bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023‒04‒16
29 papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Phenotyping mtDNA-related diseases in childhood: a cohort study of 150 patients.
  2. Mitochondrial Inheritance Following Nuclear Transfer: From Cloned Animals to Patients with Mitochondrial Disease.
  3. Mitochondrial Signaling Pathways Associated with DNA Damage Responses.
  4. Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes.
  5. An intermembrane space protein facilitates completion of mitochondrial division in yeast.
  6. The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases.
  7. Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model.
  8. Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease.
  9. Structural mechanisms of mitochondrial quality control mediated by PINK1 and parkin.
  10. FDXR-associated disease: a challenging differential diagnosis with inflammatory peripheral neuropathy.
  11. Tom40 in cholesterol transport.
  12. PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence.
  13. Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1.
  14. Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
  15. The Beneficial Effect of Mitochondrial Transfer Therapy in 5XFAD Mice via Liver-Serum-Brain Response.
  16. High-Throughput Microscopy Analysis of Mitochondrial Membrane Potential in 2D and 3D Models.
  17. Metabolic regulation of misfolded protein import into mitochondria.
  18. Differentiation-inducing factor 1 activates cofilin through pyridoxal phosphatase and AMP-activated protein kinase, resulting in mitochondrial fission.
  19. Mitochondrion: A bridge linking aging and degenerative diseases.
  20. Assisted reproductive technologies at the nexus of fertility treatment and disease prevention.
  21. Inflammation, Mitochondria and Natural Compounds Together in the Circle of Trust.
  22. Tau Transfer via Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System.
  23. Diagnosing mitochondrial, neurogastrointestinal leukoencephalopathy requires mutations in TYMP1, POLG1, LIG1, or RRM2B.
  24. Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing.
  25. Barriers to progress in pregnancy research: How can we break through?
  26. Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS.
  27. Kids and clinical trials: why the system is failing children.
  28. Mitochondrial nanomotion measured by optical microscopy.
  29. Ageing studies in five animals suggest how to reverse decline.
  1. Eur J Neurol. 2023 Apr 10.
    Phenotyping mtDNA-related diseases in childhood: a cohort study of 150 patients.
    Anna Ardissone, Giulia Ferrera, Costanza Lamperti, Valeria Tiranti, Daniele Ghezzi, Isabella Moroni, Eleonora Lamantea.
      BACKGROUND: Mitochondrial diseases (MDs) are heterogeneous disorders caused by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) associated with specific syndromes. However, especially in childhood, patients often display heterogeneity. Several reports about the biochemical and molecular profiles in children have been published, but studies tend to not differentiate between mtDNA and nDNA associated diseases and focus is often on a specific phenotype. Thus, large cohort studies specifically focusing on mtDNA defects in the pediatric population are lacking.METHODS: We reviewed the clinical, metabolic, biochemical, and neuroimaging data of 150 patients with MDs due to mtDNA alterations collected at our Neurological Institute over the past 20 years.
    RESULTS: MtDNA impairment is less frequent than nDNA in pediatric MDs. Ocular involvement is extremely frequent in our cohort, as is classical Leber Hereditary Optic Neuropathy, especially with onset before 12 years of age. Extra neurological manifestations and isolated myopathy appear to be rare, unlike adult phenotypes. Deep gray matter involvement, early disease onset and specific phenotypes, such as Pearson syndrome and Leigh syndrome, represent unfavorable prognostic factors. Phenotypes related to single large scale mtDNA deletions appear to be very frequent in the pediatric population. Furthermore, we report for the first time a mtDNA pathogenic variant associated with cavitating leukodystrophy.
    CONCLUSIONS: We report on a large cohort of pediatric patients with mtDNA defects, adding new data on the phenotypical characterization of mtDNA defects and possible suggestions for the diagnostic workup and therapeutic approach.
    Keywords:  mitochondrial DNA; mitochondrial disorder; pediatric; phenotypes
    DOI:  https://doi.org/10.1111/ene.15814
  2. Methods Mol Biol. 2023 ;2647 83-104
    Mitochondrial Inheritance Following Nuclear Transfer: From Cloned Animals to Patients with Mitochondrial Disease.
    Jörg P Burgstaller, Marcos R Chiaratti.
      Mitochondria are indispensable power plants of eukaryotic cells that also act as a major biochemical hub. As such, mitochondrial dysfunction, which can originate from mutations in the mitochondrial genome (mtDNA), may impair organism fitness and lead to severe diseases in humans. MtDNA is a multi-copy, highly polymorphic genome that is uniparentally transmitted through the maternal line. Several mechanisms act in the germline to counteract heteroplasmy (i.e., coexistence of two or more mtDNA variants) and prevent expansion of mtDNA mutations. However, reproductive biotechnologies such as cloning by nuclear transfer can disrupt mtDNA inheritance, resulting in new genetic combinations that may be unstable and have physiological consequences. Here, we review the current understanding of mitochondrial inheritance, with emphasis on its pattern in animals and human embryos generated by nuclear transfer.
    Keywords:  Cloning; Embryo; Heteroplasmy; MRT; Mitochondria; Nuclear transplantation; Oocyte; SCNT; mtDNA
    DOI:  https://doi.org/10.1007/978-1-0716-3064-8_4
  3. Int J Mol Sci. 2023 Mar 24. pii: 6128. [Epub ahead of print]24(7):
    Mitochondrial Signaling Pathways Associated with DNA Damage Responses.
    Tsutomu Shimura.
      Under physiological and stress conditions, mitochondria act as a signaling platform to initiate biological events, establishing communication from the mitochondria to the rest of the cell. Mitochondrial adenosine triphosphate (ATP), reactive oxygen species, cytochrome C, and damage-associated molecular patterns act as messengers in metabolism, oxidative stress response, bystander response, apoptosis, cellular senescence, and inflammation response. In this review paper, the mitochondrial signaling in response to DNA damage was summarized. Mitochondrial clearance via fusion, fission, and mitophagy regulates mitochondrial quality control under oxidative stress conditions. On the other hand, damaged mitochondria release their contents into the cytoplasm and then mediate various signaling pathways. The role of mitochondrial dysfunction in radiation carcinogenesis was discussed, and the recent findings on radiation-induced mitochondrial signaling and radioprotective agents that targeted mitochondria were presented. The analysis of the mitochondrial radiation effect, as hypothesized, is critical in assessing radiation risks to human health.
    Keywords:  DNA damage response; inflammation response; mitochondrial signaling; oxidative stress; radiation carcinogenesis
    DOI:  https://doi.org/10.3390/ijms24076128
  4. J Physiol. 2023 Apr 12.
    Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes.
    Javier Botella, Camilla T Schytz, Thomas F Pehrson, Rune Hokken, Simon Laugesen, Per Aagaard, Charlotte Suetta, Britt Christensen, Niels Ørtenblad, Joachim Nielsen.
      Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength-trained individuals and any potential pathways regulating the strength-specific mitochondrial remodelling. Here, we investigated the mitochondrial structural characteristics in skeletal muscle of strength athletes and age-matched untrained controls. The mitochondrial pool in strength athletes was characterised by increased mitochondrial cristae density, decreased mitochondrial size, and increased surface-to-volume ratio, despite similar mitochondrial volume density. We also provide a fibre-type and compartment specific assessment of mitochondria morphology in human skeletal muscle, which reveals across groups a compartment-specific influence on mitochondrial morphology that is largely independent of fibre-type. Furthermore, we show that resistance exercise leads to signs of mild mitochondrial stress, without an increase in the number of damaged mitochondria. Using publicly available transcriptomic data we show that acute resistance exercise increases the expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein responses (UPRmt ). Further, we observed an enrichment of the UPRmt in the basal transcriptome of strength-trained individuals. Together, these findings show that strength athletes possess a unique mitochondrial remodelling, which minimises the space required for mitochondria. We propose that the concurrent activation of markers of mitochondrial biogenesis and mitochondrial remodelling pathways (fission and UPRmt ) with resistance exercise may be partially responsible for the observed mitochondrial phenotype of strength athletes. KEY POINTS: Untrained individuals and strength athletes possess comparable skeletal muscle mitochondrial volume density. In contrast, strength athletes'mitochondria are characterised by increased cristae density, decreased size, and increased surface-to-volume ratio. Type I fibres have an increased number of mitochondrial profiles with minor differences in the mitochondrial morphological characteristics compared to type II fibres. The mitochondrial morphology is distinct across the subcellular compartments in both groups, with subsarcolemmal mitochondria being bigger in size when compared to intermyofibrillar. Acute resistance exercise leads to signs of mild morphological mitochondrial stress accompanied by increased gene expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein response (UPRmt). Abstract figure legend: Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. The present study aimed to investigate the mitochondrial structural characteristics of strength athletes when compared to age-matched untrained individuals. Here we show that the mitochondria of strength athletes have an increased mitochondrial cristae density, increased number of profiles, and an increased surface-to-volume ratio; despite similar mitochondrial volumetric density. Furthermore, we show that human type I fibres, when compared to type II fibres, are characterised by an increased number of mitochondrial profiles without differences in their morphological characteristics. Finally, we show that acute resistance exercise leads to mild signs of mitochondrial morphological stress and an increased expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein response (UPRmt ). This article is protected by copyright. All rights reserved.
    Keywords:  Mitochondria; Olympic weightlifting; cristae density; resistance exercise; skeletal muscle; strength
    DOI:  https://doi.org/10.1113/JP284394
  5. bioRxiv. 2023 Mar 31. pii: 2023.03.31.535139. [Epub ahead of print]
    An intermembrane space protein facilitates completion of mitochondrial division in yeast.
    Olivia M Connor, Srujan K Matta, Jonathan R Friedman.
      Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by the dynamin-related protein Dnm1 (Drp1 in humans), a large GTPase that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity alone is sufficient to complete fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1. Loss of Mdi1 leads to hyper-fused mitochondria networks due to defects in mitochondrial fission, but not lack of Dnm1 recruitment to mitochondria. Mdi1 plays a conserved role in fungal species and its homologs contain a putative amphipathic α-helix, mutations in which disrupt mitochondrial morphology. One model to explain these findings is that Mdi1 associates with and distorts the mitochondrial inner membrane to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of a protein that resides inside mitochondria.
    DOI:  https://doi.org/10.1101/2023.03.31.535139
  6. Int J Mol Sci. 2023 Mar 27. pii: 6268. [Epub ahead of print]24(7):
    The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases.
    Adeena Shafique, Martina Brughera, Marta Lualdi, Tiziana Alberio.
      Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause-effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration.
    Keywords:  Ras analog in brain (Rab); mitophagy; neurodegeneration; vesicular trafficking
    DOI:  https://doi.org/10.3390/ijms24076268
  7. Front Neurosci. 2023 ;17 1119724
    Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model.
    Sindhu Velmurugan, Tsung-Han Chou, Jeremy D Eastwood, Vittorio Porciatti, Yuan Liu, William W Hauswirth, John Guy, Hong Yu.
      Introduction: Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON.Methods: A LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (hND4/m.11778G>A) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease. We then attempted to rescue those mice using a second intravitreal injection of either mitochondrial-targeted or allotopic expressed wildtype human ND4. The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy.
    Results: Compared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months. However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (p = 0.0128). Post-mortem analysis showed that mitochondrial-targeted human ND4 better preserved small axons that are preferentially lost in human LHON.
    Conclusions: These results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype.
    Keywords:  Leber hereditary optic neuropathy (LHON); allotopic expression; gene therapy; mitochondrial-targeted; mitochondrial-targeted therapy
    DOI:  https://doi.org/10.3389/fnins.2023.1119724
  8. Neurol Genet. 2023 Jun;9(3): e200068
    Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease.
    Birute Burnyte, Ramune Vilimiene, Kristina Grigalioniene, Irina Adomaitiene, Algirdas Utkus.
      Objectives: To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia.Methods: We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause.
    Results: Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) in PNPLA8. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function.
    Discussion: Our findings support the theory that biallelic loss-of-function PNPLA8 variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood.
    DOI:  https://doi.org/10.1212/NXG.0000000000200068
  9. J Mol Biol. 2023 Apr 11. pii: S0022-2836(23)00152-3. [Epub ahead of print] 168090
    Structural mechanisms of mitochondrial quality control mediated by PINK1 and parkin.
    Jean-François Trempe, Kalle Gehring.
      Parkinson's disease (PD) is the second most common neurodegenerative disease and represents a looming public health crisis as the global population ages. While the etiology of the more common, idiopathic form of the disease remains unknown, the last ten years have seen a breakthrough in our understanding of the genetic forms related to two proteins that regulate a quality control system for the removal of damaged or non-functional mitochondria. Here, we review the structure of these proteins, PINK1, a protein kinase, and parkin, a ubiquitin ligase with an emphasis on the molecular mechanisms responsible for their recognition of dysfunctional mitochondria and control of the subsequent ubiquitination cascade. Recent atomic structures have revealed the basis of PINK1 substrate specificity and the conformational changes responsible for activation of PINK1 and parkin catalytic activity. Progress in understanding the molecular basis of mitochondrial quality control promises to open new avenues for therapeutic interventions in PD.
    DOI:  https://doi.org/10.1016/j.jmb.2023.168090
  10. Neurol Sci. 2023 Apr 12.
    FDXR-associated disease: a challenging differential diagnosis with inflammatory peripheral neuropathy.
    Silvia Masnada, Roberto Previtali, Paola Erba, Elena Beretta, Anna Camporesi, Luisa Chiapparini, Chiara Doneda, Maria Iascone, Marco U A Sartorio, Luigina Spaccini, Pierangelo Veggiotti, Maurizio Osio, Davide Tonduti, Isabella Moroni.
      BACKGROUND AND AIMS: Mutations in FDXR gene, involved in mitochondrial pathway, cause a rare recessive neurological disorder with variable severity of phenotypes. The most common presentation includes optic and/or auditory neuropathy, variably associated to developmental delay or regression, global hypotonia, pyramidal, cerebellar signs, and seizures. The review of clinical findings in previously described cases from literature reveals also a significant incidence of sensorimotor peripheral polyneuropathy (22.72%) and ataxia (43.18%). To date, 44 patients with FDXR mutations have been reported. We describe here on two new patients, siblings, who presented with a quite different phenotype compared to previously described patients.METHODS: Clinical, neurophysiological, and genetic features of two siblings and a systematic literature review focused on the clinical spectrum of the disease are described.
    RESULTS: Both patients presented with an acute-sub-acute onset of peripheral neuropathy and only in later stages of the disease developed the typical features of FDXR-associated disease.
    INTERPRETATION: The peculiar clinical presentation at onset and the evolution of the disease in our patients and in some cases revised from the literature shed lights on a new possible phenotype of FDXR-associated disease: a peripheral neuropathy which can mimic an acute inflammatory disease.
    Keywords:  FDXR; Peripheral neuropathy; Phenotype
    DOI:  https://doi.org/10.1007/s10072-023-06790-0
  11. iScience. 2023 Apr 21. 26(4): 106386
    Tom40 in cholesterol transport.
    Himangshu S Bose, Mahuya Bose, Randy M Whittal.
      Cholesterol initiates steroid metabolism in adrenal and gonadal mitochondria, which is essential for all mammalian survival. During stress an increased cholesterol transport rapidly increases steroidogenesis; however, the mechanism of mitochondrial cholesterol transport is unknown. Using rat testicular tissue and mouse Leydig (MA-10) cells, we report for the first time that mitochondrial translocase of outer mitochondrial membrane (OMM), Tom40, is central in cholesterol transport. Cytoplasmic cholesterol-lipids complex containing StAR protein move from the mitochondria-associated ER membrane (MAM) to the OMM, increasing cholesterol load. Tom40 interacts with StAR at the OMM increasing cholesterol transport into mitochondria. An absence of Tom40 disassembles complex formation and inhibits mitochondrial cholesterol transport and steroidogenesis. Therefore, Tom40 is essential for rapid mitochondrial cholesterol transport to initiate, maintain, and regulate activity.
    Keywords:  Biomolecules; Cell biology; Protein folding
    DOI:  https://doi.org/10.1016/j.isci.2023.106386
  12. Elife. 2023 Apr 13. pii: e81717. [Epub ahead of print]12
    PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence.
    Michael Xiao, Chia-Hua Wu, Graham Meek, Brian Kelly, Dara Buendia Castillo, Lyndsay E A Young, Sara Martire, Sajina Dhungel, Elizabeth McCauley, Purbita Saha, Altair L Dube, Matthew S Gentry, Laura A Banaszynski, Ramon C Sun, Chintan K Kikani.
      Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mitochondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PASK, resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity, and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK.
    Keywords:  cell biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.81717
  13. Front Cell Dev Biol. 2023 ;11 1072315
    Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1.
    César Vásquez-Trincado, Mario Navarro-Márquez, Pablo E Morales, Francisco Westermeier, Mario Chiong, Valentina Parra, Alejandra Espinosa, Sergio Lavandero.
      Introduction: Cardiovascular diseases, especially metabolic-related disorders, are progressively growing worldwide due to high-fat-containing foods, which promote a deleterious response at the cellular level, termed lipotoxicity, or lipotoxic stress. At the cardiac level, saturated fatty acids have been directly associated with cardiomyocyte lipotoxicity through various pathological mechanisms involving mitochondrial dysfunction, oxidative stress, and ceramide production, among others. However, integrative regulators connecting saturated fatty acid-derived lipotoxic stress to mitochondrial and cardiomyocyte dysfunction remain elusive. Methods: Here, we worked with a cardiomyocyte lipotoxicity model, which uses the saturated fatty acid myristate, which promotes cardiomyocyte hypertrophy and insulin desensitization. Results: Using this model, we detected an increase in the mitochondrial E3 ubiquitin ligase, MUL1, a mitochondrial protein involved in the regulation of growth factor signaling, cell death, and, notably, mitochondrial dynamics. In this context, myristate increased MUL1 levels and induced mitochondrial fragmentation, associated with the decrease of the mitochondrial fusion protein MFN2, and with the increase of the mitochondrial fission protein DRP1, two targets of MUL1. Silencing of MUL1 prevented myristate-induced mitochondrial fragmentation and cardiomyocyte hypertrophy. Discussion: These data establish a novel connection between cardiomyocytes and lipotoxic stress, characterized by hypertrophy and fragmentation of the mitochondrial network, and an increase of the mitochondrial E3 ubiquitin ligase MUL1.
    Keywords:  MAPL; MUL1; heart; hypertrophy; insulin-desensitization; lipotoxicity; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2023.1072315
  14. Sci Adv. 2023 Apr 14. 9(15): eadf1956
    Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
    Kazuya Nishio, Tomoyuki Kawarasaki, Yuki Sugiura, Shunsuke Matsumoto, Ayano Konoshima, Yuki Takano, Mayuko Hayashi, Fumihiko Okumura, Takumi Kamura, Tsunehiro Mizushima, Kunio Nakatsukasa.
      Deficiencies in mitochondrial protein import are associated with a number of diseases. However, although nonimported mitochondrial proteins are at great risk of aggregation, it remains largely unclear how their accumulation causes cell dysfunction. Here, we show that nonimported citrate synthase is targeted for proteasomal degradation by the ubiquitin ligase SCFUcc1. Unexpectedly, our structural and genetic analyses revealed that nonimported citrate synthase appears to form an enzymatically active conformation in the cytosol. Its excess accumulation caused ectopic citrate synthesis, which, in turn, led to an imbalance in carbon flux of sugar, a reduction of the pool of amino acids and nucleotides, and a growth defect. Under these conditions, translation repression is induced and acts as a protective mechanism that mitigates the growth defect. We propose that the consequence of mitochondrial import failure is not limited to proteotoxic insults, but that the accumulation of a nonimported metabolic enzyme elicits ectopic metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.adf1956
  15. Cells. 2023 Mar 24. pii: 1006. [Epub ahead of print]12(7):
    The Beneficial Effect of Mitochondrial Transfer Therapy in 5XFAD Mice via Liver-Serum-Brain Response.
    Sahar Sweetat, Keren Nitzan, Nir Suissa, Yael Haimovich, Michal Lichtenstein, Samar Zabit, Sandrine Benhamron, Karameh Akarieh, Kumudesh Mishra, Dinorah Barasch, Ann Saada, Tamar Ziv, Or Kakhlon, Haya Lorberboum-Galski, Hanna Rosenmann.
      We recently reported the benefit of the IV transferring of active exogenous mitochondria in a short-term pharmacological AD (Alzheimer's disease) model. We have now explored the efficacy of mitochondrial transfer in 5XFAD transgenic mice, aiming to explore the underlying mechanism by which the IV-injected mitochondria affect the diseased brain. Mitochondrial transfer in 5XFAD ameliorated cognitive impairment, amyloid burden, and mitochondrial dysfunction. Exogenously injected mitochondria were detected in the liver but not in the brain. We detected alterations in brain proteome, implicating synapse-related processes, ubiquitination/proteasome-related processes, phagocytosis, and mitochondria-related factors, which may lead to the amelioration of disease. These changes were accompanied by proteome/metabolome alterations in the liver, including pathways of glucose, glutathione, amino acids, biogenic amines, and sphingolipids. Altered liver metabolites were also detected in the serum of the treated mice, particularly metabolites that are known to affect neurodegenerative processes, such as carnosine, putrescine, C24:1-OH sphingomyelin, and amino acids, which serve as neurotransmitters or their precursors. Our results suggest that the beneficial effect of mitochondrial transfer in the 5XFAD mice is mediated by metabolic signaling from the liver via the serum to the brain, where it induces protective effects. The high efficacy of the mitochondrial transfer may offer a novel AD therapy.
    Keywords:  5XFAD; Alzheimer’s disease; amyloid; cognition; mitochondria; mitochondrial transfer
    DOI:  https://doi.org/10.3390/cells12071006
  16. Cells. 2023 Apr 05. pii: 1089. [Epub ahead of print]12(7):
    High-Throughput Microscopy Analysis of Mitochondrial Membrane Potential in 2D and 3D Models.
    Caterina Vianello, Federica Dal Bello, Sang Hun Shin, Sara Schiavon, Camilla Bean, Ana Paula Magalhães Rebelo, Tomáš Knedlík, Emad Norouzi Esfahani, Veronica Costiniti, Rodrigo S Lacruz, Giuseppina Covello, Fabio Munari, Tommaso Scolaro, Antonella Viola, Elena Rampazzo, Luca Persano, Sara Zumerle, Luca Scorrano, Alessio Gianelle, Marta Giacomello.
      Recent proteomic, metabolomic, and transcriptomic studies have highlighted a connection between changes in mitochondria physiology and cellular pathophysiological mechanisms. Secondary assays to assess the function of these organelles appear fundamental to validate these -omics findings. Although mitochondrial membrane potential is widely recognized as an indicator of mitochondrial activity, high-content imaging-based approaches coupled to multiparametric to measure it have not been established yet. In this paper, we describe a methodology for the unbiased high-throughput quantification of mitochondrial membrane potential in vitro, which is suitable for 2D to 3D models. We successfully used our method to analyze mitochondrial membrane potential in monolayers of human fibroblasts, neural stem cells, spheroids, and isolated muscle fibers. Moreover, by combining automated image analysis and machine learning, we were able to discriminate melanoma cells from macrophages in co-culture and to analyze the subpopulations separately. Our data demonstrated that our method is a widely applicable strategy for large-scale profiling of mitochondrial activity.
    Keywords:  NSCs; TMRM; co-culture; machine learning; mitochondrial membrane potential; single muscle fibers; spheroids
    DOI:  https://doi.org/10.3390/cells12071089
  17. bioRxiv. 2023 Mar 29. pii: 2023.03.29.534670. [Epub ahead of print]
    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 are imported into and degraded inside mitochondria. In this study, a genome-wide screen in yeast uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of misfolded proteins 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 misfolded proteins such as those associated with neurodegenerative diseases.
    DOI:  https://doi.org/10.1101/2023.03.29.534670
  18. J Pharmacol Sci. 2023 May;pii: S1347-8613(23)00011-7. [Epub ahead of print]152(1): 39-49
    Differentiation-inducing factor 1 activates cofilin through pyridoxal phosphatase and AMP-activated protein kinase, resulting in mitochondrial fission.
    Takeru Inoue, Koichi Miura, Ruzhe Han, Fumi Seto-Tetsuo, Masaki Arioka, Kazunobu Igawa, Katsuhiko Tomooka, Toshiyuki Sasaguri.
      Differentiation-inducing factor 1 (DIF-1) is a morphogen produced by Dictyostelium discoideum that inhibits the proliferation and migration of both D. discoideum and most mammalian cells. Herein, we assessed the effect of DIF-1 on mitochondria, because DIF-3, which is similar to DIF-1, reportedly localizes in the mitochondria when added exogenously, however the significance of this localization remains unclear. Cofilin is an actin depolymerization factor that is activated by dephosphorylation at Ser-3. By regulating the actin cytoskeleton, cofilin induces mitochondrial fission, the first step in mitophagy. Here, we report that DIF-1 activates cofilin and induces mitochondrial fission and mitophagy mainly using human umbilical vein endothelial cells (HUVECs). AMP-activated kinase (AMPK), a downstream molecule of DIF-1 signaling, is required for cofilin activation. Pyridoxal phosphatase (PDXP)-known to directly dephosphorylate cofilin-is also required for the effect of DIF-1 on cofilin, indicating that DIF-1 activates cofilin through AMPK and PDXP. Cofilin knockdown inhibits mitochondrial fission and decreases mitofusin 2 (Mfn2) protein levels, a hallmark of mitophagy. Taken together, these results indicate that cofilin is required for DIF-1- induced mitochondrial fission and mitophagy.
    Keywords:  AMP-Activated kinase; Cofilin; Differentiation-inducing factor 1; Mitophagy; Pyridoxal phosphatase
    DOI:  https://doi.org/10.1016/j.jphs.2023.02.009
  19. Life Sci. 2023 Apr 06. pii: S0024-3205(23)00300-4. [Epub ahead of print] 121666
    Mitochondrion: A bridge linking aging and degenerative diseases.
    Lanlan Zhang, Jianlong Wu, Ziguan Zhu, Yuchen He, Renpeng Fang.
      Aging is a natural process, characterized by progressive loss of physiological integrity, impaired function, and increased vulnerability to death. For centuries, people have been trying hard to understand the process of aging and find effective ways to delay it. However, limited breakthroughs have been made in anti-aging area. Since the hallmarks of aging were summarized in 2013, increasing studies focus on the role of mitochondrial dysfunction in aging and aging-related degenerative diseases, such as neurodegenerative diseases, osteoarthritis, metabolic diseases, and cardiovascular diseases. Accumulating evidence indicates that restoring mitochondrial function and biogenesis exerts beneficial effects in extending lifespan and promoting healthy aging. In this paper, we provide an overview of mitochondrial changes during aging and summarize the advanced studies in mitochondrial therapies for the treatment of degenerative diseases. Current challenges and future perspectives are proposed to provide novel and promising directions for future research.
    Keywords:  Aging; Degenerative diseases; Longevity; Mitochondrion; Mitochondrion-nuclear communication; Mitophagy
    DOI:  https://doi.org/10.1016/j.lfs.2023.121666
  20. Science. 2023 Apr 14. 380(6641): 164-167
    Assisted reproductive technologies at the nexus of fertility treatment and disease prevention.
    Mary Herbert, Meenakshi Choudhary, Deidre Zander-Fox.
      Assisted reproductive technology (ART) refers to processing gametes in vitro and usually involves in vitro fertilization. Originally developed for the treatment of infertility, culture of human embryos in vitro also provides an opportunity to screen embryos for inherited genetic disorders of the nuclear and mitochondrial genomes. Progress in identifying causative genetic variants has massively increased the scope of preimplantation genetic testing in preventing genetic disorders. However, because ART procedures are not without risk of adverse maternal and child outcomes, careful consideration of the balance of risks and benefits is warranted. Further research on early human development will help to minimize risks while maximizing the benefits of ART.
    DOI:  https://doi.org/10.1126/science.adh0073
  21. Int J Mol Sci. 2023 Mar 24. pii: 6106. [Epub ahead of print]24(7):
    Inflammation, Mitochondria and Natural Compounds Together in the Circle of Trust.
    Salvatore Nesci, Anna Spagnoletta, Francesca Oppedisano.
      Human diseases are characterized by the perpetuation of an inflammatory condition in which the levels of Reactive Oxygen Species (ROS) are quite high. Excessive ROS production leads to DNA damage, protein carbonylation and lipid peroxidation, conditions that lead to a worsening of inflammatory disorders. In particular, compromised mitochondria sustain a stressful condition in the cell, such that mitochondrial dysfunctions become pathogenic, causing human disorders related to inflammatory reactions. Indeed, the triggered inflammation loses its beneficial properties and turns harmful if dysregulation and dysfunctions are not addressed. Thus, reducing oxidative stress with ROS scavenger compounds has proven to be a successful approach to reducing inflammation. Among these, natural compounds, in particular, polyphenols, alkaloids and coenzyme Q10, thanks to their antioxidant properties, are capable of inhibiting the activation of NF-κB and the expression of target genes, including those involved in inflammation. Even more, clinical trials, and in vivo and in vitro studies have demonstrated the antioxidant and anti-inflammatory effects of phytosomes, which are capable of increasing the bioavailability and effectiveness of natural compounds, and have long been considered an effective non-pharmacological therapy. Therefore, in this review, we wanted to highlight the relationship between inflammation, altered mitochondrial oxidative activity in pathological conditions, and the beneficial effects of phytosomes. To this end, a PubMed literature search was conducted with a focus on various in vitro and in vivo studies and clinical trials from 2014 to 2022.
    Keywords:  cytokines; inflammatory response; mitochondrial dysfunction; nutraceuticals; phytosome; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms24076106
  22. Cells. 2023 Mar 23. pii: 985. [Epub ahead of print]12(7):
    Tau Transfer via Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System.
    Romain Perbet, Valentin Zufferey, Elodie Leroux, Enea Parietti, Jeanne Espourteille, Lucas Culebras, Sylvain Perriot, Renaud Du Pasquier, Séverine Bégard, Vincent Deramecourt, Nicole Déglon, Nicolas Toni, Luc Buée, Morvane Colin, Kevin Richetin.
      Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics, and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data indicate that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modifies their function.
    Keywords:  astrocytes; extracellular vesicles; mitochondria; tau spreading; tauopathies
    DOI:  https://doi.org/10.3390/cells12070985
  23. J Med Case Rep. 2023 Apr 14. 17(1): 162
    Diagnosing mitochondrial, neurogastrointestinal leukoencephalopathy requires mutations in TYMP1, POLG1, LIG1, or RRM2B.
    Josef Finsterer.
      
    Keywords:  Lactic acidosis; MNGIE; Mitochondrial disorder; TYMP1; Vomiting; White matter lesions
    DOI:  https://doi.org/10.1186/s13256-023-03916-y
  24. Nat Cell Biol. 2023 Apr 10.
    Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing.
    Guokai Yan, Jinxin Yang, Wen Li, Ao Guo, Jialiang Guan, Ying Liu.
      The mechanistic target of rapamycin complex 1 (mTORC1) is an essential hub that integrates nutrient signals and coordinates metabolism to control cell growth. Amino acid signals are detected by sensor proteins and relayed to the GATOR2 and GATOR1 complexes to control mTORC1 activity. Here we perform genome-wide CRISPR/Cas9 screens, coupled with an assay for mTORC1 activity based on fluorescence-activated cell sorting analysis of pS6, to identify potential regulators of mTORC1-dependent amino acid sensing. We then focus on interleukin enhancer binding factor 3 (ILF3), one of the candidate genes from the screen. ILF3 tethers the GATOR complexes to lysosomes to control mTORC1. Adding a lysosome-targeting sequence to the GATOR2 component WDR24 bypasses the requirement for ILF3 to modulate amino-acid-dependent mTORC1 signalling. ILF3 plays an evolutionarily conserved role in human and mouse cells, and in worms to regulate the mTORC1 pathway, control autophagy activity and modulate the ageing process.
    DOI:  https://doi.org/10.1038/s41556-023-01123-x
  25. Science. 2023 Apr 14. 380(6641): 150-153
    Barriers to progress in pregnancy research: How can we break through?
    Sarah J Stock, Catherine E Aiken.
      Healthy pregnancies are fundamental to healthy populations, but very few therapies to improve pregnancy outcomes are available. Fundamental concepts-for example, placentation or the mechanisms that control the onset of labor-remain understudied and incompletely understood. A key issue is that research efforts must capture the complexity of the tripartite maternal-placental-fetal system, the dynamics of which change throughout gestation. Studying pregnancy disorders is complicated by the difficulty of creating maternal-placental-fetal interfaces in vitro and the uncertain relevance of animal models to human pregnancy. However, newer approaches include trophoblast organoids to model the developing placenta and integrated data-science approaches to study longer-term outcomes. These approaches provide insights into the physiology of healthy pregnancy, which is the first step to identifying therapeutic targets in pregnancy disorders.
    DOI:  https://doi.org/10.1126/science.adf9347
  26. Biochim Biophys Acta Mol Basis Dis. 2023 Apr 10. pii: S0925-4439(23)00082-0. [Epub ahead of print] 166716
    Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS.
    Anna Fernàndez Bernal, Natàlia Mota, Reinald Pamplona, Estela Area-Gomez, Manuel Portero-Otin.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.
    Keywords:  Calcium metabolism; Lipid synthesis; Mitochondria; Neurodegeneration; TDP-43
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166716
  27. Nature. 2023 Apr 14.
    Kids and clinical trials: why the system is failing children.
      
    Keywords:  Diseases; Drug discovery; Medical research; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-023-01028-7
  28. Front Microbiol. 2023 ;14 1133773
    Mitochondrial nanomotion measured by optical microscopy.
    Priyanka Parmar, Maria Ines Villalba, Alexandre Seiji Horii Huber, Aleksandar Kalauzi, Dragana Bartolić, Ksenija Radotić, Ronnie Guy Willaert, Derrick F MacFabe, Sandor Kasas.
      Nanometric scale size oscillations seem to be a fundamental feature of all living organisms on Earth. Their detection usually requires complex and very sensitive devices. However, some recent studies demonstrated that very simple optical microscopes and dedicated image processing software can also fulfill this task. This novel technique, termed as optical nanomotion detection (ONMD), was recently successfully used on yeast cells to conduct rapid antifungal sensitivity tests. In this study, we demonstrate that the ONMD method can monitor motile sub-cellular organelles, such as mitochondria. Here, mitochondrial isolates (from HEK 293 T and Jurkat cells) undergo predictable motility when viewed by ONMD and triggered by mitochondrial toxins, citric acid intermediates, and dietary and bacterial fermentation products (short-chain fatty acids) at various doses and durations. The technique has superior advantages compared to classical methods since it is rapid, possesses a single organelle sensitivity, and is label- and attachment-free.
    Keywords:  metabolic substrates; mitochondria; optical nanomotion; rotenone; short chain fatty acids
    DOI:  https://doi.org/10.3389/fmicb.2023.1133773
  29. Nature. 2023 Apr 12.
    Ageing studies in five animals suggest how to reverse decline.
    Gemma Conroy.
      
    Keywords:  Ageing; Molecular biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-023-01040-x
This page is being maintained by Thomas Krichel. It was last updated on 2023‒04‒16 at 07:27:42.