bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒09‒29
thirteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Fetal and obstetrics manifestations of mitochondrial diseases.
  2. Primary mitochondrial diseases.
  3. Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.
  4. A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
  5. Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
  6. Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.
  7. Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males.
  8. Stem cells reverse woman's diabetes - a world first.
  9. DNA-PKcs modulates mouse lung homeostasis via the regulation of mitochondrial fission.
  10. Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease.
  11. The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses.
  12. Mitochondria facilitate neuronal differentiation by metabolising nuclear-encoded RNA.
  13. Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
  1. J Transl Med. 2024 Sep 23. 22(1): 853
    Fetal and obstetrics manifestations of mitochondrial diseases.
    Adelizzi Alessia, Giri Anastasia, Di Donfrancesco Alessia, Boito Simona, Prigione Alessandro, Bottani Emanuela, Bollati Valentina, Tiranti Valeria, Persico Nicola, Brunetti Dario.
      During embryonic and neonatal development, mitochondria have essential effects on metabolic and energetic regulation, shaping cell fate decisions and leading to significant short- and long-term effects on embryonic and offspring health. Therefore, perturbation on mitochondrial function can have a pathological effect on pregnancy. Several shreds of evidence collected in preclinical models revealed that severe mitochondrial dysfunction is incompatible with life or leads to critical developmental defects, highlighting the importance of correct mitochondrial function during embryo-fetal development. The mechanism impairing the correct development is unknown and may include a dysfunctional metabolic switch in differentiating cells due to decreased ATP production or altered apoptotic signalling. Given the central role of mitochondria in embryonic and fetal development, the mitochondrial dysfunction typical of Mitochondrial Diseases (MDs) should, in principle, be detectable during pregnancy. However, little is known about the clinical manifestations of MDs in embryonic and fetal development. In this manuscript, we review preclinical and clinical evidence suggesting that MDs may affect fetal development and highlight the fetal and maternal outcomes that may provide a wake-up call for targeted genetic diagnosis.
    DOI:  https://doi.org/10.1186/s12967-024-05633-6
  2. Handb Clin Neurol. 2024 ;pii: B978-0-323-99209-1.00004-1. [Epub ahead of print]204 53-76
    Primary mitochondrial diseases.
    Chiara Pizzamiglio, Michael G Hanna, Robert D S Pitceathly.
      Primary mitochondrial diseases (PMDs) are a heterogeneous group of hereditary disorders characterized by an impairment of the mitochondrial respiratory chain. They are the most common group of genetic metabolic disorders, with a prevalence of 1 in 4,300 people. The presence of leukoencephalopathy is recognized as an important feature in many PMDs and can be a manifestation of mutations in both mitochondrial DNA (classic syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; myoclonic epilepsy with ragged-red fibers [RRFs]; Leigh syndrome; and Kearns-Sayre syndrome) and nuclear DNA (mutations in maintenance genes such as POLG, MPV17, and TYMP; Leigh syndrome; and mitochondrial aminoacyl-tRNA synthetase disorders). In this chapter, PMDs associated with white matter involvement are outlined, including details of clinical presentations, brain MRI features, and elements of differential diagnoses. The current approach to the diagnosis of PMDs and management strategies are also discussed. A PMD diagnosis in a subject with leukoencephalopathy should be considered in the presence of specific brain MRI features (for example, cyst-like lesions, bilateral basal ganglia lesions, and involvement of both cerebral hemispheres and cerebellum), in addition to a complex neurologic or multisystem disorder. Establishing a genetic diagnosis is crucial to ensure appropriate genetic counseling, multidisciplinary team input, and eligibility for clinical trials.
    Keywords:  Brain MRI; Kearns-Sayre syndrome; Leber hereditary optic neuropathy; Leigh disease; Leukoencephalopathy; Mitochondrial DNA maintenance disorders; Mitochondrial aminoacyl-tRNA synthetase disorders; Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes; Mitochondrial neurogastrointestinal encephalomyopathy; Primary mitochondrial diseases
    DOI:  https://doi.org/10.1016/B978-0-323-99209-1.00004-1
  3. Cell Death Dis. 2024 Sep 27. 15(9): 692
    Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.
    Marta Cozzi, Stefania Magri, Barbara Tedesco, Guglielmo Patelli, Veronica Ferrari, Elena Casarotto, Marta Chierichetti, Paola Pramaggiore, Laura Cornaggia, Margherita Piccolella, Mariarita Galbiati, Paola Rusmini, Valeria Crippa, Jessica Mandrioli, Davide Pareyson, Chiara Pisciotta, Stefano D'Arrigo, Antonia Ratti, Lorenzo Nanetti, Caterina Mariotti, Elisa Sarto, Viviana Pensato, Cinzia Gellera, Daniela Di Bella, Riccardo M Cristofani, Franco Taroni, Angelo Poletti.
      Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.
    DOI:  https://doi.org/10.1038/s41419-024-07096-5
  4. Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]
    A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.
    Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt
    DOI:  https://doi.org/10.1016/j.cell.2024.08.045
  5. FASEB J. 2024 Sep 30. 38(18): e70066
    Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
    Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.
      Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.
    Keywords:  membrane fusion; membrane potential; mitochondria; mitochondrial dynamics; proteostasis; reactive oxygen species
    DOI:  https://doi.org/10.1096/fj.202400313R
  6. Brain Commun. 2024 ;6(5): fcae312
    Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.
    Elena Abati, Delia Gagliardi, Arianna Manini, Roberto Del Bo, Dario Ronchi, Megi Meneri, Francesca Beretta, Annalisa Sarno, Federica Rizzo, Edoardo Monfrini, Alessio Di Fonzo, Maria Teresa Pellecchia, Alberto Brusati, Vincenzo Silani, Giacomo Pietro Comi, Antonia Ratti, Federico Verde, Nicola Ticozzi, Stefania Corti.
      The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.
    Keywords:  amyotrophic lateral sclerosis; genetics; mitochondria; mitofusin 2
    DOI:  https://doi.org/10.1093/braincomms/fcae312
  7. EMBO Mol Med. 2024 Sep 27.
    Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males.
    Małgorzata Rydzanicz, Bozena Kuzniewska, Marta Magnowska, Tomasz Wójtowicz, Aleksandra Stawikowska, Anna Hojka, Ewa Borsuk, Ksenia Meyza, Olga Gewartowska, Jakub Gruchota, Jacek Miłek, Patrycja Wardaszka, Izabela Chojnicka, Ludwika Kondrakiewicz, Dorota Dymkowska, Alicja Puścian, Ewelina Knapska, Andrzej Dziembowski, Rafał Płoski, Magdalena Dziembowska.
      There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.
    Keywords:  Autism; Mitochondria; Mouse Model; Synapses; Trap1
    DOI:  https://doi.org/10.1038/s44321-024-00147-6
  8. Nature. 2024 Sep 26.
    Stem cells reverse woman's diabetes - a world first.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Diabetes; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-03129-3
  9. Life Sci. 2024 Sep 25. pii: S0024-3205(24)00668-4. [Epub ahead of print] 123078
    DNA-PKcs modulates mouse lung homeostasis via the regulation of mitochondrial fission.
    Yi Xiao, Jiahe Zhang, Xinran Li, Pinxuan Liu, Bo Gou, Zeyu Gao, Moshi Song.
      BACKGROUND: The role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is multifaceted, paradoxically promoting both cell survival and cell death across multiple organs. However, its impact on lung homeostasis remains elusive. Here, we investigate the function of DNA-PKcs in mouse lungs, aiming to elucidate its role for lung abnormalities associated with DNA-PKcs deficiency.MATERIALS AND METHODS: Histological assessment and immunohistochemistry were used to reveal the pathological changes of the lungs in DNA-PKcs-deficient mice. Transcriptomic analysis identified differentially expressed genes and pathways in DNA-PKcs-deficient lungs. Furthermore, mitochondrial dysfunction induced by DNA-PKcs deficiency was investigated by qPCR and immunoblotting. Mouse primary lung fibroblasts were used to evaluate the potential therapeutic effect of inhibiting mitochondrial fission with Mdivi-1.
    KEY FINDINGS: In DNA-PKcs-deficient mouse lungs, we observed pathological changes including alveolar septal thickening, capillary congestion and hemorrhage, along with lung cell proliferation. Transcriptome analysis revealed an upregulation of the reactive oxygen species (ROS) biosynthesis process and the apoptotic signaling pathway caused by DNA-PKcs deficiency. Further investigations demonstrated that DNA-PKcs deficiency led to mitochondrial dysfunction and increased oxidative stress, along with increased cell apoptosis in the mouse lungs. Notably, we detected enhanced phosphorylation of the mitochondrial fission protein DRP1 in DNA-PKcs-deficient mouse lungs. Intriguingly, inhibiting mitochondrial fission using Mdivi-1 suppressed cell death in primary mouse lung fibroblasts with siRNA-mediated DNA-PKcs knockdown.
    SIGNIFICANCE: Our study provides insights into the crucial role of DNA-PKcs in sustaining lung homeostasis via the maintenance of mitochondrial functionality and provides a therapeutic strategy targeting mitochondrial fission against DNA-PKcs deficiency-associated lung diseases.
    Keywords:  Apoptosis; DNA-PKcs; Lung homeostasis; Mitochondrial fission; Mitochondrial oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2024.123078
  10. Ann Neurol. 2024 Sep 25.
    Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease.
    Nandaki Keshavan, Lana Mhaldien, Kimberly Gilmour, Shamima Rahman.
      OBJECTIVE: Mitochondria are implicated in regulation of the innate immune response. We hypothesized that abnormalities in interferon signaling may contribute to pathophysiology in patients with primary mitochondrial disease (PMD).METHODS: Expression of interferon stimulated genes (ISGs) was measured by real-time polymerase chain reaction (PCR) in whole blood samples from a cohort of patients with PMD.
    RESULTS: Upregulated ISG expression was observed in a high proportion (41/55, 75%) of patients with PMD on at least 1 occasion, most frequently IFI27 upregulation, seen in 50% of the samples. Some patients had extremely high IFI27 levels, similar to those seen in patients with primary interferonopathies. A statistically significant correlation was observed between elevated IFI27 gene expression and PMD, but not between IFI27 and secondary mitochondrial dysfunction, suggesting that ISG upregulation is a biomarker of PMD. In some patients with PMD, ISG abnormalities persisted on repeat measurement over several years, indicative of ongoing chronic inflammation. Subgroup analyses suggested common ISG signatures in patients with similar mitochondrial disease mechanisms and positive correlations with disease severity among patients with identical genetic diagnoses.
    INTERPRETATION: Dysregulated interferon signaling is frequently seen in patients with PMD suggesting that interferon dysregulation is a contributor to pathophysiology. This may indicate a role for repurposing of immunomodulatory therapies for the treatment of PMDs by targeting interferon signaling. ANN NEUROL 2024.
    DOI:  https://doi.org/10.1002/ana.27081
  11. Genet Med. 2024 Sep 17. pii: S1098-3600(24)00205-3. [Epub ahead of print] 101271
    The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses.
    Rocio Rius, Alison G Compton, Naomi L Baker, Shanti Balasubramaniam, Stephanie Best, Kaustuv Bhattacharya, Kirsten Boggs, Tiffany Boughtwood, Jeffrey Braithwaite, Drago Bratkovic, Alessandra Bray, Marie-Jo Brion, Jo Burke, Sarah Casauria, Belinda Chong, David Coman, Shannon Cowie, Mark Cowley, Michelle G de Silva, Martin B Delatycki, Samantha Edwards, Carolyn Ellaway, Michael C Fahey, Keri Finlay, Janice Fletcher, Leah E Frajman, Ann E Frazier, Velimir Gayevskiy, Roula Ghaoui, Himanshu Goel, Ilias Goranitis, Matilda Haas, Daniella H Hock, Denise Howting, Matilda R Jackson, Maina P Kava, Madonna Kemp, Sarah King-Smith, Nicole J Lake, Phillipa J Lamont, Joy Lee, Janet C Long, Mandi MacShane, Evanthia O Madelli, Ellenore M Martin, Justine E Marum, Tessa Mattiske, Jim McGill, Alejandro Metke, Sean Murray, Julie Panetta, Liza K Phillips, Michael C J Quinn, Michael T Ryan, Sarah Schenscher, Cas Simons, Nicholas Smith, David A Stroud, Michel C Tchan, Melanie Tom, Mathew Wallis, Tyson L Ware, AnneMarie E Welch, Christine Wools, You Wu, John Christodoulou, David R Thorburn.
      PURPOSE: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.METHODS: 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mtDNA sequencing (ES+mtDNAseq) or genome sequencing (GS).
    RESULTS: Diagnostic yield was 55% (n=77) with variants in nuclear (n=37) and mtDNA (n=18) MD genes, as well as phenocopy genes (n=22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases, and comparable in children with non-European (78%) versus European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, three adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.
    CONCLUSION: Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.
    Keywords:  Genomics; Mitochondrial Disease; diagnosis; proteomics
    DOI:  https://doi.org/10.1016/j.gim.2024.101271
  12. Cell Commun Signal. 2024 Sep 26. 22(1): 450
    Mitochondria facilitate neuronal differentiation by metabolising nuclear-encoded RNA.
    Filip Vujovic, Mary Simonian, William E Hughes, Claire E Shepherd, Neil Hunter, Ramin M Farahani.
      Mitochondrial activity directs neuronal differentiation dynamics during brain development. In this context, the long-established metabolic coupling of mitochondria and the eukaryotic host falls short of a satisfactory mechanistic explanation, hinting at an undisclosed facet of mitochondrial function. Here, we reveal an RNA-based inter-organellar communication mode that complements metabolic coupling of host-mitochondria and underpins neuronal differentiation. We show that within minutes of exposure to differentiation cues and activation of the electron transport chain, the mitochondrial outer membrane transiently fuses with the nuclear membrane of neural progenitors, leading to efflux of nuclear-encoded RNAs (neRNA) into the positively charged mitochondrial intermembrane space. Subsequent degradation of mitochondrial neRNAs by Polynucleotide phosphorylase 1 (PNPase) located in the intermembrane space curbs the transcriptomic memory of progenitor cells. Further, acquisition of neRNA by mitochondria leads to a collapse of proton motive force, suppression of ATP production, and a resultant amplification of autophagic flux that attenuates proteomic memory. Collectively, these events force the progenitor cells towards a "tipping point" characterised by emergence of a competing neuronal differentiation program. It appears that neuronal differentiation is a consequence of reprogrammed coupling of metabolomic and transcriptomic landscapes of progenitor cells, with mitochondria emerging as key "reprogrammers" that operate by acquiring and metabolising neRNAs. However, the documented role of mitochondria as "reprogrammers" of differentiation remains to be validated in other neuronal lineages and in vivo.
    DOI:  https://doi.org/10.1186/s12964-024-01825-1
  13. Autophagy. 2024 Oct;20(10): 2164-2185
    Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
    Hortense de Calbiac, Solène Renault, Grégoire Haouy, Vincent Jung, Kevin Roger, Qihui Zhou, Maria-Letizia Campanari, Loïc Chentout, Doris Lou Demy, Anca Marian, Nicolas Goudin, Dieter Edbauer, Chiara Guerrera, Sorana Ciura, Edor Kabashi.
      The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.
    Keywords:  Amyotrophic lateral sclerosis; apoptosis; mitochondria; motor neuron; neurodegeneration; poly-GP
    DOI:  https://doi.org/10.1080/15548627.2024.2358736
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