joelma Freire De Mesquita.
      Friedreich's Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys®), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.
    Keywords:  Friedreich’s ataxia; frataxin; in silico analysis
    DOI:  https://doi.org/10.3390/ijms25115796
  16. Nat Commun. 2024 Jun 18. 15(1): 5210
    A single-cell atlas of pig gastrulation as a resource for comparative embryology.
    Luke Simpson, Andrew Strange, Doris Klisch, Sophie Kraunsoe, Takuya Azami, Daniel Goszczynski, Triet Le Minh, Benjamin Planells, Nadine Holmes, Fei Sang, Sonal Henson, Matthew Loose, Jennifer Nichols, Ramiro Alberio.
      Cell-fate decisions during mammalian gastrulation are poorly understood outside of rodent embryos. The embryonic disc of pig embryos mirrors humans, making them a useful proxy for studying gastrulation. Here we present a single-cell transcriptomic atlas of pig gastrulation, revealing cell-fate emergence dynamics, as well as conserved and divergent gene programs governing early porcine, primate, and murine development. We highlight heterochronicity in extraembryonic cell-types, despite the broad conservation of cell-type-specific transcriptional programs. We apply these findings in combination with functional investigations, to outline conserved spatial, molecular, and temporal events during definitive endoderm specification. We find early FOXA2 + /TBXT- embryonic disc cells directly form definitive endoderm, contrasting later-emerging FOXA2/TBXT+ node/notochord progenitors. Unlike mesoderm, none of these progenitors undergo epithelial-to-mesenchymal transition. Endoderm/Node fate hinges on balanced WNT and hypoblast-derived NODAL, which is extinguished upon endodermal differentiation. These findings emphasise the interplay between temporal and topological signalling in fate determination during gastrulation.
    DOI:  https://doi.org/10.1038/s41467-024-49407-6
  17. Int J Mol Sci. 2024 May 31. pii: 6056. [Epub ahead of print]25(11):
    An Amino Acid Mixture to Counteract Skeletal Muscle Atrophy: Impact on Mitochondrial Bioenergetics.
    Francesco Bellanti, Aurelio Lo Buglio, Giuseppe Pannone, Maria Carmela Pedicillo, Ilenia Sara De Stefano, Angela Pignataro, Cristiano Capurso, Gianluigi Vendemiale.
      Skeletal muscle atrophy (SMA) is caused by a rise in muscle breakdown and a decline in protein synthesis, with a consequent loss of mass and function. This study characterized the effect of an amino acid mixture (AA) in models of SMA, focusing on mitochondria. C57/Bl6 mice underwent immobilization of one hindlimb (I) or cardiotoxin-induced muscle injury (C) and were compared with controls (CTRL). Mice were then administered AA in drinking water for 10 days and compared to a placebo group. With respect to CTRL, I and C reduced running time and distance, along with grip strength; however, the reduction was prevented by AA. Tibialis anterior (TA) muscles were used for histology and mitochondria isolation. I and C resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio and smaller myofibers than those of CTRL. Interestingly, these alterations were lightly observed in mice treated with AA. The mitochondrial yield from the TA of I and C mice was lower than that of CTRL but not in AA-treated mice. AA also preserved mitochondrial bioenergetics in TA muscle from I and C mice. To conclude, this study demonstrates that AA prevents loss of muscle mass and function in SMA by protecting mitochondria.
    Keywords:  amino acids; cardiotoxin; immobilization; sarcopenia
    DOI:  https://doi.org/10.3390/ijms25116056
  18. Cell Rep Med. 2024 Jun 11. pii: S2666-3791(24)00323-9. [Epub ahead of print] 101619
    Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases.
    Federica Esposito, Fabio Dell'Aquila, Manuel Rhiel, Stefano Auricchio, Kay Ole Chmielewski, Geoffroy Andrieux, Rita Ferla, Paula Sureda Horrach, Arjun Padmanabhan, Roberto Di Cunto, Simone Notaro, Manel Llado Santeularia, Melanie Boerries, Margherita Dell'Anno, Edoardo Nusco, Agnese Padula, Sofia Nutarelli, Tatjana I Cornu, Nicolina Cristina Sorrentino, Pasquale Piccolo, Ivana Trapani, Toni Cathomen, Alberto Auricchio.
      Liver-directed adeno-associated viral (AAV) vector-mediated homology-independent targeted integration (AAV-HITI) by CRISPR-Cas9 at the highly transcribed albumin locus is under investigation to provide sustained transgene expression following neonatal treatment. We show that targeting the 3' end of the albumin locus results in productive integration in about 15% of mouse hepatocytes achieving therapeutic levels of systemic proteins in two mouse models of inherited diseases. We demonstrate that full-length HITI donor DNA is preferentially integrated upon nuclease cleavage and that, despite partial AAV genome integrations in the target locus, no gross chromosomal rearrangements or insertions/deletions at off-target sites are found. In line with this, no evidence of hepatocellular carcinoma is observed within the 1-year follow-up. Finally, AAV-HITI is effective at vector doses considered safe if directly translated to humans providing therapeutic efficacy in the adult liver in addition to newborn. Overall, our data support the development of this liver-directed AAV-based knockin strategy.
    Keywords:  AAV; CAST-Seq; CRISPR-Cas9; HITI; genome editing; hemophilia A; homology-independent targeted integration; inherited diseases; in vivo; liver; mucopolysaccharidosis type VI; persistent transgene expression
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101619
  19. Cell Rep. 2024 Jun 19. pii: S2211-1247(24)00702-2. [Epub ahead of print]43(7): 114374
    Spatial proteomics of skeletal muscle using thin cryosections reveals metabolic adaptation at the muscle-tendon transition zone.
    Luisa Schmidt, Michael Saynisch, Christian Hoegsbjerg, Andreas Schmidt, Abigail Mackey, Jan-Wilm Lackmann, Stefan Müller, Manuel Koch, Bent Brachvogel, Michael Kjaer, Philipp Antczak, Marcus Krüger.
      Morphological studies of skeletal muscle tissue provide insights into the architecture of muscle fibers, the surrounding cells, and the extracellular matrix (ECM). However, a spatial proteomics analysis of the skeletal muscle including the muscle-tendon transition zone is lacking. Here, we prepare cryotome muscle sections of the mouse soleus muscle and measure each slice using short liquid chromatography-mass spectrometry (LC-MS) gradients. We generate 3,000 high-resolution protein profiles that serve as the basis for a network analysis to reveal the complex architecture of the muscle-tendon junction. Among the protein profiles that increase from muscle to tendon, we find proteins related to neuronal activity, fatty acid biosynthesis, and the renin-angiotensin system (RAS). Blocking the RAS in cultured mouse tenocytes using losartan reduces the ECM synthesis. Overall, our analysis of thin cryotome sections provides a spatial proteome of skeletal muscle and reveals that the RAS acts as an additional regulator of the matrix within muscle-tendon junctions.
    Keywords:  CP: Metabolism; distance-based network; myotendinous junction; skeletal muscle; spatial proteomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114374
  20. Cell Res. 2024 Jun 19.
    AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.
    Mengqi Li, Yu Wang, Xiaoyan Wei, Wei-Feng Cai, Jianfeng Wu, Mingxia Zhu, Yongliang Wang, Yan-Hui Liu, Jinye Xiong, Qi Qu, Yan Chen, Xiao Tian, Luming Yao, Renxiang Xie, Xiaomin Li, Siwei Chen, Xi Huang, Cixiong Zhang, Changchuan Xie, Yaying Wu, Zheni Xu, Baoding Zhang, Bin Jiang, Zhi-Chao Wang, Qinxi Li, Gang Li, Shu-Yong Lin, Li Yu, Hai-Long Piao, Xianming Deng, Jiahuai Han, Chen-Song Zhang, Sheng-Cai Lin.
      The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.
    DOI:  https://doi.org/10.1038/s41422-024-00985-6
  21. 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
  22. Cardiovasc Drugs Ther. 2024 Jun 15.
    A Mitochondrial Basis for Heart Failure Progression.
    William D Watson, Per M Arvidsson, Jack J J Miller, Andrew J Lewis, Oliver J Rider.
      In health, the human heart is able to match ATP supply and demand perfectly. It requires 6 kg of ATP per day to satisfy demands of external work (mechanical force generation) and internal work (ion movements and basal metabolism). The heart is able to link supply with demand via direct responses to ADP and AMP concentrations but calcium concentrations within myocytes play a key role, signalling both inotropy, chronotropy and matched increases in ATP production. Calcium/calmodulin-dependent protein kinase (CaMKII) is a key adapter to increased workload, facilitating a greater and more rapid calcium concentration change. In the failing heart, this is dysfunctional and ATP supply is impaired. This review aims to examine the mechanisms and pathologies that link increased energy demand to this disrupted situation. We examine the roles of calcium loading, oxidative stress, mitochondrial structural abnormalities and damage-associated molecular patterns.
    Keywords:  ATP; Calcium; Heart failure; Mitochondria; Redox
    DOI:  https://doi.org/10.1007/s10557-024-07582-0
  23. Int J Mol Sci. 2024 May 28. pii: 5855. [Epub ahead of print]25(11):
    Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review.
    Antonio da Silva Menezes Junior, Ana Luísa Guedes de França-E-Silva, Henrique Lima de Oliveira, Khissya Beatryz Alves de Lima, Iane de Oliveira Pires Porto, Thays Millena Alves Pedroso, Daniela de Melo E Silva, Aguinaldo F Freitas.
      Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities.
    Keywords:  hypertrophic cardiomyopathy; metabolism; mitochondrial dysfunction; mitochondrial redox signaling
    DOI:  https://doi.org/10.3390/ijms25115855
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