Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10S59L/+ mouse


Recently, we provided genetic basis showing that mitochondrial dysfunction can trigger motor neuron degeneration, through identification of CHCHD10 encoding a mitochondrial protein. We reported patients, carrying the p.Ser59Leu heterozygous mutation in CHCHD10, from a large family with a mitochondrial myopathy associated with motor neuron disease (MND). Rapidly, our group and others reported CHCHD10 mutations in amyotrophic lateral sclerosis (ALS), frontotemporal dementia-ALS and other neurodegenerative diseases. Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family. Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy. CHCHD10S59L/+ mice also displayed neuromuscular junction (NMJ) and motor neuron degeneration with hyper-fragmentation of the motor end plate and moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease. At this stage, we observed TDP-43 cytoplasmic aggregates in spinal neurons. We also showed that motor neurons differentiated from human iPSC carrying the p.Ser59Leu mutation were much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells. These data confirm that mitochondrial deficiency associated with CHCHD10 mutations can be at the origin of MND. CHCHD10 is highly expressed in the NMJ post-synaptic part. Importantly, the fragmentation of the motor end plate was associated with abnormal CHCHD10 expression that was also observed closed to NMJs which were morphologically normal. Furthermore, we found OXPHOS deficiency in muscle of CHCHD10S59L/+ mice at 3 months of age in the absence of neuron loss in spinal cord. Our data show that the pathological effects of the p.Ser59Leu mutation target muscle prior to NMJ and motor neurons. They likely lead to OXPHOS deficiency, loss of cristae junctions and destabilization of internal membrane structure within mitochondria at motor end plate of NMJ, impairing neurotransmission. These data are in favor with a key role for muscle in MND associated with CHCHD10 mutations.

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We thank our colleagues from Genetic Engineering and Mouse Transgenesis department at service unit CIPHE (Centre d’Immunophénomique, Aix Marseille Université, INSERM, CNRS, Phenomin, Marseille, France) and mainly Frederic Fiore who provided expertise and know-how and perform the generation of the CHCHD10S59L/+ mice that greatly assisted our project. We also thank our colleagues, including Benoit Petit-Demoulière, Ghina Bou-About, Hamid Meziane, Hugues Jacobs, Marie-France Champy, Patrick Reilly, Tania Sorg and Yann Herault from Phenomin (Institut Clinique de la souris, 1 rue Laurent Fries, 67404 ILLKIRCH cedex 2—CNRS, UMR7104, Illkirch, France—INSERM, U964, Illkirch, France—Université de Strasbourg, France) for their help in phenotyping mice. We gratefully acknowledge the IRCAN’s Molecular and Cellular Core Imaging (PICMI) facility, supported financially by FEDER, Conseil régional Provence Alpes-Côte d’Azur, Conseil Départemental 06, Cancéropôle PACA, Gis Ibisa and Inserm, the IRCAN’s Animal core facility, supported by Région Provence Alpes-Côte d’Azur and Inserm, the IRCAN’s Histology core facility, supported by Région Provence Alpes-Côte d’Azur and Université de Nice Sophia-Antipolis, the Centre Méditerranéen de Médecine Moléculaire (C3 M) imaging facility, the University’s CCMA Electron Microscopy facility supported by Université de Nice Sophia-Antipolis, Région Provence Alpes-Côte d’Azur, Conseil Départemental 06, and Gis Ibisa and, the ICM CELIS-iPS internal platform. We also thank Dr Luisa Villa and Dr Pamela Moceri for their help in interpreting muscle and cardiac results, respectively, and Sandra Foustoul and Alyssia Mari for technical help.


This work was made possible by Grants to VP-F from the ANR (Agence Nationale de la Recherche) ANR-16-CE16-0024-01, from the AFM-Téléthon (Association Française contre les Myopathies) #20947 and from the Fondation Maladies Rares. The research leading to the iPSC results has received funding from the program “Investissements d’avenir” ANR-11-INBS-0011-NeurATRIS: Translational Research Infrastructure for Biotherapies in Neurosciences”. ECG and BMH are postdoctoral fellows supported by ANR-16-CE16-0024-01. CL-O is a Ph.D. fellow supported by ANR-10-LABX-73.

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ECG and SBa designed, performed experiments and analyzed data on mouse models, and contributed to the main text. BMH designed, performed experiments and analyzed data on cell models (NSC34 and iPSCs-derived motor neurons), and contributed to the main text. KF designed, performed experiments and analyzed data on respiratory chain experiments. SL-G performed electron microscopy experiments. JN, AM-C, FL, BR, GA and CC performed and analyzed experiments on mouse models. SBi generated iPSC. CL-O and DB provided the motor neuron differentiation protocol and advices on the iPSC daily culture and motor neuron differentiation. DB provides advices and helped in data interpretation on iPSC-derived motor neuron experiments and contributed to the main text. AC provided technical advices for motor neurons staining and count. FM helped with the interpretation of metabolic data. SBo and CL provided advices for the NMJ and motor neurons analyses and helped in data interpretation. J‐ER designed and analyzed data on cell models and contributed to the main text. VP‐F designed, supervised the project and drafted the manuscript. All the authors read and approved the final submission.

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Correspondence to Véronique Paquis-Flucklinger.

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Supplementary material 1 (MP4 21757 kb)

Supplementary material 2 (MP4 50009 kb)

Supplementary Figure 1. CHCHD10 and TOM20 expression around NMJs in the gastrocnemius muscle from

+/+and S59L/+ mice. a-b. CHCHD10 and TOM20 (translocase of outer mitochondrial membrane 20) expression around NMJs in the gastrocnemius muscle from one +/+ (a) and one S59L/+ (b) mice. A maximum intensity projection of Z-stacked confocal images showed immunofluorescent staining of TOM20 (cyan), CHCHD10 (red) and α-Bungarotoxin (BTX, green) to mark NMJ (n = 2 +/+ and 2 S59L/+ mice). Scale bar: 10µm. The low panel of each image is a magnification (area indicated by the square in the upper panel) of muscle fibers around NMJ with a higher intensity of fluorescence. Scale bare: 5µm. (PPTX 1072 kb)

Supplementary Figure 2. Ultrastructural analysis of motor neurons

in the ventral horn of lumbar spinal cord from +/+ (left panels) and S59L/+ (right panels) mice showing vacuolated mitochondria with abnormal cristae in mutant animals at end stage (a). The low panel of each image is a magnification of the area indicated by the square in the middle panel. Scale bar: 10 µm (upper panels), 1 µm (middle panels) and 0.25 µm (lower panels). b. Quantification of mitochondrial morphology observed in a. Intermediary refers to mitochondria that cannot be clearly classified as abnormal despite the presence of slight cristae anomalies. Shown are mean ± SEM (n = 2 +/+ and 2 S59L/+ mice with 45 mitochondria per animal randomly chosen and analyzed). Statistical analysis was performed using Student’s t-test. P-value = *<0.05, **<0.01. (PPTX 3572 kb)

Supplementary Figure 3. Sensory–motor functions of

CHCHD10S59L/+mice. Motor abilities assessed by rotarod (a), grip (b), string (c) and crenelated beam (d) tests. EMG measurements (e-g). All experiments were performed in 10 CHCHD10S59L/+ and 10 CHCHD10+/+ mice of each sex. Data are expressed as mean ± SEM and analyzed using Student t-test. (PPTX 107 kb)

Supplementary Figure 4. Apoptosis analysis in MEFs and mice at end point, and characterization of iPSCs. a.

MEFs were isolated from two +/+ or two S59L/+ mice (S59L-1 and -2) and treated with 1 µM STS for 8 hours and 16 hours (O/N). Cell death was determined by flow cytometry using Annexin V/DAPI staining. n=3 per condition. b-c. DEVDase activity measurement (b) and Western-Blot analysis of pro-caspase 3 (C3) and cleaved caspase-3 (CC3) (c) on brain, spinal cord, muscle and heart protein extracts. d-g. Characterization of iPSC clones. d. Representative immunofluorescent staining of the S59L/+ iPSC clone for pluripotency markers TRA1-60, NANOG and SSEA-4, and the differentiation marker SSEA-1. Nuclei are stained with Hoechst. Scale bars: 100 µm. e. Representative immunofluorescent staining of plated EBs for lineage-specific markers: nestin for ectoderm, SMA for mesoderm, and β-catenin for endoderm. Scale bars: 100 µm. f. Pluripotency and tri-lineage differentiation potential were characterized by TaqMan® hPSC Scorecard™. Results are expressed as a score relative to a reference set of standard iPSC and ESC clones. g. Karyogram show genome integrity of the S59L/+ iPSC clone compared to parental fibroblasts. Illumina SNP array data were analyzed using Karyostudio. An autosomal detected region deviating from reference data is annotated with orange band (deletion). This alteration was below the level that would be detected by G-banding and was present in both parental fibroblasts and the derived iPSC clone. h. Phase contrast images of iPSC-derived motor neuron from control (C1, C2), and S59L/+ lines at day 35 (scale bar, 100 µm). Differences between groups were analyzed by two-way ANOVA (Tukey’s multiple comparisons test). P-value = *<0.05, **<0.01. (PPTX 1271 kb)

Supplementary Figure 5. Heart analysis of

CHCHD10S59L/+mice at 3 months of age. a. Spectrophotometric analysis of respiratory chain in heart from +/+ and S59L/+ mice. Results represent the mean ± SD of 3 +/+ and 3 S59L/+ mice. b. Representative western blot analysis from equal amounts (2.5μg) of heart homogenates of +/+ and S59L/+ mice using OXPHOS antibodies cocktail detecting complexes I to V and anti-GAPDH antibody for loading control. c. Quantification of relative intensities of OXPHOS proteins shown in b. Data are shown as the mean ± SD of 3 independent experiments (n= 3 +/+ and 3 S59L/+ mice). d. Long extension PCR of mtDNA from heart of 6 +/+ (lanes 3-8) and 6 S59L/+ (lanes 9-14) mice. mtDNA indicates the 12.8kb amplicon. Lanes 1,2: molecular weight markers. Lane 13: negative PCR control. e. Mitochondrial DNA quantification in heart of +/+ or S59L/+ mice. The mouse mitochondrial 12S rRNA (mtDNA) and the nuclear GAPDH (nDNA) genes were individually amplified by real-time PCR. Data were expressed as ratio between mtDNA and nDNA concentration. Results represent the mean of relative PCR ± SD of 3 independent experiments from 4 +/+ and 5 S59L/+ mice. The data from S59L/+ mice were compared to the controls. Statistical analysis was performed using Student’s t-test in a and Mann-Whitney’s test in c and e. P-value = **<0.01, ***<0.001. (PPTX 9061 kb)

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Genin, E.C., Madji Hounoum, B., Bannwarth, S. et al. Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10S59L/+ mouse. Acta Neuropathol 138, 123–145 (2019).

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  • CHCHD10
  • Mitochondrial disorder
  • ALS
  • Mouse model
  • iPSC