Current lab members:

• Véronique PAQUIS-FLUCKLINGER, Professor-Clinician, PU-PHCE
• Mélanie ABOU-ALI, PhD student
• S. Ait El Mkadem-Saadi, IR CHU
• G. Augé, technicienne CHU
• S. Bannwarth, PU- PH
• Aurore Bernardin, post-doc Inserm; A. Chaussenot, PH CHU
• K. Fragaki, IR CHU
• E. Genin, CRCN Inserm
• Justine Labory, PhD student
• F. Lespinasse, IE CNRS
• A. Mauri-Crouzet, IA UCA
• M. PERON, M1 student
• C. Rouzier, PH CHU
• Loan Vaillant-Beuchot, post-doc UCA.

Lab Alumni:

Mitochondrial diseases, caused by respiratory chain deficiency, display heterogeneous clinical presentations in terms of age at onset, progression and symptoms. Our principal goal is to identify and/or to characterize new genes and mechanisms involved in mitochondrial diseases, thanks to patients and model organisms. These steps are essential especially for the development of new therapeutic strategies for these severe diseases without treatment available at present.

Among recent data :

• The description of a new disease of the Krebs cycle through the role of MDH2, encoding the mitochondrial malate dehydrogenase, whose mutations are responsible for severe childhood encephalopathy. MDH2 had been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We showed that loss-of-function mutations are associated with severe neurological clinical presentations in children. 
• The genetic evidence that mitochondrial dysfunction can trigger motor neuron disease (MND) through the identification of CHCHD10, encoding a mitochondrial protein, in a large family with a late-onset mitochondrial myopathy associated with MND. Rapidly, our group and others reportedCHCHD10 mutations in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and other neurodegenerative diseases. We generated knock-in mice that mimic the phenotype displayed by the patients. We also showed that motor neurons differentiated from human iPSC carrying CHCHD10 mutations are much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells. Our data are in favor with a key role for muscle in MND associated with CHCHD10

The team works in direct collaboration with the Department of Medical Genetics (CHU of Nice) and the Reference Centre for Mitochondrial Diseases involved in diagnosis and follow-up of patients, both headed by Veronique Paquis-Flucklinger. This allows the phenotyping of patient cohorts and the collection of biological samples. This also allows a continuum between basic and clinical research. The group is composed on the one hand by physicians and biologists, experts in the clinical, biochemical and molecular diagnosis of mitochondrial disorders, and on the other hand by scientists, experts in studying mitochondrial functions who benefit from the platforms of the IRCAN.

Current Projects

Top Publications

• Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models
  31 octobre 2024 par Baptiste Ropert
  The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600…
• Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis
  25 novembre 2023 par Emmanuelle C Genin
  Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of…
• CHCHD10 and SLP2 control the stability of the PHB complex: a key factor for motor neuron viability
  3 juin 2022 par Emmanuelle C Genin
  CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing protein 10 interacts with the Stomatin-Like Protein 2 and participates in the stability of the prohibitin complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p.Ser59Leu), we show that Stomatin-Like Protein 2…
• Molecular diagnosis and genetic counseling for spinal muscular atrophy (SMA)
  28 décembre 2020 par C Rouzier
  Spinal muscular atrophy (SMA) is a neuromuscular autosomal recessive disorder caused by bi-allelic pathogenic variants in the SMN1 gene. 95% of SMA patients have a SMN1 homozygous deletion. In the 5% remaining affected patients, a heterozygous SMN1 deletion is associated with an intragenic SMN1 rare inactivating pathogenic variant on the other allele. The clinical phenotype of SMA is heterogeneous and severity is inversely correlated with the number of SMN2 copies, a non-functional SMN1 copy….
• A novel variant m.8561C&gt;T in the overlapping region of <em>MT-ATP6</em> and <em>MT-ATP8</em> in a child with early-onset severe neurological signs
  3 décembre 2019 par Konstantina Fragaki
  Among mitochondrial diseases, isolated complex V (CV) deficiency represents a rare cause of respiratory chain (RC) dysfunction. In mammalian mitochondrial DNA (mtDNA), MT-ATP6 partly overlaps with MT-ATP8 making double mutations possible, yet extremely rarely reported principally in patients with cardiomyopathy. Here, we report a novel m.8561 C>T substitution in the overlapping region of MT-ATP6 and MT-ATP8 in a child with early-onset ataxia, psychomotor delay and microcephaly, enlarging the…
• Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10^S59L/+ mouse
  16 mars 2019 par Emmanuelle C Genin
  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…
• Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases
  10 août 2018 par Emmanuelle C Genin
  Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different…
• Assembly defects of multiple respiratory chain complexes in a child with cardiac hypertrophy associated with a novel ACAD9 mutation
  23 mai 2017 par Konstantina Fragaki
  Patients carrying Acyl-CoA dehydrogenase 9 (ACAD9) mutations reported to date mainly present with severe hypertrophic cardiomyopathy and isolated complex I (CI) dysfunction. Here we report a novel ACAD9 mutation in a young girl presenting with severe hypertrophic cardiomyopathy, isolated CI deficiency and interestingly multiple respiratory chain complexes assembly defects. We show that ACAD9 analysis has to be performed in first intention in patients presenting with cardiac hypertrophy even in…
• A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions
  6 mai 2017 par Cécile Rouzier
  No abstract
• A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions
  24 mars 2017 par Cécile Rouzier
  Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and…
• A new mutation in the mitochondrial tRNA^Pro gene associated with early-onset neuromuscular phenotype and ragged-red fibers
  7 novembre 2016 par Godelieve Morel
  An 11-year-old boy with psychomotor delay, exercise intolerance, ptosis and growth delay had a muscle biopsy showing typical mitochondrial alterations (60% of ragged-red fibers and 90% of cytochrome-c oxidase-deficient fibers). Next-generation sequencing revealed a novel heteroplasmic mutation (m.15958A>T) in the MTTP gene that encodes tRNA^(Pro). The mutation was not present in the accessible non-muscle tissues of the patient's asymptomatic mother. Mutations in the rarely affected MTTP gene are…
• Severe defect in mitochondrial complex I assembly with mitochondrial DNA deletions in ACAD9-deficient mild myopathy
  21 juillet 2016 par Konstantina Fragaki
  CONCLUSION: Our data suggest that a major defect of CI assembly is not responsible for a severe phenotype. Muscle Nerve 55: 919-922, 2017.
• Inactivation of Pif1 helicase causes a mitochondrial myopathy in mice
  1 mars 2016 par Sylvie Bannwarth
  Mutations in genes coding for mitochondrial helicases such as TWINKLE and DNA2 are involved in mitochondrial myopathies with mtDNA instability in both human and mouse. We show that inactivation of Pif1, a third member of the mitochondrial helicase family, causes a similar phenotype in mouse. pif1-/- animals develop a mitochondrial myopathy with respiratory chain deficiency. Pif1 inactivation is responsible for a deficiency to repair oxidative stress-induced mtDNA damage in mouse embryonic…
• Coenzyme Q10 defects may be associated with a deficiency of Q10-independent mitochondrial respiratory chain complexes
  9 janvier 2016 par Konstantina Fragaki
  CONCLUSIONS: Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.
• Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China
  1 janvier 2016 par Sylvie Bannwarth
  No abstract
• CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis
  16 décembre 2015 par Emmanuelle C Genin
  CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a…
• CHCHD10 mutations are not a common cause of SMN1-negative type III/IV spinal motor atrophy
  23 juin 2015 par Godelieve Morel
  No abstract
• Reply: Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?
  9 mai 2015 par Sylvie Bannwarth
  No abstract
• Letter to the Editor on a paper by Hsiao C-T, Tsai P-C, Liao Y-C, Lee Y-C, Soong B-W. C9ORF72 repeat expansion is not a significant cause of late-onset cerebellar ataxia syndrome. J Neurol Sci 2014;347:322-324
  4 mars 2015 par Morgane Plutino
  No abstract
• Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation
  15 février 2015 par Sylvie Bannwarth
  No abstract

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