bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–03–24
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
  2. A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models.
  3. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
  4. A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
  5. Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
  6. Integrating the response to stressed mitochondria.
  7. Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
  8. Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.
  9. MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.
  10. The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
  11. AMPK Suppression Due to Obesity Drives Oocyte mtDNA Heteroplasmy via ATF5-POLG Axis.
  12. Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient.
  13. A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
  14. Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins.
  15. Identity and nature of neural stem cells in the adult human subventricular zone.
  16. In vitro and in vivo studies on the effect of a mitochondrial fusion promoter on Leydig cell integrity and function.
  17. Genome Aggregation Database Version 4-New Challenges of Variant Analysis in Movement Disorders.
  18. Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
  19. Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner.
  20. An optimized culture system for efficient derivation of porcine expanded potential stem cells from preimplantation embryos and by reprogramming somatic cells.
  21. Mitochondrial transcription factor A (TFAM) has 5'-deoxyribose phosphate lyase activity in vitro.
  22. Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.
  23. Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.
  24. The role of mitochondria in eosinophil function: implications for severe asthma pathogenesis.
  25. APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.
  1. Nat Metab. 2024 Mar 19.
    AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
      
    DOI:  https://doi.org/10.1038/s42255-024-01006-x
  2. Front Pharmacol. 2024 ;15 1352311
    A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models.
    Yi Na Dong, Lucie Vanessa Ngaba, Jacob An, Miniat W Adeshina, Nathan Warren, Johnathan Wong, David R Lynch.
      Friedreich's ataxia (FRDA), the most common recessive inherited ataxia, results from homozygous guanine-adenine-adenine (GAA) repeat expansions in intron 1 of the FXN gene, which leads to the deficiency of frataxin, a mitochondrial protein essential for iron-sulphur cluster synthesis. The study of frataxin protein regulation might yield new approaches for FRDA treatment. Here, we report tumorous imaginal disc 1 (TID1), a mitochondrial J-protein cochaperone, as a binding partner of frataxin that negatively controls frataxin protein levels. TID1 interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Acute and subacute depletion of frataxin using RNA interference markedly increases TID1 protein levels in multiple cell types. In addition, TID1 overexpression significantly increases frataxin precursor but decreases intermediate and mature frataxin levels in HEK293 cells. In primary cultured human skin fibroblasts, overexpression of TID1S results in decreased levels of mature frataxin and increased fragmentation of mitochondria. This effect is mediated by the last 6 amino acids of TID1S as a peptide made from this sequence rescues frataxin deficiency and mitochondrial defects in FRDA patient-derived cells. Our findings show that TID1 negatively modulates frataxin levels, and thereby suggests a novel therapeutic target for treating FRDA.
    Keywords:  ATP; Friedreich ataxia (FRDA); Tid1; frataxin; mitochondrial fragmentation
    DOI:  https://doi.org/10.3389/fphar.2024.1352311
  3. Nat Metab. 2024 Mar 19.
    Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
    Mathieu Membrez, Eugenia Migliavacca, Stefan Christen, Keisuke Yaku, Jennifer Trieu, Alaina K Lee, Francesco Morandini, Maria Pilar Giner, Jade Stiner, Mikhail V Makarov, Emma S Garratt, Maria F Vasiloglou, Lucie Chanvillard, Emilie Dalbram, Amy M Ehrlich, José Luis Sanchez-Garcia, Carles Canto, Leonidas G Karagounis, Jonas T Treebak, Marie E Migaud, Ramin Heshmat, Farideh Razi, Neerja Karnani, Afshin Ostovar, Farshad Farzadfar, Stacey K H Tay, Matthew J Sanders, Karen A Lillycrop, Keith M Godfrey, Takashi Nakagawa, Sofia Moco, René Koopman, Gordon S Lynch, Vincenzo Sorrentino, Jerome N Feige.
      Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.
    DOI:  https://doi.org/10.1038/s42255-024-00997-x
  4. bioRxiv. 2024 Mar 07. pii: 2024.03.05.583623. [Epub ahead of print]
    A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities 11 , thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.
    DOI:  https://doi.org/10.1101/2024.03.05.583623
  5. Dev Cell. 2024 Mar 18. pii: S1534-5807(24)00110-2. [Epub ahead of print]
    Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
    Daiana N Moretti-Horten, Carlotta Peselj, Asli Aras Taskin, Lisa Myketin, Uwe Schulte, Oliver Einsle, Friedel Drepper, Marcin Luzarowski, F-Nora Vögtle.
      Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the MitochondrialRegulatory hub for respiratoryAssembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.
    Keywords:  complex stoichiometry; mitochondria; mitoribosome; protein complex assembly; protein import; protein quality control; respiratory chain
    DOI:  https://doi.org/10.1016/j.devcel.2024.02.011
  6. Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00168-0. [Epub ahead of print]84(6): 995-997
    Integrating the response to stressed mitochondria.
    Elliot Dine, Richard J Youle.
      Chakrabarty et al.1 demonstrate that phospho-EIF2α (pEIF2α), the translation initiation factor that mediates the integrated stress response (ISR), is necessary and sufficient for the autophagic degradation of mitochondria following the addition of mitochondrial stressors.
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.026
  7. bioRxiv. 2024 Mar 07. pii: 2024.03.06.583589. [Epub ahead of print]
    Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
    Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.
      Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in the cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Nevertheless, the signaling consequences of primary mitochondrial malfunction and of primary lysosomal defects are not similar, despite in both cases there are impairments of mitochondria and of lysosomes. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects, to identify what are the global cellular consequences that are associated with malfunction of mitochondria or lysosomes. We used these data to determine what are the pathways that are affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. This pathway is transcriptionally up-regulated in cellular and mouse models of lysosomal defects and is transcriptionally down-regulated in cellular and mouse models of mitochondrial defects. We identified a role for post-transcriptional regulation of the transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, the retention of Ca 2+ in the lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo , using models of mitochondria-associated diseases in C. elegans , that normalization of lysosomal Ca 2+ levels results in partial rescue of the developmental arrest induced by the respiratory chain deficiency.
    DOI:  https://doi.org/10.1101/2024.03.06.583589
  8. Brain Commun. 2024 ;6(2): fcae070
    Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.
    Danique Beijer, Sheila Marte, Jiaxin C Li, Willem De Ridder, Jessie Z Chen, Abigail L D Tadenev, Kathy E Miers, Tine Deconinck, Richard Macdonell, Wilson Marques, Peter De Jonghe, Samia L Pratt, Rebecca Meyer-Schuman, Stephan Züchner, Anthony Antonellis, Robert W Burgess, Jonathan Baets.
      Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.
    Keywords:  Charcot–Marie–Tooth disease; NARS1; aminoacyl-tRNA synthetases; asparaginyl-tRNA synthetase; axonal sensorimotor neuropathy
    DOI:  https://doi.org/10.1093/braincomms/fcae070
  9. Sci Rep. 2024 Mar 21. 14(1): 6751
    MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.
    Michael J Bround, Eaman Abay, Jiuzhou Huo, Julian R Havens, Allen J York, Donald M Bers, Jeffery D Molkentin.
      Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.
    DOI:  https://doi.org/10.1038/s41598-024-57340-3
  10. Nat Commun. 2024 Mar 21. 15(1): 2487
    The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
    Marine Lanfranchi, Sozerko Yandiev, Géraldine Meyer-Dilhet, Salma Ellouze, Martijn Kerkhofs, Raphael Dos Reis, Audrey Garcia, Camille Blondet, Alizée Amar, Anita Kneppers, Hélène Polvèche, Damien Plassard, Marc Foretz, Benoit Viollet, Kei Sakamoto, Rémi Mounier, Cyril F Bourgeois, Olivier Raineteau, Evelyne Goillot, Julien Courchet.
      The cellular mechanisms underlying axonal morphogenesis are essential to the formation of functional neuronal networks. We previously identified the autism-linked kinase NUAK1 as a central regulator of axon branching through the control of mitochondria trafficking. However, (1) the relationship between mitochondrial position, function and axon branching and (2) the downstream effectors whereby NUAK1 regulates axon branching remain unknown. Here, we report that mitochondria recruitment to synaptic boutons supports collateral branches stabilization rather than formation in mouse cortical neurons. NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration, and upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Finally, we found that NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN. Our results demonstrate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondrial distribution and metabolic activity.
    DOI:  https://doi.org/10.1038/s41467-024-46146-6
  11. Adv Sci (Weinh). 2024 Mar 18. e2307480
    AMPK Suppression Due to Obesity Drives Oocyte mtDNA Heteroplasmy via ATF5-POLG Axis.
    Yanting Chen, Guiling Ma, Yang Gai, Qiyuan Yang, Xiangdong Liu, Jeanene M de Avila, Shengyong Mao, Mei-Jun Zhu, Min Du.
      Due to the exclusive maternal transmission, oocyte mitochondrial dysfunction reduces fertility rates, affects embryonic development, and programs offspring to metabolic diseases. However, mitochondrial DNA (mtDNA) are vulnerable to mutations during oocyte maturation, leading to mitochondrial nucleotide variations (mtSNVs) within a single oocyte, referring to mtDNA heteroplasmy. Obesity (OB) accounts for more than 40% of women at the reproductive age in the USA, but little is known about impacts of OB on mtSNVs in mature oocytes. It is found that OB reduces mtDNA content and increases mtSNVs in mature oocytes, which impairs mitochondrial energetic functions and oocyte quality. In mature oocytes, OB suppresses AMPK activity, aligned with an increased binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions. Similarly, AMPK knockout increases the binding affinity of ATF5-POLG proteins to mutated mtDNA, leading to the replication of heteroplasmic mtDNA and impairing oocyte quality. Consistently, AMPK activation blocks the detrimental impacts of OB by preventing ATF5-POLG protein recruitment, improving oocyte maturation and mitochondrial energetics. Overall, the data uncover key features of AMPK activation in suppressing mtSNVs, and improving mitochondrial biogenesis and oocyte maturation in obese females.
    Keywords:  AMPK; female obesity; mature oocyte; mtDNA heteroplasmy
    DOI:  https://doi.org/10.1002/advs.202307480
  12. Cytotherapy. 2024 Mar 04. pii: S1465-3249(24)00087-2. [Epub ahead of print]
    Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient.
    Omer Faruk Taner, Oner Ulger, Simay Ersahin, Nesrin Tan Baser, Onur Genc, Gokhan Burcin Kubat.
       BACKGROUND AIMS: Wound healing is a multistage process that requires a concerted effort of various cell types. The intricate processes involved in the healing of wounds result in high energy requirements. Furthermore, mitochondria play a crucial role in the healing process because of their involvement in neo angiogenesis, growth factor synthesis, and cell differentiation. It is unclear how mitochondria transplantation, a promising new approach, influences wound healing.
    METHODS: In this study, healthy autologous mitochondria obtained from skeletal muscle were injected into chronic pressure wounds as an intervention to promote wound healing.
    RESULTS: Mitochondrial transplantation accelerated wound healing by reducing wound size, increasing granulation tissue, and hastening epithelialization.
    CONCLUSIONS: This study is the first to demonstrate the therapeutic efficacy of mitochondrial transplantation in wound healing.
    Keywords:  chronic wounds; mitochondrial transplantation; skeletal muscle; wound healing
    DOI:  https://doi.org/10.1016/j.jcyt.2024.02.027
  13. Mol Cell. 2024 Mar 14. pii: S1097-2765(24)00170-9. [Epub ahead of print]
    A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
    Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M Smalec, Iliana Soto, Autum R Baxter-Koenigs, Karine Choquet, L Stirling Churchman.
      Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC and FASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.
    Keywords:  LRPPRC; Leighs disease; RNA life cycle; gene regulation; genetic conflict; metabolic regulation; mitochondrial gene expression; mitochondrial translation; mitonuclear balance; organellular biogenesis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.028
  14. iScience. 2024 Apr 19. 27(4): 109136
    Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins.
    Carlos Cardanho-Ramos, Rúben Alves Simões, Yi-Zhi Wang, Andreia Faria-Pereira, Ewa Bomba-Warczak, Katleen Craessaerts, Marco Spinazzi, Jeffrey N Savas, Vanessa A Morais.
      In neurons, it is commonly assumed that mitochondrial replication only occurs in the cell body, after which the mitochondria must travel to the neuron's periphery. However, while mitochondrial DNA replication has been observed to occur away from the cell body, the specific mechanisms involved remain elusive. Using EdU-labelling in mouse primary neurons, we developed a tool to determine the mitochondrial replication rate. Taking of advantage of microfluidic devices, we confirmed that mitochondrial replication also occurs locally in the periphery of neurons. To achieve this, mitochondria require de novo nuclear-encoded, but not mitochondrial-encoded protein translation. Following a proteomic screen comparing synaptic with non-synaptic mitochondria, we identified two elongation factors - eEF1A1 and TUFM - that were upregulated in synaptic mitochondria. We found that mitochondrial replication is impaired upon the downregulation of eEF1A1, and this is particularly relevant in the periphery of neurons.
    Keywords:  Biochemistry; Biological sciences; Cellular neuroscience; Molecular neuroscience; Natural sciences; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.109136
  15. iScience. 2024 Apr 19. 27(4): 109342
    Identity and nature of neural stem cells in the adult human subventricular zone.
    Salma Baig, Javad Nadaf, Redouane Allache, Phuong U Le, Michael Luo, Annisa Djedid, Andriniaina Nkili-Meyong, Maryam Safisamghabadi, Alex Prat, Jack Antel, Marie-Christine Guiot, Kevin Petrecca.
      The existence of neural stem cells (NSCs) in adult human brain neurogenic regions remains unresolved. To address this, we created a cell atlas of the adult human subventricular zone (SVZ) derived from fresh neurosurgical samples using single-cell transcriptomics. We discovered 2 adult radial glia (RG)-like populations, aRG1 and aRG2. aRG1 shared features with fetal early RG (eRG) and aRG2 were transcriptomically similar to fetal outer RG (oRG). We also captured early neuronal and oligodendrocytic NSC states. We found that the biological programs driven by their transcriptomes support their roles as early lineage NSCs. Finally, we show that these NSCs have the potential to transition between states and along lineage trajectories. These data reveal that multipotent NSCs reside in the adult human SVZ.
    Keywords:  Cell biology; Molecular biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109342
  16. Front Toxicol. 2024 ;6 1357857
    In vitro and in vivo studies on the effect of a mitochondrial fusion promoter on Leydig cell integrity and function.
    Samuel Garza, Chantal Sottas, Hovhannes J Gukasyan, Vassilios Papadopoulos.
      Background: The interstitial testicular Leydig cells are responsible for the production of testosterone, which functionally deteriorate with normal aging. Decreased expression of mitochondrial steroidogenic interactome proteins and diminished mitochondrial function in aging Leydig cells suggest that mitochondrial dynamics play a role in maintaining adequate levels of testosterone. Optic atrophy 1 (OPA1) protein regulates mitochondrial dynamics and cristae formation in many cell types. Previous studies showed that increasing OPA1 expression in dysfunctional Leydig cells restored mitochondrial function and recovered androgen production to levels found in healthy Leydig cells. These findings suggested that mitochondrial dynamics may be a promising target to ameliorate diminished testosterone levels in aging males. Methods: We used twelve-month-old rats to explore the relationship between mitochondrial dynamics and Leydig cell function. Isolated Leydig cells from aged rats were treated ex vivo with the cell-permeable mitochondrial fusion promoter 4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl)hydrazono)ethyl) phenol (mitochondrial fusion promoter M1), which enhances mitochondrial tubular network formation. In parallel, rats were treated with 2 mg/kg/day M1 for 6 weeks before Leydig cells were isolated. Results: Ex vivo M1-treated cells showed enhanced mitochondrial tubular network formation by transmission electron microscopy, enhanced Leydig cell mitochondrial integrity, improved mitochondrial function, and higher testosterone biosynthesis compared to controls. However, in vivo treatment of aged rats with M1 not only failed to re-establish testosterone levels to that of young rats, it also led to further reduction of testosterone levels and increased apoptosis, suggesting M1 toxicity in the testis. The in vivo M1 toxicity seemed to be tissue-specific, however. Conclusion: Promoting mitochondrial fusion may be one approach to enhancing cell health and wellbeing with aging, but more investigations are warranted. Our findings suggest that fusion promoters could potentially enhance the productivity of aged Leydig cells when carefully regulated.
    Keywords:  aging; bioenergetics; hypogonadism; mitochondrial fusion; steroidogenesis; testosterone; toxicity
    DOI:  https://doi.org/10.3389/ftox.2024.1357857
  17. Mov Disord. 2024 Mar 22.
    Genome Aggregation Database Version 4-New Challenges of Variant Analysis in Movement Disorders.
    Elisabetta Indelicato, Luigi Michele Romito, Philip Harrer, Nico Golfrè Andreasi, Isabel Colangelo, Robert Kopajtich, Juliane Winkelmann, Holger Prokisch, Barbara Garavaglia, Michael Zech.
      
    DOI:  https://doi.org/10.1002/mds.29797
  18. Nat Metab. 2024 Mar 19.
    Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
    J Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B Harbauer.
      Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42255-024-01007-w
  19. Nat Commun. 2024 Mar 20. 15(1): 2358
    Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner.
    Zaher ElBeck, Mohammad Bakhtiar Hossain, Humam Siga, Nikolay Oskolkov, Fredrik Karlsson, Julia Lindgren, Anna Walentinsson, Dominique Koppenhöfer, Rebecca Jarvis, Roland Bürli, Tanguy Jamier, Elske Franssen, Mike Firth, Andrea Degasperi, Claus Bendtsen, Robert I Menzies, Katrin Streckfuss-Bömeke, Michael Kohlhaas, Alexander G Nickel, Lars H Lund, Christoph Maack, Ákos Végvári, Christer Betsholtz.
      While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.
    DOI:  https://doi.org/10.1038/s41467-024-46384-8
  20. Nat Protoc. 2024 Mar 20.
    An optimized culture system for efficient derivation of porcine expanded potential stem cells from preimplantation embryos and by reprogramming somatic cells.
    Degong Ruan, Yiyi Xuan, Timothy Theodore Ka Ki Tam, ZhuoXuan Li, Xiao Wang, Shao Xu, Doris Herrmann, Heiner Niemann, Liangxue Lai, Xuefei Gao, Monika Nowak-Imialek, Pentao Liu.
      Pigs share anatomical and physiological traits with humans and can serve as a large-animal model for translational medicine. Bona fide porcine pluripotent stem cells (PSCs) could facilitate testing cell and drug therapies. Agriculture and biotechnology may benefit from the ability to produce immune cells for studying animal infectious diseases and to readily edit the porcine genome in stem cells. Isolating porcine PSCs from preimplantation embryos has been intensively attempted over the past decades. We previously reported the derivation of expanded potential stem cells (EPSCs) from preimplantation embryos and by reprogramming somatic cells of multiple mammalian species, including pigs. Porcine EPSCs (pEPSCs) self-renew indefinitely, differentiate into embryonic and extra-embryonic lineages, and permit precision genome editing. Here we present a highly reproducible experimental procedure and data of an optimized and robust porcine EPSC culture system and its use in deriving new pEPSC lines from preimplantation embryos and reprogrammed somatic cells. No particular expertise is required for the protocols, which take ~4-6 weeks to complete. Importantly, we successfully established pEPSC lines from both in vitro fertilized and somatic cell nuclear transfer-derived embryos. These new pEPSC lines proliferated robustly over long-term passaging and were amenable to both simple indels and precision genome editing, with up to 100% targeting efficiency. The pEPSCs differentiated into embryonic cell lineages in vitro and teratomas in vivo, and into porcine trophoblast stem cells in human trophoblast stem cell medium. We show here that pEPSCs have unique epigenetic features, particularly H3K27me3 levels substantially lower than fibroblasts.
    DOI:  https://doi.org/10.1038/s41596-024-00958-4
  21. DNA Repair (Amst). 2024 Mar 08. pii: S1568-7864(24)00042-9. [Epub ahead of print]137 103666
    Mitochondrial transcription factor A (TFAM) has 5'-deoxyribose phosphate lyase activity in vitro.
    Wenxin Zhao, Adil S Hussen, Bret D Freudenthal, Zucai Suo, Linlin Zhao.
      Mitochondrial DNA (mtDNA) plays a key role in mitochondrial and cellular functions. mtDNA is maintained by active DNA turnover and base excision repair (BER). In BER, one of the toxic repair intermediates is 5'-deoxyribose phosphate (5'dRp). Human mitochondrial DNA polymerase γ has weak dRp lyase activities, and another known dRp lyase in the nucleus, human DNA polymerase β, can also localize to mitochondria in certain cell and tissue types. Nonetheless, whether additional proteins have the ability to remove 5'dRp in mitochondria remains unknown. Our prior work on the AP lyase activity of mitochondrial transcription factor A (TFAM) has prompted us to examine its ability to remove 5'dRp residues in vitro. TFAM is the primary DNA-packaging factor in human mitochondria and interacts with mitochondrial DNA extensively. Our data demonstrate that TFAM has the dRp lyase activity with different DNA substrates. Under single-turnover conditions, TFAM removes 5'dRp residues at a rate comparable to that of DNA polymerase (pol) β, albeit slower than that of pol λ. Among the three proteins examined, pol λ shows the highest single-turnover rates in dRp lyase reactions. The catalytic effect of TFAM is facilitated by lysine residues of TFAM via Schiff base chemistry, as evidenced by the observation of dRp-lysine adducts in mass spectrometry experiments. The catalytic effect of TFAM observed here is analogous to the AP lyase activity of TFAM reported previously. Together, these results suggest a potential role of TFAM in preventing the accumulation of toxic DNA repair intermediates.
    Keywords:  5'-deoxyribose phosphate; DNA repair intermediates; DNA-protein cross-links; abasic sites; base excision repair; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.dnarep.2024.103666
  22. Muscle Nerve. 2024 Mar 21.
    Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.
    Nicolette A Cilenti, Jaclyn G Tamaroff, Christopher J Capiola, Walter Faig, Michael G McBride, Stephen M Paridon, Shannon O'Malley, Jonathan B Edelson, David R Lynch, Shana E McCormack, Kimberly Y Lin.
       INTRODUCTION/AIMS: Traditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA.
    METHODS: Participants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test-retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis.
    RESULTS: In our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14-23), median age of FRDA onset was 8 years (IQR 6-13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54-62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650-900). Twenty-one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year.
    DISCUSSION: Adaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.
    Keywords:  adaptive; ataxia; exercise; feasibility; outcomes
    DOI:  https://doi.org/10.1002/mus.28085
  23. Cell Death Differ. 2024 Mar 19.
    Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.
    Sarah V Schweighofer, Daniel C Jans, Jan Keller-Findeisen, Anne Folmeg, Peter Ilgen, Mark Bates, Stefan Jakobs.
      One hallmark of apoptosis is the oligomerization of BAX and BAK to form a pore in the mitochondrial outer membrane, which mediates the release of pro-apoptotic intermembrane space proteins into the cytosol. Cells overexpressing BAX or BAK fusion proteins are a powerful model system to study the dynamics and localization of these proteins in cells. However, it is unclear whether overexpressed BAX and BAK form the same ultrastructural assemblies following the same spatiotemporal hierarchy as endogenously expressed proteins. Combining live- and fixed-cell STED super-resolution microscopy, we show that overexpression of BAK results in novel BAK structures, which are virtually absent in non-overexpressing apoptotic cells. We further demonstrate that in wild type cells, BAK is recruited to apoptotic pores before BAX. Both proteins together form unordered, mosaic rings on apoptotic mitochondria in immortalized cell culture models as well as in human primary cells. In BAX- or BAK- single-knockout cells, the remaining protein is able to form rings independently. The heterogeneous nature of these rings in both wild type as well as single-knockout cells corroborates the toroidal apoptotic pore model.
    DOI:  https://doi.org/10.1038/s41418-024-01273-x
  24. Front Cell Dev Biol. 2024 ;12 1360079
    The role of mitochondria in eosinophil function: implications for severe asthma pathogenesis.
    Janice Koranteng, Kian Fan Chung, Charalambos Michaeloudes, Pankaj Bhavsar.
      Mitochondria are key metabolic hubs involved in cellular energy production and biosynthesis. ATP is generated primarily by glucose and fatty acid oxidation through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in the mitochondria. During OXPHOS there is also production of reactive oxygen species (ROS), which are involved in the regulation of cellular function. Mitochondria are also central in the regulating cell survival and death, particularly in the intrinsic apoptosis pathway. Severe asthma is a heterogeneous disease driven by various immune mechanisms. Severe eosinophilic asthma entails a type 2 inflammatory response and peripheral and lung eosinophilia, associated with severe airflow obstruction, frequent exacerbations and poor response to treatment. Mitochondrial dysfunction and altered metabolism have been observed in airway epithelial and smooth muscle cells from patients with asthma. However, the role of mitochondria in the development of eosinophilia and eosinophil-mediated inflammation in severe asthma is unknown. In this review, we discuss the currently limited literature on the role of mitochondria in eosinophil function and how it is regulated by asthma-relevant cytokines, including interleukin (IL)-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), as well as by corticosteroid drugs. Moreover, we summarise the evidence on the role of mitochondria in the regulation of eosinophils apoptosis and eosinophil extracellular trap formation. Finally, we discuss the possible role of altered mitochondrial function in eosinophil dysfunction in severe asthma and suggest possible research avenues in order to better understand their role in disease pathogenesis, and identify novel therapeutic targets.
    Keywords:  eosinophils; metabolism; mitochondria; pathogenesis; severe asthma
    DOI:  https://doi.org/10.3389/fcell.2024.1360079
  25. Mol Ther. 2024 Mar 18. pii: S1525-0016(24)00165-5. [Epub ahead of print]
    APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.
    Rosemary J Jackson, Megan S Keiser, Jonah C Meltzer, Dustin P Fykstra, Steven E Dierksmeier, Soroush Hajizadeh, Johannes Kreuzer, Robert Morris, Alexandra Melloni, Tsuneo Nakajima, Luis Tecedor, Paul T Ranum, Ellie Carrell, YongHong Chen, Maryam A Nishtar, David M Holtzman, Wilhelm Haas, Beverly L Davidson, Bradley T Hyman.
      Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE4. This result suggests a promising protective effect of exogenous APOE2 and reveals a a cell non-autonomous effect of the protein on microglial activation which we go on to show is similar to plaque associated microglia in the brain of Alzheimer patients who inherit APOE2. These data raise the potential that an APOE2 therapeutic could be effective in Alzheimer disease even in individuals born with the risk ε4 allele.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.03.024
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