bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒04‒14
twenty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico 
  1. MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
  2. Hydrogen sulfide supplementation as a potential treatment for primary mitochondrial diseases.
  3. Replication and Transcription of Human Mitochondrial DNA.
  4. Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
  5. Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
  6. Mitochondrial morphology, distribution and activity during oocyte development.
  7. Cavitating leukodystrophy in a case of mitochondrial complex III deficiency due to LYRM7 mutation.
  8. Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.
  9. Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.
  10. Machine learning-based 3D segmentation of mitochondria in polarized epithelial cells.
  11. Mitochondrial Differentiation during Spermatogenesis: Lessons from Drosophila melanogaster.
  12. Expression and processing of mature human frataxin after gene therapy in mice.
  13. Oocyte mitochondria link maternal environment to offspring phenotype.
  14. The Schizosaccharomyces pombe DEAD-box protein Mss116 is required for mitoribosome assembly and mitochondrial translation.
  15. Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis.
  16. Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.
  17. Right place at the right time: Mitochondrial shape, distribution and inter-organelle interaction during skeletal muscle postnatal development.
  18. Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
  19. PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.
  20. Interdisciplinary fetal neurology care: Current practice, challenges, and future directions.
  1. Autophagy. 2024 Apr 10.
    MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
    Mohamed A Eldeeb, Armaan Fallahi, Andrea Soumbasis, Andrew N Bayne, Jean-François Trempe, Edward A Fon.
      Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.
    Keywords:  Mitochondrial import; PINK1; Parkinson’s disease; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2340399
  2. Pharmacol Res. 2024 Apr 08. pii: S1043-6618(24)00124-5. [Epub ahead of print] 107180
    Hydrogen sulfide supplementation as a potential treatment for primary mitochondrial diseases.
    Luke Slade, Colleen S Deane, Nathaniel J Szewczyk, Timothy Etheridge, Matthew Whiteman.
      Primary mitochondrial diseases (PMD) are amongst the most common inborn errors of metabolism causing fatal outcomes within the first decade of life. With marked heterogeneity in both inheritance patterns and physiological manifestations, these conditions present distinct challenges for targeted drug therapy, where effective therapeutic countermeasures remain elusive within the clinic. Hydrogen sulfide (H2S)-based therapeutics may offer a new option for patient treatment, having been proposed as a conserved mitochondrial substrate and post-translational regulator across species, displaying therapeutic effects in age-related mitochondrial dysfunction and neurodegenerative models of mitochondrial disease. H2S can stimulate mitochondrial respiration at sites downstream of common PMD-defective subunits, augmenting energy production, mitochondrial function and reducing cell death. Here, we highlight the primary signalling mechanisms of H2S in mitochondria relevant for PMD and outline key cytoprotective proteins/pathways amenable to post-translational restoration via H2S-mediated persulfidation. The mechanisms proposed here, combined with the advent of potent mitochondria-targeted sulfide delivery molecules, could provide a framework for H2S as a countermeasure for PMD disease progression.
    Keywords:  Hydrogen sulfide; mitochondria; persulfidation; primary mitochondrial disease; therapeutics
    DOI:  https://doi.org/10.1016/j.phrs.2024.107180
  3. Annu Rev Biochem. 2024 Apr 09.
    Replication and Transcription of Human Mitochondrial DNA.
    Maria Falkenberg, Nils-Göran Larsson, Claes M Gustafsson.
      Mammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiation of both replication and transcription. Mutations affecting the molecular machineries replicating and transcribing mtDNA are important causes of human mitochondrial disease, reflecting the critical role of the genome in oxidative phosphorylation system biogenesis. Mechanisms controlling mtDNA replication and transcription still need to be clarified, and future research in this area is likely to open novel therapeutic possibilities for treating mitochondrial dysfunction.
    DOI:  https://doi.org/10.1146/annurev-biochem-052621-092014
  4. Neuron. 2024 Mar 26. pii: S0896-6273(24)00167-3. [Epub ahead of print]
    Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
    Sandra M V Kochan, Meret Cepero Malo, Milica Jevtic, Hannah M Jahn-Kelleter, Gulzar A Wani, Kristiano Ndoci, Laura Pérez-Revuelta, Felix Gaedke, Iris Schäffner, Dieter Chichung Lie, Astrid Schauss, Matteo Bergami.
      Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival but left neurons poorly responsive to experience at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.
    Keywords:  LTP; Mfn2; adult neurogenesis; competition; experience; hippocampus; mitochondria; mitochondrial fusion; neural stem cell; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.neuron.2024.03.013
  5. J Biol Chem. 2024 Apr 06. pii: S0021-9258(24)01770-8. [Epub ahead of print] 107269
    Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
    Laura H Steenberge, Sean Rogers, Andrew Y Sung, Jing Fan, David J Pagliarini.
      Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.
    Keywords:  Antioxidant; Bioenergetics; Coenzyme Q10 (CoQ10); Ferroptosis; Membrane lipid; Mitochondrial respiratory chain complex; Mitochondrial therapeutics; Pyrimidine biosynthesis; Ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2024.107269
  6. Trends Endocrinol Metab. 2024 Apr 09. pii: S1043-2760(24)00064-X. [Epub ahead of print]
    Mitochondrial morphology, distribution and activity during oocyte development.
    Devesh Bahety, Elvan Böke, Aida Rodríguez-Nuevo.
      Mitochondria have a crucial role in cellular function and exhibit remarkable plasticity, adjusting both their structure and activity to meet the changing energy demands of a cell. Oocytes, female germ cells that become eggs, undergo unique transformations: the extended dormancy period, followed by substantial increase in cell size and subsequent maturation involving the segregation of genetic material for the next generation, present distinct metabolic challenges necessitating varied mitochondrial adaptations. Recent findings in dormant oocytes challenged the established respiratory complex hierarchies and underscored the extent of mitochondrial plasticity in long-lived oocytes. In this review, we discuss mitochondrial adaptations observed during oocyte development across three vertebrate species (Xenopus, mouse, and human), emphasising current knowledge, acknowledging limitations, and outlining future research directions.
    Keywords:  metabolism; mitochondria; oocyte; plasticity
    DOI:  https://doi.org/10.1016/j.tem.2024.03.002
  7. Acta Neurol Belg. 2024 Apr 09.
    Cavitating leukodystrophy in a case of mitochondrial complex III deficiency due to LYRM7 mutation.
    Mojtaba Rezaei, Zahra Dourandish, Gilda Kiani Mehr, Askar Ghorbani, Farzad Fatehi.
      
    Keywords:  Cavitating lesions; LYRM7 protein; Leukodystrophy; Mitochondrial complex III deficiency; Mitochondrial diseases
    DOI:  https://doi.org/10.1007/s13760-024-02529-6
  8. Mitochondrion. 2024 Apr 09. pii: S1567-7249(24)00037-0. [Epub ahead of print]76 101879
    Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.
    Laura Bermejo-Guerrero, Ana Hernández-Voth, Pablo Serrano-Lorenzo, Alberto Blázquez, Paloma Martin-Jimenez, Miguel A Martin, Cristina Domínguez-González.
      OBJECTIVES: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d.METHODS: An adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented.
    RESULTS: After 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea.
    DISCUSSION: Treatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d.
    Keywords:  Case report; Mitochondrial myopathy; TK2 deficiency
    DOI:  https://doi.org/10.1016/j.mito.2024.101879
  9. Cell Rep. 2024 Apr 06. pii: S2211-1247(24)00395-4. [Epub ahead of print]43(4): 114067
    Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.
    Dong Tian, Mingxue Cui, Min Han.
      Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.
    Keywords:  ATP synthase; CP: Cell biology; CP: Metabolism; Leigh syndrome; PGN; ROS; antibiotic-induced microbiome depletion; electron transfer chain; energy metabolism; intestinal epithelial cells; intestinal homeostasis; mitochondrial diseases; oxidative phosphorylation; oxidative stress; peptidoglycan
    DOI:  https://doi.org/10.1016/j.celrep.2024.114067
  10. Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00040-0. [Epub ahead of print] 101882
    Machine learning-based 3D segmentation of mitochondria in polarized epithelial cells.
    Nan W Hultgren, Tianli Zhou, David S Williams.
      Mitochondria are dynamic organelles that alter their morphological characteristics in response to functional needs. Therefore, mitochondrial morphology is an important indicator of mitochondrial function and cellular health. Reliable segmentation of mitochondrial networks in microscopy images is a crucial initial step for further quantitative evaluation of their morphology. However, 3D mitochondrial segmentation, especially in cells with complex network morphology, such as in highly polarized cells, remains challenging. To improve the quality of 3D segmentation of mitochondria in super-resolution microscopy images, we took a machine learning approach, using 3D Trainable Weka, an ImageJ plugin. We demonstrated that, compared with other commonly used methods, our approach segmented mitochondrial networks effectively, with improved accuracy in different polarized epithelial cell models, including differentiated human retinal pigment epithelial (RPE) cells. Furthermore, using several tools for quantitative analysis following segmentation, we revealed mitochondrial fragmentation in bafilomycin-treated RPE cells.
    Keywords:  3D segmentation; ImageJ; Machine learning algorithm; Mitochondrial morphology; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.mito.2024.101882
  11. Int J Mol Sci. 2024 Apr 03. pii: 3980. [Epub ahead of print]25(7):
    Mitochondrial Differentiation during Spermatogenesis: Lessons from Drosophila melanogaster.
    Viktor Vedelek, Ferenc Jankovics, János Zádori, Rita Sinka.
      Numerous diseases can arise as a consequence of mitochondrial malfunction. Hence, there is a significant focus on studying the role of mitochondria in cancer, ageing, neurodegenerative diseases, and the field of developmental biology. Mitochondria could exist as discrete organelles in the cell; however, they have the ability to fuse, resulting in the formation of interconnected reticular structures. The dynamic changes between these forms correlate with mitochondrial function and mitochondrial health, and consequently, there is a significant scientific interest in uncovering the specific molecular constituents that govern these transitions. Moreover, the specialized mitochondria display a wide array of variable morphologies in their cristae formations. These inner mitochondrial structures are closely associated with the specific functions performed by the mitochondria. In multiple cases, the presence of mitochondrial dysfunction has been linked to male sterility, as it has been observed to cause a range of abnormal spermatogenesis and sperm phenotypes in different species. This review aims to elucidate the dynamic alterations and functions of mitochondria in germ cell development during the spermatogenesis of Drosophila melanogaster.
    Keywords:  Drosophila melanogaster; mitochondria; mitochondrial differentiation; nebenkern; paracristalline material; spermatogenesis; testis
    DOI:  https://doi.org/10.3390/ijms25073980
  12. Sci Rep. 2024 04 10. 14(1): 8391
    Expression and processing of mature human frataxin after gene therapy in mice.
    Teerapat Rojsajjakul, Nithya Selvan, Bishnu De, Jonathan B Rosenberg, Stephen M Kaminsky, Dolan Sondhi, Peter Janki, Ronald G Crystal, Clementina Mesaros, Richie Khanna, Ian A Blair.
      Friedreich's ataxia is a degenerative and progressive multisystem disorder caused by mutations in the highly conserved frataxin (FXN) gene that results in FXN protein deficiency and mitochondrial dysfunction. While gene therapy approaches are promising, consistent induction of therapeutic FXN protein expression that is sub-toxic has proven challenging, and numerous therapeutic approaches are being tested in animal models. FXN (hFXN in humans, mFXN in mice) is proteolytically modified in mitochondria to produce mature FXN. However, unlike endogenous hFXN, endogenous mFXN is further processed into N-terminally truncated, extra-mitochondrial mFXN forms of unknown function. This study assessed mature exogenous hFXN expression levels in the heart and liver of C57Bl/6 mice 7-10 months after intravenous administration of a recombinant adeno-associated virus encoding hFXN (AAVrh.10hFXN) and examined the potential for hFXN truncation in mice. AAVrh.10hFXN induced dose-dependent expression of hFXN in the heart and liver. Interestingly, hFXN was processed into truncated forms, but found at lower levels than mature hFXN. However, the truncations were at different positions than mFXN. AAVrh.10hFXN induced mature hFXN expression in mouse heart and liver at levels that approximated endogenous mFXN levels. These results suggest that AAVrh.10hFXN can likely induce expression of therapeutic levels of mature hFXN in mice.
    DOI:  https://doi.org/10.1038/s41598-024-59060-0
  13. Res Sq. 2024 Mar 29. pii: rs.3.rs-4087193. [Epub ahead of print]
    Oocyte mitochondria link maternal environment to offspring phenotype.
    Nick Burton, Jason Cooper, Kim Nguyen, Darrick Gates, Emily Wolfram, Colt Capan, Hyoungjoo Lee, Devia Williams, Chidozie Okoye, Andrew Wojtovich.
      During maturation oocytes undergo a recently discovered mitochondrial proteome remodeling event in flies 1 , frogs 1 , and humans 2 . This oocyte mitochondrial remodeling, which includes substantial changes in electron transport chain (ETC) subunit abundance 1,2 , is regulated by maternal insulin signaling 1 . Why oocytes undergo mitochondrial remodeling is unknown, with some speculating that it might be an evolutionarily conserved mechanism to protect oocytes from genotoxic damage by reactive oxygen species (ROS) 2 . In Caenorhabditis elegans , we previously found that maternal exposure to osmotic stress drives a 50-fold increase in offspring survival in response to future osmotic stress3. Like mitochondrial remodeling, we found that this intergenerational adaptation is also regulated by insulin signaling to oocytes 3 . Here, we used proteomics and genetic manipulations to show that insulin signaling to oocytes regulates offspring's ability to adapt to future stress via a mechanism that depends on ETC composition in maternal oocytes. Specifically, we found that maternally expressed mutant alleles of nduf-7 (complex I subunit) or isp -1 (complex III subunit) altered offspring's response to osmotic stress at hatching independently of offspring genotype. Furthermore, we found that expressing wild44 type isp -1 in germ cells (oocytes) was sufficient to restore offspring's normal response to osmotic stress. Chemical mutagenesis screens revealed that maternal ETC composition regulates offspring's response to stress by altering AMP kinase function in offspring which in turn regulates both ATP and glycerol metabolism in response to continued osmotic stress. To our knowledge, these data are the first to show that proper oocyte ETC composition is required to link a mother's environment to adaptive changes in offspring metabolism. The data also raise the possibility that the reason diverse animals exhibit insulin regulated remodeling of oocyte mitochondria is to tailor offspring metabolism to best match the environment of their mother.
    DOI:  https://doi.org/10.21203/rs.3.rs-4087193/v1
  14. Mitochondrion. 2024 Apr 09. pii: S1567-7249(24)00039-4. [Epub ahead of print]76 101881
    The Schizosaccharomyces pombe DEAD-box protein Mss116 is required for mitoribosome assembly and mitochondrial translation.
    Yirong Wang, Gang Feng, Ying Huang.
      DEAD-box helicases are important players in mitochondrial gene expression, which is necessary for mitochondrial respiration. In this study, we characterized Schizosaccharomyces pombe Mss116 (spMss116), a member of the family of DEAD-box RNA helicases. Deletion of spmss116 in a mitochondrial intron-containing background significantly reduced the levels of mitochondrial DNA (mtDNA)-encoded cox1 and cob1 mRNAs and impaired mitochondrial translation, leading to a severe respiratory defect and a loss of cell viability during stationary phase. Deletion of mitochondrial introns restored the levels of cox1 and cob1 mRNAs to wide-type (WT) levels but could not restore mitochondrial translation and respiration in Δspmss116 cells. Furthermore, deletion of spmss116 in both mitochondrial intron-containing and intronless backgrounds impaired mitoribosome assembly and destabilization of mitoribosomal proteins. Our findings suggest that defective mitochondrial translation caused by deletion of spmss116 is most likely due to impaired mitoribosome assembly.
    Keywords:  DEAD-box protein; Mitochondrial translation; Mitoribosome assembly; OXPHOS, Respiration
    DOI:  https://doi.org/10.1016/j.mito.2024.101881
  15. bioRxiv. 2024 Mar 28. pii: 2024.03.26.586649. [Epub ahead of print]
    Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis.
    Luis R Rodriguez, Konstantinos-Dionysios Alysandratos, Jeremy Katzen, Aditi Murthy, Willy Roque Barboza, Yaniv Tomer, Rebeca Acin-Perez, Anton Petcherski, Kasey Minakin, Paige Carson, Swati Iyer, Katrina Chavez, Charlotte H Cooper, Apoorva Babu, Aaron I Weiner, Andrew E Vaughan, Zoltan Arany, Orian S Shirihai, Darrell N Kotton, Michael F Beers.
      Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.
    DOI:  https://doi.org/10.1101/2024.03.26.586649
  16. Sci Adv. 2024 Apr 12. 10(15): eadl0372
    Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.
    Yu Zhuang, Shengjie Jiang, Xiaoling Deng, An Lao, Xiaolin Hua, Yun Xie, Lingyong Jiang, Xudong Wang, Kaili Lin.
      Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation in accumulated senescent cells (SnCs) with aging is essential for tissue homeostasis, and adequate ATP is important in cell activation for aged tissue repair. Strategies for ATP metabolism intervention hold prospects for therapeutic advances. Here, we found energy metabolic changes in aging skin from patients and mice. Our data show that metformin engineered EV (Met-EV) can enhance aged mouse skin repair, as well as ameliorate cellular senescence and restore cell dysfunctions. Notably, ATP metabolism was remodeled as reduced glycolysis and enhanced OXPHOS after Met-EV treatment. We show Met-EV rescue senescence-induced mitochondria dysfunctions and mitophagy suppressions, indicating the role of Met-EV in remodeling mitochondrial functions via mitophagy for adequate ATP production in aged tissue repair. Our results reveal the mechanism for SnCs rejuvenation by EV and suggest the disturbed energy metabolism, essential in age-related defects, to be a potential therapeutic target for facilitating aged tissue repair.
    DOI:  https://doi.org/10.1126/sciadv.adl0372
  17. J Physiol. 2024 Apr 11.
    Right place at the right time: Mitochondrial shape, distribution and inter-organelle interaction during skeletal muscle postnatal development.
    Itamar C G Jesus, Marcos Eliezeck, Débora L Scheffer.
      
    Keywords:  inter‐organelle interaction; lipid droplet; mitochondria; postnatal development; skeletal muscle
    DOI:  https://doi.org/10.1113/JP286517
  18. Nat Cell Biol. 2024 Apr 09.
    Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
    Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.
      Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.
    DOI:  https://doi.org/10.1038/s41556-024-01400-3
  19. Exp Gerontol. 2024 Apr 11. pii: S0531-5565(24)00070-6. [Epub ahead of print]190 112428
    PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.
    Yimin Fu, Lei Tao, Xiaojun Wang, Binyou Wang, Weilin Qin, Lei Song.
      BACKGROUND: Mitochondrial dysregulation in skeletal myocytes is considered a major factor in aged sarcopenia. In this study, we aimed to study the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on Sestrin2-mediated mechanistic target of rapamycin complex 1 (mTORC1) in aged skeletal muscles.METHODS: C2C12 myoblasts were stimulated by 50 μM 7β-hydroxycholesterol (7β-OHC) to observe the changes of DNA damage, mitochondrial membrane potential (Δψm), mitochondrial ROS and PGC-1α protein. The PGC-1α silence in the C2C12 cells was established by siRNA transfection. The levels of DNA damage, Δψm, mitochondrial ROS, Sestrin2 and p-S6K1/S6K1 proteins were observed after the PGC-1α silence in the C2C12 cells. Recombinant Sestrin2 treatment was used to observe the changes of DNA damage, Δψm, mitochondrial ROS and p-S6K1/S6K1 protein in the 7β-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. Wild-type (WT) mice and muscle-specific PGC-1α conditional knockout (MKO) mice, including young and old, were used to analyse the effects of PGC-1α on muscle function and the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles. Recombinant Sestrin2 was administrated to analyse its effects on muscle function in the old WT mice and old MKO mice.
    RESULTS: 7β-OHC treatment induced DNA damage, mitochondrial dysfunction and decrease of PGC-1α protein in the C2C12 cells. PGC-1α silence also induced DNA damage and mitochondrial dysfunction in the C2C12 cells. Additionally, PGC-1α silence or 7β-OHC treatment decreased the levels of Sestrin2 and p-S6K1/S6K1 protein in the C2C12 cells. Recombinant Sestrin2 treatment significantly improved the DNA damage and mitochondrial dysfunction in the 7β-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia and decreased the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles when compared to the WT mice. Recombinant Sestrin2 treatment improved muscle function and increased p-S6K1 levels in the old two genotypes.
    CONCLUSION: This research demonstrates that PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.
    Keywords:  7β-hydroxycholesterol; Mitochondrial dysregulation; Muscle function; PGC-1α conditional knockout
    DOI:  https://doi.org/10.1016/j.exger.2024.112428
  20. Semin Fetal Neonatal Med. 2024 Apr 10. pii: S1744-165X(24)00005-2. [Epub ahead of print] 101523
    Interdisciplinary fetal neurology care: Current practice, challenges, and future directions.
    Charu Venkatesan, DonnaMaria Cortezzo, Mounira Habli, Sonika Agarwal.
      As the field of fetal-neonatal neurology has expanded over the past 2 decades with increasingly complex diagnoses, multidisciplinary collaboration with many subspecialties including genetics, neonatology, obstetrics, maternal fetal medicine, surgical sub-specialties, cardiology, radiology, palliative care, and ethics has needed to evolve to strive to offer optimal patient care. While comprehensive care delivery with an inter-disciplinary approach is preferred, there are often barriers based on numerous health disparities especially in resource limited settings. Even in the context of comprehensive care, diagnostic and prognostic uncertainty lead to challenges for providers during fetal neurology consultations. We present a case that highlights advantages of a comprehensive multi-disciplinary team in caring for the medical and social challenges of patients faced with a fetal neurologic diagnosis. Inter-disciplinary training focusing on maternal, fetal, neonatal, and childhood neurodevelopmental course and collaboration among the numerous stakeholders that contribute to fetal neurology practice is needed to provide optimal counseling and care for families faced with a fetal neurological diagnosis.
    DOI:  https://doi.org/10.1016/j.siny.2024.101523
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