bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–07–07
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. The germline coordinates mitokine signaling.
  2. Bridging lipid metabolism and mitochondrial genome maintenance.
  3. Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
  4. SLC25A19 is required for NADH homeostasis and mitochondrial respiration.
  5. Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
  6. Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.
  7. Mitochondrial Parkinsonism: A Practical Guide to Genes and Clinical Diagnosis.
  8. GTPBP8 plays a role in mitoribosome formation in human mitochondria.
  9. From whence it came: Mitochondrial mRNA leaves, a protein returns.
  10. A mitochondrial checkpoint to NF-κB signaling.
  11. Fit for purpose: Selecting the best mitochondrial DNA for the job.
  12. Mitochondrial regulation of erythropoiesis in homeostasis and disease.
  13. Alterations in coenzyme Q10 status in a cybrid line harboring the 3243A>G mutation of mitochondrial DNA is associated with abnormal mitochondrial bioenergetics and dysregulated mitochondrial biogenesis.
  14. Mitochondrial genetics through the lens of single-cell multi-omics.
  15. Sex-dependent differences in macaque brain mitochondria.
  16. Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
  17. Tracking longitudinal thalamic volume changes during early stages of SCA1 and SCA2.
  18. Renal and cardiac biopsy findings in an adolescent patient with the 3243A>G mitochondrial DNA mutation: Favorable renal prognosis post renal transplantation from the mother.
  19. Mutation of mpv17 results in loss of iridophores due to mitochondrial dysfunction in tilapia.
  20. NCLX controls hepatic mitochondrial Ca2+ extrusion and couples hormone-mediated mitochondrial Ca2+ oscillations with gluconeogenesis.
  21. Preexisting maternal immunity to AAV but not Cas9 impairs in utero gene editing in mice.
  22. TFEB safeguards trophoblast syncytialization in humans and mice.
  23. X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.
  24. Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.
  1. Cell. 2024 Jun 26. pii: S0092-8674(24)00650-0. [Epub ahead of print]
    The germline coordinates mitokine signaling.
    Koning Shen, Jenni Durieux, Cesar G Mena, Brant M Webster, C Kimberly Tsui, Hanlin Zhang, Larry Joe, Kristen M Berendzen, Andrew Dillin.
      The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPRMT) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPRMT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPRMT activation. We also find that the germline tissue itself is essential for UPRMT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.
    Keywords:  C. elegans; aging; germline; lipids; mitochondria; mtUPR; proteostasis; stress response
    DOI:  https://doi.org/10.1016/j.cell.2024.06.010
  2. J Biol Chem. 2024 Jun 27. pii: S0021-9258(24)01999-9. [Epub ahead of print] 107498
    Bridging lipid metabolism and mitochondrial genome maintenance.
    Casadora Boone, Samantha C Lewis.
      Mitochondria are the nexus of cellular energy metabolism and major signaling hubs that integrate information from within and without the cell to implement cell function. Mitochondria harbor a distinct polyploid genome, mitochondrial DNA (mtDNA), that encodes respiratory chain components required for energy production. MtDNA mutation and depletion have been linked to obesity and metabolic syndrome in humans. At the cellular and subcellular levels, mtDNA synthesis is coordinated by membrane contact sites implicated in lipid transfer from the endoplasmic reticulum, tying genome maintenance to lipid storage and homeostasis. Here, we examine the relationship between mtDNA and lipid trafficking, the influence of lipotoxicity on mtDNA integrity, and how lipid metabolism may be disrupted in primary mtDNA disease.
    Keywords:  Mitochondria; lipid metabolism; lipotoxicity; mitochondrial DNA (mtDNA); mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2024.107498
  3. PLoS Biol. 2024 Jul;22(7): e3002671
    Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
    Noga Preminger, Maya Schuldiner.
      Mitochondrial shape and network formation have been primarily associated with the well-established processes of fission and fusion. However, recent research has unveiled an intricate and multifaceted landscape of mitochondrial morphology that extends far beyond the conventional fission-fusion paradigm. These less-explored dimensions harbor numerous unresolved mysteries. This review navigates through diverse processes influencing mitochondrial shape and network formation, highlighting the intriguing complexities and gaps in our understanding of mitochondrial architecture. The exploration encompasses various scales, from biophysical principles governing membrane dynamics to molecular machineries shaping mitochondria, presenting a roadmap for future research in this evolving field.
    DOI:  https://doi.org/10.1371/journal.pbio.3002671
  4. Free Radic Biol Med. 2024 Jun 27. pii: S0891-5849(24)00536-7. [Epub ahead of print]222 317-330
    SLC25A19 is required for NADH homeostasis and mitochondrial respiration.
    Zongsheng Jiang.
      Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity. Although many mitochondrial transporters are associated with metabolic diseases, how they regulate mitochondrial function and their metabolic contributions at the cellular level are largely unknown. Here, we show that mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 is required for mitochondrial respiration. SLC25A19 deficiency leads to reduced cell viability, increased integrated stress response (ISR), enhanced glycolysis and elevated cell sensitivity to 2-deoxyglucose (2-DG) treatment. Through a series of biochemical assays, we found that the depletion of mitochondrial NADH is the primary cause of the impaired mitochondrial respiration in SLC25A19 deficient cells. We also showed involvement of SLC25A19 in regulating the enzymatic activities of complexes I and III, the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle and amino acid metabolism. Consistently, addition of idebenone, an analog of coenzyme Q10, restores mitochondrial respiration and cell viability in SLC25A19 deficient cells. Together, our findings provide new insight into the functions of SLC25A19 in mitochondrial and cellular physiology, and suggest that restoring mitochondrial respiration could be a novel strategy for treating SLC25A19-associated disorders.
    Keywords:  Electron transport chain; Idebenone; Mitochondrial respiration; Mitochondrial transporter; NADH; SLC25A19; TPP
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.019
  5. Aging Cell. 2024 Jul 02. e14262
    Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
    Annika Traa, Allison Keil, Abdelrahman AlOkda, Suleima Jacob-Tomas, Aura A Tamez González, Shusen Zhu, Zenith Rudich, Jeremy M Van Raamsdonk.
      The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.
    Keywords:   C. elegans ; aging; biological resilience; genetics; lifespan; mitochondria; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1111/acel.14262
  6. J Clin Invest. 2024 Jul 01. pii: e175560. [Epub ahead of print]134(13):
    Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.
    Chien-Hui Lo, Zhiquan Liu, Siyu Chen, Frank Lin, Andrew R Berneshawi, Charles Q Yu, Euna B Koo, Tia J Kowal, Ke Ning, Yang Hu, Won-Jing Wang, Y Joyce Liao, Yang Sun.
      Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
    Keywords:  Cell biology; Neurodegeneration; Neurological disorders; Ophthalmology; Retinopathy
    DOI:  https://doi.org/10.1172/JCI175560
  7. Mov Disord Clin Pract. 2024 Jun 28.
    Mitochondrial Parkinsonism: A Practical Guide to Genes and Clinical Diagnosis.
    Piervito Lopriore, Giovanni Palermo, Adriana Meli, Gabriele Bellini, Elena Benevento, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso, Roberto Ceravolo.
       BACKGROUND: Primary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. They can result from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). These disorders are multisystemic and mainly affect high energy-demanding tissues, such as muscle and the central nervous system (CNS). Among many clinical features of CNS involvement, parkinsonism is one of the most common movement disorders in PMDs.
    METHODS: This review provides a pragmatic educational overview of the most recent advances in the field of mitochondrial parkinsonism, from pathophysiology and genetic etiologies to phenotype and diagnosis.
    RESULTS: mtDNA maintenance and mitochondrial dynamics alterations represent the principal mechanisms underlying mitochondrial parkinsonism. It can be present in isolation, alongside other movement disorders or, more commonly, as part of a multisystemic phenotype. Mutations in several nuclear-encoded genes (ie, POLG, TWNK, SPG7, and OPA1) and, more rarely, mtDNA mutations, are responsible for mitochondrial parkinsonism. Progressive external opthalmoplegia and optic atrophy may guide genetic etiology identification.
    CONCLUSION: A comprehensive deep-phenotyping approach is needed to reach a diagnosis of mitochondrial parkinsonism, which lacks distinctive clinical features and exemplifies the intricate genotype-phenotype interplay of PMDs.
    Keywords:  mitochondrial parkinsonism; neurogenetics; parkinsonism; primary mitochondrial diseases
    DOI:  https://doi.org/10.1002/mdc3.14148
  8. Nat Commun. 2024 Jul 05. 15(1): 5664
    GTPBP8 plays a role in mitoribosome formation in human mitochondria.
    Miriam Cipullo, Genís Valentín Gesé, Shreekara Gopalakrishna, Annika Krueger, Vivian Lobo, Maria A Pirozhkova, James Marks, Petra Páleníková, Dmitrii Shiriaev, Yong Liu, Jelena Misic, Yu Cai, Minh Duc Nguyen, Abubakar Abdelbagi, Xinping Li, Michal Minczuk, Markus Hafner, Daniel Benhalevy, Aishe A Sarshad, Ilian Atanassov, B Martin Hällberg, Joanna Rorbach.
      Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.
    DOI:  https://doi.org/10.1038/s41467-024-50011-x
  9. Cell Metab. 2024 Jul 02. pii: S1550-4131(24)00227-4. [Epub ahead of print]36(7): 1433-1435
    From whence it came: Mitochondrial mRNA leaves, a protein returns.
    Kevin A Janssen, Angela Song.
      Small peptides have previously been reported to be encoded in mitochondrial rRNA and translated by cytosolic ribosomes. In this issue of Cell Metabolism, Hu et al. use mass spectrometry to identify a cytosolically translated protein, encoded instead in mitochondrial mRNA, that is surprisingly targeted back into the mitochondrial matrix.
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.002
  10. Cell Death Dis. 2024 Jul 03. 15(7): 477
    A mitochondrial checkpoint to NF-κB signaling.
    Emma Guilbaud, Lorenzo Galluzzi.
      Mitochondrial dysfunction can elicit multiple inflammatory pathways, especially when apoptotic caspases are inhibited. Such an inflammatory program is negatively regulated by the autophagic disposal of permeabilized mitochondria. Recent data demonstrate that the ubiquitination of mitochondrial proteins is essential for NEMO-driven NF-kB activation downstream of mitochondrial permeabilization.
    DOI:  https://doi.org/10.1038/s41419-024-06868-3
  11. Cell Metab. 2024 Jul 02. pii: S1550-4131(24)00236-5. [Epub ahead of print]36(7): 1436-1438
    Fit for purpose: Selecting the best mitochondrial DNA for the job.
    Sarah J Pickett, Robert W Taylor, Robert McFarland.
      The factors determining levels of pathogenic mitochondrial DNA in cells and tissues are critical to disease pathology but remain poorly understood and contentious. In Nature, Kotrys et al. published a single-cell-based analysis casting fresh light on this thorny problem and introduced a powerful new investigative tool.
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.011
  12. Br J Haematol. 2024 Jun 30.
    Mitochondrial regulation of erythropoiesis in homeostasis and disease.
    Vijay Menon, Mary Slavinsky, Olivier Hermine, Saghi Ghaffari.
      Erythroid cells undergo a highly complex maturation process, resulting in dynamic changes that generate red blood cells (RBCs) highly rich in haemoglobin. The end stages of the erythroid cell maturation process primarily include chromatin condensation and nuclear polarization, followed by nuclear expulsion called enucleation and clearance of mitochondria and other organelles to finally generate mature RBCs. While healthy RBCs are devoid of mitochondria, recent evidence suggests that mitochondria are actively implicated in the processes of erythroid cell maturation, erythroblast enucleation and RBC production. However, the extent of mitochondrial participation that occurs during these ultimate steps is not completely understood. This is specifically important since abnormal RBC retention of mitochondria or mitochondrial DNA contributes to the pathophysiology of sickle cell and other disorders. Here we review some of the key findings so far that elucidate the importance of this process in various aspects of erythroid maturation and RBC production under homeostasis and disease conditions.
    Keywords:  RBCs; erythropoiesis; mitochondria; mitochondrial biogenesis; mitochondrial metabolism; mitophagy; terminal erythroid maturation
    DOI:  https://doi.org/10.1111/bjh.19600
  13. Biochim Biophys Acta Bioenerg. 2024 Jul 01. pii: S0005-2728(24)00462-6. [Epub ahead of print] 149492
    Alterations in coenzyme Q10 status in a cybrid line harboring the 3243A>G mutation of mitochondrial DNA is associated with abnormal mitochondrial bioenergetics and dysregulated mitochondrial biogenesis.
    Hsiu-Chuan Yen, Chia-Tzu Hsu, Shin-Yu Wu, Chia-Chi Kan, Chun-Wei Chang, Hsing-Ming Chang, Yu-An Chien, Yau-Huei Wei, Chun-Yen Wu.
      Mitochondrial DNA (mtDNA) mutations, including the m.3243A>G mutation that causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), are associated with secondary coenzyme Q10 (CoQ10) deficiency. We previously demonstrated that PPARGC1A knockdown repressed the expression of PDSS2 and several COQ genes. In the present study, we compared the mitochondrial function, CoQ10 status, and levels of PDSS and COQ proteins and genes between mutant cybrids harboring the m.3243A>G mutation and wild-type cybrids. Decreased mitochondrial energy production, defective respiratory function, and reduced CoQ10 levels were observed in the mutant cybrids. The ubiquinol-10:ubiquinone-10 ratio was lower in the mutant cybrids, indicating blockage of the electron transfer upstream of CoQ, as evident from the reduced ratio upon rotenone treatment and increased ratio upon antimycin A treatment in 143B cells. The mutant cybrids exhibited downregulation of PDSS2 and several COQ genes and upregulation of COQ8A. In these cybrids, the levels of PDSS2, COQ3-a isoform, COQ4, and COQ9 were reduced, whereas those of COQ3-b and COQ8A were elevated. The mutant cybrids had repressed PPARGC1A expression, elevated ATP5A levels, and reduced levels of mtDNA-encoded proteins, nuclear DNA-encoded subunits of respiratory enzyme complexes, MNRR1, cytochrome c, and DHODH, but no change in TFAM, TOM20, and VDAC1 levels. Alterations in the CoQ10 level in MELAS may be associated with mitochondrial energy deficiency and abnormal gene regulation. The finding of a reduction in the ubiquinol-10:ubiquinone-10 ratio in the MELAS mutant cybrids differs from our previous discovery that cybrids harboring the m.8344A>G mutation exhibit a high ubiquinol-10:ubiquinone-10 ratio.
    Keywords:  COQ proteins; MELAS; Mitochondrial energy deficiency; PDSS2; Rotenone; Ubiquinol:ubiquinone ratio
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149492
  14. Nat Genet. 2024 Jul 01.
    Mitochondrial genetics through the lens of single-cell multi-omics.
    Lena Nitsch, Caleb A Lareau, Leif S Ludwig.
      Mitochondria carry their own genetic information encoding for a subset of protein-coding genes and translational machinery essential for cellular respiration and metabolism. Despite its small size, the mitochondrial genome, its natural genetic variation and molecular phenotypes have been challenging to study using bulk sequencing approaches, due to its variation in cellular copy number, non-Mendelian modes of inheritance and propensity for mutations. Here we highlight emerging strategies designed to capture mitochondrial genetic variation across individual cells for lineage tracing and studying mitochondrial genetics in primary human cells and clinical specimens. We review recent advances surrounding single-cell mitochondrial genome sequencing and its integration with functional genomic readouts, including leveraging somatic mitochondrial DNA mutations as clonal markers that can resolve cellular population dynamics in complex human tissues. Finally, we discuss how single-cell whole mitochondrial genome sequencing approaches can be utilized to investigate mitochondrial genetics and its contribution to cellular heterogeneity and disease.
    DOI:  https://doi.org/10.1038/s41588-024-01794-8
  15. Biochim Biophys Acta Bioenerg. 2024 Jul 01. pii: S0005-2728(24)00464-X. [Epub ahead of print] 149494
    Sex-dependent differences in macaque brain mitochondria.
    Ivan Guerrero, Belem Yoval-Sánchez, Csaba Konrad, Giovanni Manfredi, Ilka Wittig, Alexander Galkin.
      Mitochondrial bioenergetics in females and males is different. Whether mitochondria from male and female brains display differences in mitochondrial enzymes is unknown. We measured the function of mitochondrial complexes from the brains of male and female macaques (Macaca mulatta). Cerebral tissue of macaques males exhibit elevated content and activity of mitochondrial complex I (NADH:ubiquinone oxidoreductase) and activity of complex II compared to females. No significant differences between sexes were found in the content of α-ketoglutarate dehydrogenase and activities of cytochrome c oxidase and F1Fo ATPase. Our results, underscore the need for further investigations to elucidate sex-related mitochondrial distinctions in humans.
    Keywords:  ATPase; Mitochondria; Mitochondrial complex I; Primates; Sex; Succinate dehydrogenase; TCA cycle; α-Ketoglutarate dehydrogenase
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149494
  16. Life Sci Alliance. 2024 Sep;pii: e202302396. [Epub ahead of print]7(9):
    Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
    Matthew R Krieger, Melania Abrahamian, Kevin L He, Sean Atamdede, Hesamedin Hakimjavadi, Milica Momcilovic, Dejerianne Ostrow, Simran Ds Maggo, Yik Pui Tsang, Xiaowu Gai, Guillaume F Chanfreau, David B Shackelford, Michael A Teitell, Carla M Koehler.
      In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
    DOI:  https://doi.org/10.26508/lsa.202302396
  17. Radiol Med. 2024 Jul 02.
    Tracking longitudinal thalamic volume changes during early stages of SCA1 and SCA2.
    Marina Grisoli, Anna Nigri, Jean Paul Medina Carrion, Sara Palermo, Greta Demichelis, Chiara Giacosa, Alessia Mongelli, Mario Fichera, Lorenzo Nanetti, Caterina Mariotti.
       PURPOSE: Spinocerebellar ataxia SCA1 and SCA2 are adult-onset hereditary disorders, due to triplet CAG expansion in their respective causative genes. The pathophysiology of SCA1 and SCA2 suggests alterations of cerebello-thalamo-cortical pathway and its connections to the basal ganglia. In this framework, thalamic integrity is crucial for shaping efficient whole-brain dynamics and functions. The aims of the study are to identify structural changes in thalamic nuclei in presymptomatic and symptomatic SCA1 and SCA2 patients and to assess disease progression within a 1-year interval.
    MATERIAL AND METHODS: A prospective 1-year clinical and MRI assessment was conducted in 27 presymptomatic and 23 clinically manifest mutation carriers for SCA1 and SCA2 expansions. Cross-sectional and longitudinal changes of thalamic nuclei volume were investigated in SCA1 and SCA2 individuals and in healthy participants (n = 20).
    RESULTS: Both SCA1 and SCA2 patients had significant atrophy in the majority of thalamic nuclei, except for the posterior and partly medial nuclei. The 1-year longitudinal evaluation showed a specific pattern of atrophy in ventral and posterior thalamus, detectable even at the presymptomatic stage of the disease.
    CONCLUSION: For the first time in vivo, our exploratory study has shown that different thalamic nuclei are involved at different stages of the degenerative process in both SCA1 and SCA2. It is therefore possible that thalamic alterations might significantly contribute to the progression of the disease years before overt clinical manifestations occur.
    Keywords:  MRI; Presymptomatic carriers; SCA1; SCA2; Spinocerebellar ataxias; Thalamus
    DOI:  https://doi.org/10.1007/s11547-024-01839-2
  18. Clin Nephrol Case Stud. 2024 ;12 42-47
    Renal and cardiac biopsy findings in an adolescent patient with the 3243A>G mitochondrial DNA mutation: Favorable renal prognosis post renal transplantation from the mother.
    Hisashi Kamido, Shigekazu Kurihara, Yuki Oba, Masayuki Yamanouchi, Tatsuya Suwabe, Katsuyuki Miki, Yuki Nakamura, Yasuo Ishi, Kei Kono, Kenichi Ohashi, Naoki Sawa, Yoshifumi Ubara.
      We investigated the pathogenesis of a perihilar variant of focal segmental glomerulosclerosis detected by kidney biopsy in a 16-year-old male. The disease was refractory to steroid therapy, and at the second kidney biopsy, abnormal mitochondrial proliferation was newly observed in the podocytes. The patient also developed late-onset hearing loss and had a family history of diabetes, and genetic testing confirmed the mitochondrial DNA mutation 3243A>G (48%). Eight months after hemodialysis was started, encephalopathy occurred presumably due to rapid dehydration. After changing dialysis into continuous ambulatory peritoneal dialysis, encephalopathy was resolved, but the patient developed myocardial hypertrophy, probably because of the myocardial overreaction to congestion. A myocardial biopsy showed mitochondrial proliferation in the myocardium. After renal transplantation from his mother with a heteroplasmy of 4%, the cardiomyopathy improved, and the renal function has remained stable for 4 years. We speculated that the abnormal mitochondrial morphology in the kidney and heart may be characteristic of mitochondrial genetic disease, and renal transplantation from the mother with a low heteroplasmy was considered desirable for mitochondrial nephropathy with poor prognosis.
    Keywords:  mitochondrial DNA mutation 3243A>G; mitochondrial cardiomyopathy; mitochondrial encephalopathy; mitochondrial nephropathy; renal transplantation
    DOI:  https://doi.org/10.5414/CNCS111422
  19. J Hered. 2024 Jul 01. pii: esae034. [Epub ahead of print]
    Mutation of mpv17 results in loss of iridophores due to mitochondrial dysfunction in tilapia.
    Jia Xu, Peng Li, Mengmeng Xu, Chenxu Wang, Thomas D Kocher, Deshou Wang.
      Mpv17 (mitochondrial inner membrane protein MPV17) deficiency causes severe mitochondrial DNA depletion syndrome in mammals and loss of pigmentation of iridophores and a significant decrease of melanophores in zebrafish. The reasons for this are still unclear. In this study, we established an mpv17 homozygous mutant line in Nile tilapia. The developing mutants are transparent due to loss of iridophores and aggregation of pigment granules in the melanophores and disappearance of the vertical pigment bars on the side of the fish. Transcriptome analysis using skin of fish at 30 dpf (days post fertilization) revealed that the genes related to purine (especially pnp4a) and melanin synthesis were significantly downregulated. However, administration of guanine diets failed to rescue the phenotype of the mutants. In addition, no obvious apoptosis signals were observed in the iris of the mutants by TUNEL staining. Significant downregulation of genes related to iridophore differentiation was detected by qPCR. Insufficient ATP, as revealed by ATP assay, α-MSH treatment and adcy5 mutational analysis, might account for the defects of melanophores in mpv17 mutants. Several tissues displayed less mtDNA and decreased ATP levels. Taken together, these results indicated that mutation of mpv17 led to mitochondrial dTMP deficiency, followed by impaired mtDNA content and mitochondrial function, which in turn, led to loss of iridophores and a transparent body color in tilapia.
    Keywords:   mpv17 mutation; iridophore; melanophore; mitochondrial dysfunction; tilapia
    DOI:  https://doi.org/10.1093/jhered/esae034
  20. Mol Metab. 2024 Jul 01. pii: S2212-8778(24)00113-3. [Epub ahead of print] 101982
    NCLX controls hepatic mitochondrial Ca2+ extrusion and couples hormone-mediated mitochondrial Ca2+ oscillations with gluconeogenesis.
    Mahmoud Taha, Essam A Assali, Tsipi Ben-Kasus, Grace E Stuzmann, Orian S Shirihai, Michal Hershfinkel, Israel Sekler.
       OBJECTIVE: Hepatic Ca2+ signaling has been identified as a crucial key factor in driving gluconeogenesis. The involvement of mitochondria in hormone-induced Ca2+ signaling and their contribution to metabolic activity remain, however, poorly understood. Moreover, the molecular mechanism governing the mitochondrial Ca2+ efflux signaling remains unresolved. This study investigates the role of the Na+ /Ca2+ exchanger, NCLX, in modulating hepatic mitochondrial Ca2+ efflux, and examines its physiological significance in hormonal hepatic Ca2+ signaling, gluconeogenesis, and mitochondrial bioenergetics.
    METHODS: Primary mouse hepatocytes from both an AAV-mediated conditional hepatic-specific and a total mitochondrial Na+/Ca2+ exchanger, NCLX, knock-out (KO) mouse models were employed for fluorescent monitoring of purinergic and glucagon/vasopressin-dependent mitochondrial and cytosolic hepatic Ca2+ responses in cultured hepatocytes. Isolated liver mitochondria and permeabilized primary hepatocytes were utilized to analyze the ion-dependence of Ca2+ efflux. Utilizing the conditional hepatic-specific NCLX KO model, the rate of gluconeogenesis was assessed first through the monitoring of glucose levels in fasted mice in vivo and by subjecting the fasted mice to a pyruvate tolerance test while monitoring blood glucose. Additionally, cultured primary hepatocytes from both genotypes were assessed in vitro for glucagon-dependent glucose production and cellular bioenergetics through glucose oxidase assay and Seahorse respirometry, respectively.
    RESULTS: Analysis of Ca2+ responses in isolated liver mitochondria and cultured primary hepatocytes from NCLX KO versus WT mice showed that NCLX serves as the principal mechanism for mitochondrial calcium extrusion in hepatocytes. We then determined the role of NCLX in glucagon and vasopressin-induced Ca2+ oscillations. Consistent with previous studies, glucagon and vasopressin triggered Ca2+ oscillations in WT hepatocytes, however, the deletion of NCLX resulted in selective elimination of mitochondrial, but not cytosolic, Ca2+ oscillations or level of IP3R1 expression, underscoring NCLX's pivotal role in mitochondrial Ca2+ regulation. Subsequent in vivo investigation for hepatic NCLX role in gluconeogenesis revealed that, as opposed to WT mice which maintained normoglycemic blood glucose levels when fasted, conditional hepatic-specific NCLX KO mice exhibited a faster drop in glucose levels, becoming hypoglycemic, and with a compromised conversion of pyruvate to glucose when provided challenged under fasting conditions. Concurrent in vitro assessments showed impaired glucagon-dependent glucose production and compromised bioenergetics in KO hepatocytes, thereby underscoring NCLX's significant contribution to hepatic glucose metabolism.
    CONCLUSIONS: The study findings demonstrate that NCLX acts as the primary Ca2+ efflux mechanism in hepatocytes. NCLX is indispensable for the regulation of hormone-induced mitochondrial Ca2+ oscillations, mitochondrial metabolism and sustenance of hepatic gluconeogenesis.
    Keywords:  Calcium signaling; Mitocondrial calcium; NCLX; gluconeogenesis; hepatic calcium signaling
    DOI:  https://doi.org/10.1016/j.molmet.2024.101982
  21. J Clin Invest. 2024 May 09. pii: e179848. [Epub ahead of print]134(12):
    Preexisting maternal immunity to AAV but not Cas9 impairs in utero gene editing in mice.
    John S Riley, Valerie L Luks, Cara L Berkowitz, Ana Maria Dumitru, Nicole J Kus, Apeksha Dave, Pallavi Menon, Monique E De Paepe, Rajan Jain, Li Li, Lorraine Dugoff, Christina Paidas Teefey, Mohamad-Gabriel Alameh, Philip W Zoltick, William H Peranteau.
      In utero gene editing (IUGE) is a potential treatment for inherited diseases that cause pathology before or soon after birth. Preexisting immunity to adeno-associated virus (AAV) vectors and Cas9 endonuclease may limit postnatal gene editing. The tolerogenic fetal immune system minimizes a fetal immune barrier to IUGE. However, the ability of maternal immunity to limit fetal gene editing remains a question. We investigated whether preexisting maternal immunity to AAV or Cas9 impairs IUGE. Using a combination of fluorescent reporter mice and a murine model of a metabolic liver disease, we demonstrated that maternal anti-AAV IgG antibodies were efficiently transferred from dam to fetus and impaired IUGE in a maternal titer-dependent fashion. By contrast, maternal cellular immunity was inefficiently transferred to the fetus, and neither maternal cellular nor humoral immunity to Cas9 impaired IUGE. Using human umbilical cord and maternal blood samples collected from mid- to late-gestation pregnancies, we demonstrated that maternal-fetal transmission of anti-AAV IgG was inefficient in midgestation compared with term, suggesting that the maternal immune barrier to clinical IUGE would be less relevant at midgestation. These findings support immunologic advantages for IUGE and inform maternal preprocedural testing protocols and exclusion criteria for future clinical trials.
    Keywords:  Gene therapy; Genetic diseases; Immunology; Therapeutics
    DOI:  https://doi.org/10.1172/JCI179848
  22. Proc Natl Acad Sci U S A. 2024 Jul 09. 121(28): e2404062121
    TFEB safeguards trophoblast syncytialization in humans and mice.
    Wanshan Zheng, Yue Zhang, Peiqun Xu, Zexin Wang, Xuan Shao, Chunyan Chen, Han Cai, Yinan Wang, Ming-An Sun, Wenbo Deng, Fan Liu, Jinhua Lu, Xueqin Zhang, Dunjin Cheng, Indira U Mysorekar, Haibin Wang, Yan-Ling Wang, Xiaoqian Hu, Bin Cao.
      Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth-restricted placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
    Keywords:  ERVFRD-1; TFEB; fetal growth restriction; human trophoblast stem cell; syncytiotrophoblast
    DOI:  https://doi.org/10.1073/pnas.2404062121
  23. Nat Commun. 2024 Jul 02. 15(1): 5571
    X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.
    Peixiang Zhang, Joseph J Munier, Carrie B Wiese, Laurent Vergnes, Jenny C Link, Fahim Abbasi, Emilio Ronquillo, Katherine Scheker, Antonio Muñoz, Yu-Lin Kuang, Elizabeth Theusch, Meng Lu, Gabriela Sanchez, Akinyemi Oni-Orisan, Carlos Iribarren, Michael J McPhaul, Daniel K Nomura, Joshua W Knowles, Ronald M Krauss, Marisa W Medina, Karen Reue.
      Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.
    DOI:  https://doi.org/10.1038/s41467-024-49764-2
  24. Cell Stem Cell. 2024 Jun 25. pii: S1934-5909(24)00215-7. [Epub ahead of print]
    Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.
    Chengfang Zhou, Mei Kuang, Yin Tao, Jianming Wang, Yu Luo, Yinghao Fu, Zhe Chen, Yuanyuan Liu, Zhigang Li, Weiru Wu, Li Wang, Ying Dou, Junping Wang, Yu Hou.
      Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.
    Keywords:  Nynrin; Ppif; ROS; hematopoietic stem cells; irradiation; mPTP opening; mitochondrial membrane potential; mitochondrial metabolism; mitochondrial swelling; radiotherapy
    DOI:  https://doi.org/10.1016/j.stem.2024.06.007
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