bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–01–21
thirty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
  2. NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
  3. Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.
  4. The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function.
  5. Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2.
  6. A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy.
  7. Obstetric complications in women with mitochondrial disease.
  8. Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation.
  9. Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
  10. Loss of the WDR23 proteostasis impacts mitochondrial homeostasis in the mouse brain.
  11. Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia.
  12. A clinical approach to diagnosis and management of mitochondrial myopathies.
  13. Extracellular vesicle mitochondrial DNA levels are associated with race and mitochondrial DNA haplogroup.
  14. PMPCA-Related Encephalopathy: Novel Variants, Phenotype Extension, and Mitochondrial Morphology.
  15. In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
  16. Mitochondrial Dynamics, Diabetes, and Cardiovascular Disease.
  17. Mitochondrial dysfunction in neurodegenerative disorders.
  18. Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.
  19. Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis.
  20. Making the connection: How membrane contact sites have changed our view of organelle biology.
  21. Interaction of PINK1 with nucleotides and kinetin.
  22. USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
  23. Stem cell-derived embryo models: a frontier of human embryology.
  24. Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy.
  25. NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
  26. Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal.
  27. Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle.
  28. A mitochondrial regulator protein, MNRR1, is elevated in the maternal blood of women with preeclampsia.
  29. Oxaloacetic acid induces muscle energy substrate depletion and fatigue by JNK-mediated mitochondrial uncoupling.
  30. Improving prenatal diagnosis through standards and aggregation.
  1. Cell Death Differ. 2024 Jan 18.
    Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
    Elena Marchesan, Alice Nardin, Sofia Mauri, Greta Bernardo, Vivek Chander, Simone Di Paola, Monica Chinellato, Sophia von Stockum, Joy Chakraborty, Stephanie Herkenne, Valentina Basso, Emilie Schrepfer, Oriano Marin, Laura Cendron, Diego L Medina, Luca Scorrano, Elena Ziviani.
      Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.
    DOI:  https://doi.org/10.1038/s41418-023-01251-9
  2. Nat Commun. 2024 Jan 16. 15(1): 546
    NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
    Liang Yang, Zifeng Ruan, Xiaobing Lin, Hao Wang, Yanmin Xin, Haite Tang, Zhijuan Hu, Yunhao Zhou, Yi Wu, Junwei Wang, Dajiang Qin, Gang Lu, Kerry M Loomes, Wai-Yee Chan, Xingguo Liu.
      Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.
    DOI:  https://doi.org/10.1038/s41467-024-44808-z
  3. Mol Neurobiol. 2024 Jan 15.
    Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.
    Mazyar Yazdani.
      Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder. It is caused by mitochondrial DNA (mtDNA) rearrangements, mostly large-scale deletions of 1.1-10 kb. These deletions primarily affect energy supply through impaired oxidative phosphorylation and reduced ATP production. This impairment gives rise to dysfunction of several tissues, in particular those with high energy demand like brain and muscles. Over the past decades, changes in respiratory chain complexes and energy metabolism have been emphasized, whereas little attention has been paid to other reports on ROS overproduction, protein synthesis inhibition, myelin vacuolation, demyelination, autophagy, apoptosis, and involvement of lipid raft and oligodendrocytes in KSS. Therefore, this paper draws attention towards these relatively underemphasized findings that might further clarify the pathologic cascades following deletions in the mtDNA.
    Keywords:  Apoptosis; Autophagy; Lipid raft; Myelin Vacuolation; Oligodendrocyte; Reactive Oxygen Species (ROS)
    DOI:  https://doi.org/10.1007/s12035-024-03938-7
  4. Cell Death Dis. 2024 Jan 17. 15(1): 58
    The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function.
    Giulia Di Marco, Gaia Gherardi, Agnese De Mario, Ilaria Piazza, Martina Baraldo, Andrea Mattarei, Bert Blaauw, Rosario Rizzuto, Diego De Stefani, Cristina Mammucari.
      MitoKATP is a channel of the inner mitochondrial membrane that controls mitochondrial K+ influx according to ATP availability. Recently, the genes encoding the pore-forming (MITOK) and the regulatory ATP-sensitive (MITOSUR) subunits of mitoKATP were identified, allowing the genetic manipulation of the channel. Here, we analyzed the role of mitoKATP in determining skeletal muscle structure and activity. Mitok-/- muscles were characterized by mitochondrial cristae remodeling and defective oxidative metabolism, with consequent impairment of exercise performance and altered response to damaging muscle contractions. On the other hand, constitutive mitochondrial K+ influx by MITOK overexpression in the skeletal muscle triggered overt mitochondrial dysfunction and energy default, increased protein polyubiquitination, aberrant autophagy flux, and induction of a stress response program. MITOK overexpressing muscles were therefore severely atrophic. Thus, the proper modulation of mitoKATP activity is required for the maintenance of skeletal muscle homeostasis and function.
    DOI:  https://doi.org/10.1038/s41419-024-06426-x
  5. Acta Neuropathol. 2024 Jan 19. 147(1): 19
    Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2.
    Felix Kleefeld, Rita Horvath, Iago Pinal-Fernandez, Andrew L Mammen, Maria Casal-Dominguez, Denisa Hathazi, Sarah Melchert, Katrin Hahn, Albert Sickmann, Claudia Muselmann-Genschow, Andreas Hentschel, Corinna Preuße, Andreas Roos, Benedikt Schoser, Werner Stenzel.
      Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.
    Keywords:  Mitochondrial dysfunction; Myotonic dystrophy type 2; Proximal myotonic myopathy
    DOI:  https://doi.org/10.1007/s00401-023-02673-y
  6. J Neuromuscul Dis. 2024 Jan 08.
    A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy.
    Andrea Gangfuß, Philipp Rating, Tomas Ferreira, Andreas Hentschel, Adela Della Marina, Heike Kölbel, Albert Sickmann, Angela Abicht, Florian Kraft, Tobias Ruck, Johann Böhm, Anne Schänzer, Ulrike Schara-Schmidt, Teresa M Neuhann, Rita Horvath, Andreas Roos.
       BACKGROUND: The NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 (NDUFS6) gene encodes for an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Bi-allelic NDUFS6 variants have been linked with a severe disorder mostly reported as a lethal infantile mitochondrial disease (LMID) or Leigh syndrome (LS).
    OBJECTIVE: Here, we identified a homozygous variant (c.309 + 5 G >  A) in NDUFS6 in one male patient with axonal neuropathy accompanied by loss of small fibers in skin biopsy and further complicated by optic atrophy and borderline intellectual disability.
    METHODS: To address the pathogenicity of the variant, biochemical studies (mtDNA copy number quantification, ELISA, Proteomic profiling) of patient-derived leukocytes were performed.
    RESULTS: The analyses revealed loss of NDUFS6 protein associated with a decrease of three further mitochondrial NADH dehydrogenase subunit/assembly proteins (NDUFA12, NDUFS4 and NDUFV1). Mitochondrial copy number is not altered in leukocytes and the mitochondrial biomarker GDF15 is not significantly changed in serum.
    CONCLUSIONS: Hence, our combined clinical and biochemical data strengthen the concept of NDUFS6 being causative for a very rare form of axonal neuropathy associated with optic atrophy and borderline intellectual disability, and thus expand (i) the molecular genetic landscape of neuropathies and (ii) the clinical spectrum of NDUFS6-associated phenotypes.
    Keywords:  Charcot-Marie-Tooth disease; NDUFS6; axonal neuropathy; white blood cell proteomics
    DOI:  https://doi.org/10.3233/JND-230181
  7. Acta Diabetol. 2024 Jan 18.
    Obstetric complications in women with mitochondrial disease.
    M M Byrne, B Sanchez-Lechuga, N Ng, B Byrne.
      
    DOI:  https://doi.org/10.1007/s00592-023-02225-6
  8. Open Biol. 2024 Jan;14(1): 230279
    Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation.
    Swati Agarwala, Sukhamoy Dhabal, Kasturi Mitra.
      Mitochondria, classically known as the powerhouse of cells, are unique double membrane-bound multifaceted organelles carrying a genome. Mitochondrial content varies between cell types and precisely doubles within cells during each proliferating cycle. Mitochondrial content also increases to a variable degree during cell differentiation triggered after exit from the proliferating cycle. The mitochondrial content is primarily maintained by the regulation of mitochondrial biogenesis, while damaged mitochondria are eliminated from the cells by mitophagy. In any cell with a given mitochondrial content, the steady-state mitochondrial number and shape are determined by a balance between mitochondrial fission and fusion processes. The increase in mitochondrial content and alteration in mitochondrial fission and fusion are causatively linked with the process of differentiation. Here, we critically review the quantitative aspects in the detection methods of mitochondrial content and shape. Thereafter, we quantitatively link these mitochondrial properties in differentiating cells and highlight the implications of such quantitative link on stem cell functionality. Finally, we discuss an example of cell size regulation predicted from quantitative analysis of mitochondrial shape and content. To highlight the significance of quantitative analyses of these mitochondrial properties, we propose three independent rationale based hypotheses and the relevant experimental designs to test them.
    Keywords:  cell differentiation; cell proliferation; mitochondrial content; mitochondrial heterogeneity; mitochondrial shape; stem cells
    DOI:  https://doi.org/10.1098/rsob.230279
  9. Cell Rep. 2024 Jan 17. pii: S2211-1247(24)00009-3. [Epub ahead of print]43(2): 113681
    Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
    Madeleine J Twyning, Roberta Tufi, Thomas P Gleeson, Kinga M Kolodziej, Susanna Campesan, Ana Terriente-Felix, Lewis Collins, Federica De Lazzari, Flaviano Giorgini, Alexander J Whitworth.
      Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.
    Keywords:  Alzheimer's disease; CP: Neuroscience; Drosophila; Huntington's disease; MCU; NCLX; Parkinson's disease; calcium overload; frontotemporal dementia; mitochondrial calcium; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2024.113681
  10. Cell Signal. 2024 Jan 17. pii: S0898-6568(24)00029-9. [Epub ahead of print] 111061
    Loss of the WDR23 proteostasis impacts mitochondrial homeostasis in the mouse brain.
    Chatrawee Duangjan, Ronald W Irwin, Sean P Curran.
      Mitochondrial adaptation is important for stress resistance throughout life. Here we show that WDR23 loss results in an enrichment for genes regulated by nuclear respiratory factor 1 (NRF1), which coordinates mitochondrial biogenesis and respiratory functions, and an increased steady state level of several nuclear coded mitochondrial resident proteins in the brain. Wdr23KO also increases the endogenous levels of insulin degrading enzyme (IDE) and the relaxin-3 peptide (RLN3), both of which have established roles in mediating mitochondrial metabolic and oxidative stress responses. Taken together, these studies reveal an important role for WDR23 as a component of the mitochondrial homeostat in the murine brain.
    Keywords:  Complex I; Homeostasis; Mitochondria; Wdr23; hippocampus
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111061
  11. Sci Rep. 2024 Jan 19. 14(1): 1729
    Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia.
    Dora Ravasz, David Bui, Sara Nazarian, Gergely Pallag, Noemi Karnok, Jennie Roberts, Bryan P Marzullo, Daniel A Tennant, Bennett Greenwood, Alex Kitayev, Collin Hill, Timea Komlódi, Carolina Doerrier, Kristyna Cunatova, Erika Fernandez-Vizarra, Erich Gnaiger, Michael A Kiebish, Alexandra Raska, Krasimir Kolev, Bence Czumbel, Niven R Narain, Thomas N Seyfried, Christos Chinopoulos.
      Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in the mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extent in isolated mitochondria in real-time, we demonstrate that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. 13C metabolic tracing or untargeted analysis of metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system showed that NAD+ regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase Complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Complex II operated amphidirectionally during the anoxic event, providing quinones to Complex I and reducing fumarate to succinate. Our results highlight the importance of quinone provision to Complex I oxidizing NADH maintaining glutamate catabolism and mtSLP in the absence of OXPHOS.
    DOI:  https://doi.org/10.1038/s41598-024-51365-4
  12. Neurotherapeutics. 2023 Dec 19. pii: S1878-7479(23)01940-2. [Epub ahead of print]21(1): e00304
    A clinical approach to diagnosis and management of mitochondrial myopathies.
    Hui-Lin Chin, Poh San Lai, Stacey Kiat Hong Tay.
      This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders.
    Keywords:  Diagnostic approach; Genetic sequencing; Mitochondrial disease; Mitochondrial disease treatment; Mitochondrial myopathy
    DOI:  https://doi.org/10.1016/j.neurot.2023.11.001
  13. iScience. 2024 Jan 19. 27(1): 108724
    Extracellular vesicle mitochondrial DNA levels are associated with race and mitochondrial DNA haplogroup.
    Anjali M Byappanahalli, Victor Omoniyi, Nicole Noren Hooten, Jessica T Smith, Nicolle A Mode, Ngozi Ezike, Alan B Zonderman, Michele K Evans.
      Circulating cell-free mitochondrial DNA (ccf-mtDNA) acts as a damage-associated molecular pattern molecule and may be cargo within extracellular vesicles (EVs). ccf-mtDNA and select mitochondrial DNA (mtDNA) haplogroups are associated with cardiovascular disease. We hypothesized that ccf-mtDNA and plasma EV mtDNA would be associated with hypertension, sex, self-identified race, and mtDNA haplogroup ancestry. Participants were normotensive (n = 107) and hypertensive (n = 108) African American and White adults from the Healthy Aging in Neighborhoods of Diversity across the Life Span study. ccf-mtDNA levels were higher in African American participants compared with White participants in both plasma and EVs, but ccf-mtDNA levels were not related to hypertension. EV mtDNA levels were highest in African American participants with African mtDNA haplogroup. Circulating inflammatory protein levels were altered with mtDNA haplogroup, race, and EV mtDNA. Our findings highlight that race is a social construct and that ancestry is crucial when examining health and biomarker differences between groups.
    Keywords:  Biochemistry; Biological sciences; Cell biology; Immunology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108724
  14. Neurol Genet. 2023 Dec;9(6): e200106
    PMPCA-Related Encephalopathy: Novel Variants, Phenotype Extension, and Mitochondrial Morphology.
    Vibhuti Rambani, Miriam Kolnikova, Michal Cagalinec, Martina Skopkova, Daniela Gasperikova.
       Objectives: The PMPCA gene encodes the α-subunit of mitochondrial processing peptidase (α-MPP), an enzyme responsible for cleavage of nuclear-encoded mitochondrial precursor proteins after their import into mitochondria. Mutations in this gene have been described in patients with nonprogressive or slow progressive cerebellar ataxia, with variable age at onset and severity. Cerebellar atrophy and striatum changes were found in severe cases.
    Methods: The patient was diagnosed using whole exome sequencing. Skin fibroblasts were used for confirmation of α-MPP levels using western blot and mitochondrial morphology assessment of immunofluorescent confocal microscopy images.
    Results: Two novel compound heterozygous variants in the PMPCA gene (p.Tyr241Ser and p.Met251Val) were identified in an 8-year-old proband with progressive spastic quadriparesis, delayed psychomotor development, and intellectual disability, with onset at 13 months. The brain imaging showed cortical and cerebellar atrophy, reduced volume of basal ganglia with striatum hyperintensity, and periventricular white matter changes. The patient's fibroblasts showed a decreased α-MPP level and reduced and fragmented mitochondria.
    Discussion: The described case contributes to the number of patients with progressive PMPCA-related disease with a severe intermediate phenotype. Moreover, we extend the phenotype to Leigh-like white matter changes that have not been described in previously reported cases.
    DOI:  https://doi.org/10.1212/NXG.0000000000200106
  15. EMBO J. 2024 Jan 15.
    In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
    Michelle Y Fry, Paula P Navarro, Pusparanee Hakim, Virly Y Ananda, Xingping Qin, Juan C Landoni, Sneha Rath, Zintis Inde, Camila Makhlouta Lugo, Bridget E Luce, Yifan Ge, Julie L McDonald, Ilzat Ali, Leillani L Ha, Benjamin P Kleinstiver, David C Chan, Kristopher A Sarosiek, Luke H Chao.
      Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.
    Keywords:  Cristae Remodeling; Cryo-Electron Tomography; Cryo-Focused Ion Beam Milling; Mitochondrial Biology
    DOI:  https://doi.org/10.1038/s44318-024-00027-2
  16. Diabetes. 2024 Feb 01. 73(2): 151-161
    Mitochondrial Dynamics, Diabetes, and Cardiovascular Disease.
    Luis Miguel García-Peña, E Dale Abel, Renata O Pereira.
      Mitochondria undergo repeated cycles of fusion and fission that regulate their size and shape by a process known as mitochondrial dynamics. Numerous studies have revealed the importance of this process in maintaining mitochondrial health and cellular homeostasis, particularly in highly metabolically active tissues such as skeletal muscle and the heart. Here, we review the literature on the relationship between mitochondrial dynamics and the pathophysiology of type 2 diabetes and cardiovascular disease (CVD). Importantly, we emphasize divergent outcomes resulting from downregulating distinct mitochondrial dynamics proteins in various tissues. This review underscores compensatory mechanisms and adaptive pathways that offset potentially detrimental effects, resulting instead in improved metabolic health. Finally, we offer a perspective on potential therapeutic implications of modulating mitochondrial dynamics proteins for treatment of diabetes and CVD.
    ARTICLE HIGHLIGHTS:
    DOI:  https://doi.org/10.2337/dbi23-0003
  17. Neurotherapeutics. 2023 Dec 19. pii: S1878-7479(23)01900-1. [Epub ahead of print]21(1): e00292
    Mitochondrial dysfunction in neurodegenerative disorders.
    Madelyn M Klemmensen, Seth H Borrowman, Colin Pearce, Benjamin Pyles, Bharatendu Chandra.
      Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.
    Keywords:  Aging; Bioenergetics; Mitochondria; Neurodegeneration; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.neurot.2023.10.002
  18. Nat Commun. 2024 Jan 19. 15(1): 611
    Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.
    Ason C Y Chiang, Jan Ježek, Peiqiang Mu, Ying Di, Anna Klucnika, Martin Jabůrek, Petr Ježek, Hansong Ma.
      Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.
    DOI:  https://doi.org/10.1038/s41467-024-44964-2
  19. J Neuroinflammation. 2024 Jan 20. 21(1): 28
    Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis.
    Peng-Fei Wang, Fei Jiang, Qiu-Ming Zeng, Wei-Fan Yin, Yue-Zi Hu, Qiao Li, Zhao-Lan Hu.
      Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction has been implicated in the pathogenesis of MS, as studies have shown abnormalities in mitochondrial activities, metabolism, mitochondrial DNA (mtDNA) levels, and mitochondrial morphology in immune cells of individuals with MS. The presence of mitochondrial dysfunctions in immune cells contributes to immunological dysregulation and neurodegeneration in MS. This review provided a comprehensive overview of mitochondrial dysfunction in immune cells associated with MS, focusing on the potential consequences of mitochondrial metabolic reprogramming on immune function. Current challenges and future directions in the field of immune-metabolic MS and its potential as a therapeutic target were also discussed.
    Keywords:  Immune cells; Immune-metabolic; MS; Mitochondrion
    DOI:  https://doi.org/10.1186/s12974-024-03016-8
  20. Cell. 2024 Jan 18. pii: S0092-8674(23)01328-4. [Epub ahead of print]187(2): 257-270
    Making the connection: How membrane contact sites have changed our view of organelle biology.
    G K Voeltz, E M Sawyer, G Hajnóczky, W A Prinz.
      The view of organelles and how they operate together has changed dramatically over the last two decades. The textbook view of organelles was that they operated largely independently and were connected by vesicular trafficking and the diffusion of signals through the cytoplasm. We now know that all organelles make functional close contacts with one another, often called membrane contact sites. The study of these sites has moved to center stage in cell biology as it has become clear that they play critical roles in healthy and developing cells and during cell stress and disease states. Contact sites have important roles in intracellular signaling, lipid metabolism, motor-protein-mediated membrane dynamics, organelle division, and organelle biogenesis. Here, we summarize the major conceptual changes that have occurred in cell biology as we have come to appreciate how contact sites integrate the activities of organelles.
    DOI:  https://doi.org/10.1016/j.cell.2023.11.040
  21. Sci Adv. 2024 Jan 19. 10(3): eadj7408
    Interaction of PINK1 with nucleotides and kinetin.
    Zhong Yan Gan, Sylvie Callegari, Thanh N Nguyen, Nicholas S Kirk, Andrew Leis, Michael Lazarou, Grant Dewson, David Komander.
      The ubiquitin kinase PINK1 accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson's disease. Nucleotide analogs such as kinetin triphosphate (KTP) were reported to enhance PINK1 activity and may represent a therapeutic strategy for the treatment of Parkinson's disease. Here, we investigate the interaction of PINK1 with nucleotides, including KTP. We establish a cryo-EM platform exploiting the dodecamer assembly of Pediculus humanus corporis (Ph) PINK1 and determine PINK1 structures bound to AMP-PNP and ADP, revealing conformational changes in the kinase N-lobe that help establish PINK1's ubiquitin binding site. Notably, we find that KTP is unable to bind PhPINK1 or human (Hs) PINK1 due to a steric clash with the kinase "gatekeeper" methionine residue, and mutation to Ala or Gly is required for PINK1 to bind and use KTP as a phosphate donor in ubiquitin phosphorylation and mitophagy. HsPINK1 M318G can be used to conditionally uncouple PINK1 stabilization and activity on mitochondria.
    DOI:  https://doi.org/10.1126/sciadv.adj7408
  22. Cell Death Dis. 2024 Jan 15. 15(1): 52
    USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
    Justyna Okarmus, Jette Bach Agergaard, Tina C Stummann, Henriette Haukedal, Malene Ambjørn, Kristine K Freude, Karina Fog, Morten Meyer.
      Ubiquitination of mitochondrial proteins plays an important role in the cellular regulation of mitophagy. The E3 ubiquitin ligase parkin (encoded by PARK2) and the ubiquitin-specific protease 30 (USP30) have both been reported to regulate the ubiquitination of outer mitochondrial proteins and thereby mitophagy. Loss of E3 ligase activity is thought to be pathogenic in both sporadic and inherited Parkinson's disease (PD), with loss-of-function mutations in PARK2 being the most frequent cause of autosomal recessive PD. The aim of the present study was to evaluate whether mitophagy induced by USP30 inhibition provides a functional rescue in isogenic human induced pluripotent stem cell-derived dopaminergic neurons with and without PARK2 knockout (KO). Our data show that healthy neurons responded to CCCP-induced mitochondrial damage by clearing the impaired mitochondria and that this process was accelerated by USP30 inhibition. Parkin-deficient neurons showed an impaired mitophagic response to the CCCP challenge, although mitochondrial ubiquitination was enhanced. USP30 inhibition promoted mitophagy in PARK2 KO neurons, independently of whether left in basal conditions or treated with CCCP. In PARK2 KO, as in control neurons, USP30 inhibition balanced oxidative stress levels by reducing excessive production of reactive oxygen species. Interestingly, non-dopaminergic neurons were the main driver of the beneficial effects of USP30 inhibition. Our findings demonstrate that USP30 inhibition is a promising approach to boost mitophagy and improve cellular health, also in parkin-deficient cells, and support the potential relevance of USP30 inhibitors as a novel therapeutic approach in diseases with a need to combat neuronal stress mediated by impaired mitochondria.
    DOI:  https://doi.org/10.1038/s41419-024-06439-6
  23. Med Rev (2021). 2023 Aug;3(4): 343-346
    Stem cell-derived embryo models: a frontier of human embryology.
    Norio Kobayashi, Jianping Fu.
      Studying human development remains difficult due to limited accessibility to human embryonic tissues. Prompted by the availability of human stem cells that share molecular and cellular similarities with embryonic and extraembryonic cells in peri-implantation human embryos, researchers have now successfully developed stem cell-based human embryo models that are promising as experimental tools for studying early human development. In this Perspective, we discuss the current progress in mouse and human stem cell-derived embryo models and highlight their promising applications in advancing the fundamental understanding of mammalian development.
    Keywords:  embryo models; embryonic development; pluripotent stem cells
    DOI:  https://doi.org/10.1515/mr-2023-0009
  24. Brain. 2024 Jan 18. pii: awae020. [Epub ahead of print]
    Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy.
    Lucia Abela, Lorita Gianfrancesco, Erica Tagliatti, Giada Rossignoli, Katy Barwick, Clara Zourray, Kimberley M Reid, Dimitri Budinger, Joanne Ng, John Counsell, Arlo Simpson, Toni S Pearson, Simon Edvardson, Orly Elpeleg, Frances M Brodsky, Gabriele Lignani, Serena Barral, Manju A Kurian.
      DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently, there are no disease-modifying treatments for this condition, resulting in significant morbidity and risk of premature mortality. To investigate the underlying disease mechanisms in childhood-onset DNAJC6 parkinsonism, we generated induced pluripotent stem cells (iPSC) from three patients harboring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic (mDA) neuronal model of disease. When compared to age-matched and CRISPR-corrected isogenic controls, the neuronal cell model revealed disease-specific auxilin deficiency as well as disturbance of synaptic vesicle (SV) recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. In order to explore the feasibility of a viral vector-mediated gene therapy approach, iPSC-derived neuronal cultures were treated with lentiviral DNAJC6 gene transfer, which restored auxilin expression and rescued CME. Our patient-derived neuronal model provides deeper insights into the molecular mechanisms of auxilin deficiency as well as a robust platform for the development of targeted precision therapy approaches.
    Keywords:  CME; DNAJC6; auxilin; gene therapy; neurodevelopmental; parkinsonism
    DOI:  https://doi.org/10.1093/brain/awae020
  25. J Cell Biochem. 2024 Jan 15.
    NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
    Bin Ye, Yingting Pei, Lujing Wang, Dehao Meng, Yu Zhang, Shuang Zou, Henian Li, Jinying Liu, Ziying Xie, Changhong Tian, Yuqi Jiang, Yu Qiao, Xu Gao, Yanfen Zhang, Ning Ma.
      Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.
    Keywords:  SASP; cGAS-STING; mitochondria; nicotinamide mononucleotide; senescence
    DOI:  https://doi.org/10.1002/jcb.30522
  26. J Clin Invest. 2024 Jan 18. pii: e171995. [Epub ahead of print]
    Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal.
    Changyou Jiang, Han Huang, Xiao Yang, Qiumin Le, Xing Liu, Lan Ma, Feifei Wang.
      Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity, dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.
    Keywords:  Addiction; Mitochondria; Neurological disorders; Neuroscience; Therapeutics
    DOI:  https://doi.org/10.1172/JCI171995
  27. J Cell Physiol. 2024 Jan 14.
    Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle.
    Fatemeh Sadeghsoltani, Parisa Hassanpour, Mir-Meghdad Safari, Sanya Haiaty, Reza Rahbarghazi, Mohamad Rahmati, Ali Mota.
      Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.
    Keywords:  Phosphatase and Tensin Homolog; angiogenesis; autophagy; endothelial cells; exosomes; mitochondrial donation; tunneling nanotubes
    DOI:  https://doi.org/10.1002/jcp.31185
  28. J Matern Fetal Neonatal Med. 2024 Dec;37(1): 2297158
    A mitochondrial regulator protein, MNRR1, is elevated in the maternal blood of women with preeclampsia.
    Manaphat Suksai, Roberto Romero, Mariachiara Bosco, Francesca Gotsch, Eunjung Jung, Piya Chaemsaithong, Adi L Tarca, Dereje W Gudicha, Nardhy Gomez-Lopez, Marcia Arenas-Hernandez, Arun Meyyazhagan, Lawrence I Grossman, Siddhesh Aras, Tinnakorn Chaiworapongsa.
       OBJECTIVE: Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative stress and an anti-angiogenic state play a crucial role. Mitochondria are a major source of cellular reactive oxygen species. Abnormalities in mitochondrial structures, proteins, and functions have been observed in the placentae of patients with preeclampsia, thus mitochondrial dysfunction has been implicated in the mechanism of the disease. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a newly characterized bi-organellar protein with pleiotropic functions. In the mitochondria, this protein regulates cytochrome c oxidase activity and reactive oxygen species production, whereas in the nucleus, it regulates the transcription of a number of genes including response to tissue hypoxia and inflammatory signals. Since MNRR1 expression changes in response to hypoxia and to an inflammatory signal, MNRR1 could be a part of mitochondrial dysfunction and involved in the pathologic process of preeclampsia. This study aimed to determine whether the plasma MNRR1 concentration of women with preeclampsia differed from that of normal pregnant women.
    METHODS: This retrospective case-control study included 97 women with preeclampsia, stratified by gestational age at delivery into early (<34 weeks, n = 40) and late (≥34 weeks, n = 57) preeclampsia and by the presence or absence of placental lesions consistent with maternal vascular malperfusion (MVM), the histologic counterpart of an anti-angiogenic state. Women with an uncomplicated pregnancy at various gestational ages who delivered at term served as controls (n = 80) and were further stratified into early (n = 25) and late (n = 55) controls according to gestational age at venipuncture. Maternal plasma MNRR1 concentrations were determined by an enzyme-linked immunosorbent assay.
    RESULTS: 1) Women with preeclampsia at the time of diagnosis (either early or late disease) had a significantly higher median (interquartile range, IQR) plasma MNRR1 concentration than the controls [early preeclampsia: 1632 (924-2926) pg/mL vs. 630 (448-4002) pg/mL, p = .026, and late preeclampsia: 1833 (1441-5534) pg/mL vs. 910 (526-6178) pg/mL, p = .021]. Among women with early preeclampsia, those with MVM lesions in the placenta had the highest median (IQR) plasma MNRR1 concentration among the three groups [with MVM: 2066 (1070-3188) pg/mL vs. without MVM: 888 (812-1781) pg/mL, p = .03; and with MVM vs. control: 630 (448-4002) pg/mL, p = .04]. There was no significant difference in the median plasma MNRR1 concentration between women with early preeclampsia without MVM lesions and those with an uncomplicated pregnancy (p = .3). By contrast, women with late preeclampsia, regardless of MVM lesions, had a significantly higher median (IQR) plasma MNRR1 concentration than women in the control group [with MVM: 1609 (1392-3135) pg/mL vs. control: 910 (526-6178), p = .045; and without MVM: 2023 (1578-8936) pg/mL vs. control, p = .01].
    CONCLUSIONS: MNRR1, a mitochondrial regulator protein, is elevated in the maternal plasma of women with preeclampsia (both early and late) at the time of diagnosis. These findings may reflect some degree of mitochondrial dysfunction, intravascular inflammation, or other unknown pathologic processes that characterize this obstetrical syndrome.
    Keywords:  CHCHD2; early preeclampsia; intravascular inflammation; late preeclampsia; maternal vascular malperfusion; oxidative stress; placenta; pregnancy
    DOI:  https://doi.org/10.1080/14767058.2023.2297158
  29. FASEB J. 2024 Feb;38(2): e23373
    Oxaloacetic acid induces muscle energy substrate depletion and fatigue by JNK-mediated mitochondrial uncoupling.
    Cong Yin, Rui Qin, Zewei Ma, Fan Li, Jiao Liu, Hong Liu, Gang Shu, Hairong Xiong, Qingyan Jiang.
      Fatigue is a common phenomenon closely related to physical discomfort and numerous diseases, which is severely threatening the life quality and health of people. However, the exact mechanisms underlying fatigue are not fully characterized. Herein, we demonstrate that oxaloacetic acid (OAA), a crucial tricarboxylic acid cycle intermediate, modulates the muscle fatigue. The results showed that serum OAA level was positively correlated with fatigue state of mice. OAA-treated induced muscle fatigue impaired the exercise performance of mice. Mechanistically, OAA increased the c-Jun N-terminal kinase (JNK) phosphorylation and uncoupling protein 2 (UCP2) levels in skeletal muscle, which led to decreased energy substrate and enhanced glycolysis. On the other hand, OAA boosted muscle mitochondrial oxidative phosphorylation uncoupled with energy production. In addition, either UCP2 knockout or JNK inhibition totally reversed the effects of OAA on skeletal muscle. Therein, JNK mediated UCP2 activation with OAA-treated. Our studies reveal a novel role of OAA in skeletal muscle metabolism, which would shed light on the mechanism of muscle fatigue and weakness.
    Keywords:  JNK; UCP2; fatigue; oxaloacetic acid; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202301796R
  30. Prenat Diagn. 2024 Jan 19.
    Improving prenatal diagnosis through standards and aggregation.
    Michael H Duyzend, Pilar Cacheiro, Julius O B Jacobsen, Jessica Giordano, Harrison Brand, Ronald J Wapner, Michael E Talkowski, Peter N Robinson, Damian Smedley.
      Advances in sequencing and imaging technologies enable enhanced assessment in the prenatal space, with a goal to diagnose and predict the natural history of disease, to direct targeted therapies, and to implement clinical management, including transfer of care, election of supportive care, and selection of surgical interventions. The current lack of standardization and aggregation stymies variant interpretation and gene discovery, which hinders the provision of prenatal precision medicine, leaving clinicians and patients without an accurate diagnosis. With large amounts of data generated, it is imperative to establish standards for data collection, processing, and aggregation. Aggregated and homogeneously processed genetic and phenotypic data permits dissection of the genomic architecture of prenatal presentations of disease and provides a dataset on which data analysis algorithms can be tuned to the prenatal space. Here we discuss the importance of generating aggregate data sets and how the prenatal space is driving the development of interoperable standards and phenotype-driven tools.
    DOI:  https://doi.org/10.1002/pd.6522
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