NEURODYN – NEUROnal DYNamics in Mitochondrial Disease

Arnaud Chevrollier, Professor University of Angers

Medical Biology, Biotechnology

Head of the SCIAM university microscopy platform, ICAT federated research structure, Faculty of Medicine, Angers

arnaud.chevrollier @ univ-angers.fr

Keywords : Mitochondria dynamics OPA1, MFN2 ; mitophagy ; proteostasis, mitochondrial DNA  Nucleoids ; microscopy Super resolution imaging dSTORM. 

State of the art and objectives              

Mitochondria form a dynamic, interconnected network within cells, constantly adapting to cellular requirements by changing their shape and position through fission and fusion. Over the past decade, studies have revealed that this dynamic behavior plays a crucial role in processes such as mitochondrial bioenergetics, axonal transport, calcium homeostasis, reactive oxygen species production, and apoptosis.

Mutations in genes encoding fission and fusion proteins disrupt mitochondrial network organization and lead to fragmentation, resulting in inherited diseases such as optic atrophy (OPA1, MIM#16550) and peripheral neuropathies (GDAP1, MIM#607831; MFN2, MIM#609260). Our research projects focus on mitochondrial shaping through genetic, biochemical, and structural investigations in patient samples and mouse models, with a particular emphasis on mitochondrial dynamics impairments caused by mutations in OPA1, MFN2, GDAP1, DRP1, and OXPHOS genes.

Our goal is to determine the precise mechanisms of the mitochondrial fusion–fission machinery in order to better understand their role in disease pathogenesis and to develop new therapeutic strategies. To this end, we explore the main pathways that maintain cellular proteostasis, namely the ubiquitin–proteasome system (UPS) and the autophagic and mitophagy machineries. Using fluorescence microscopy, we analyze mitochondrial organization, protein aggregation, and autophagic flux under conditions of fusion/fission defects. We further achieve nanoscale resolution with Stochastic Optical Reconstruction Microscopy (dSTORM) and employ 3D multi-color super-resolution microscopy (SMLM, Single-Molecule Localization Microscopy) to unravel the nanoscale spatial organization and interactions of different mitochondrial targets.

Team members 

• Solenn Plouzennec  PhD student, Angers university, co-supervision with Pr. Julien Cassereau, MD-PhD, Neurology CHU ANGERS
• Pr Philippe Codron, MD-PhD, Neurology CHU ANGERS
• Pauline Teixeira, PhD student, Angers university co-supervision with Pr. P. May- Panloup and Magalie Boguenet, human reproduction
• Florence Pascaretti, Technician, microscopy
• Anaïs Girardeau, Technician AFM Telethon, cell biology

Scientific partners

• Naïg Gueguen, CHU Angers, Biochemistry
• Valérie Desquiret-Dumas , CHU Angers, Biochemistry, molecular biology
• Janelle Drouin-Ouellet, Associate Professor, Canada Research Chair in Direct Neural Reprogramming, Montréal
• Mafalda Escobar-Henriques, Institut für Genetik, Köln
• Jean-Baptiste Sibarita, Remi Galland, Imagerie cellulaire Quantitative Bordeaux
• Majida Charif, Professor of Genetics and Molecular Biology, Oujda, Maroc

Transdifferenciated Neurons  

The forced expression of different transcription factors through lentiviral vector delivery together with adding to small molecules and growth factors to the medium reprograms human fibroblasts to transdifferenciated neurons tdN.  (Drouin-Ouellet et al., 2022). Besides retaining aging signatures of the patient, tdN offer several other advantages, including their non-clonal characteristic, thus avoiding the risk of clonal bias, and being compatible with handling dozens of lines by one experimenter, conferring a gain in time and working efficiency. tdN allow to obtain mature neurons quickly (within a month).

Charcot–Marie–Tooth disease type 2A

Charcot-Marie-Tooth (CMT) constitutes a group of heterogeneous hereditary motor and sensor neuropathies. Mutations in mitofusin-2 (MFN2) cause CMT type 2A by altering mitochondrial fusion and trafficking along with the axonal microtubule system.

Dominant Optic Atrophy

Hereditary optic neuropathies are caused by the degeneration of retinal ganglion cells whose axons form the optic nerves, with a consistent genetic heterogeneity. The identified top 10 nuclear genes included OPA1, WFS1, ACO2, SPG7, MFN2, AFG3L2, RTN4IP1, TMEM126A, NR2F1 and FDXR. Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability.

Disorders linked to DNM1L mutations

Mutations in DNM1L (DRP1), which encode a key player of mitochondrial and peroxisomal fission, have been reported in patients with the variable phenotypic spectrum, ranging from non-syndromic optic atrophy to lethal infantile encephalopathy.

Alumni

• Selma Kane : Kane SM, Alban J, Desquiret-Dumas V, Gueguen N, Ishac L, Ferre M, Amati-Bonneau P, Procaccio V, Bonneau D, Lenaers G, Reynier P, Chevrollier A. Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy. JCMM, (2017) 21(10):2284-2297. DOI: 10.1111/jcmm.13149

• Sophie Belal, PhD student co-supervision Pr. Vincent Procaccio : Belal S, Goudenège D, Bocca C, Dumont F, Chao De La Barca JM, Desquiret-Dumas V, Gueguen N, Geffroy G, Benyahia R, Kane S, Khiati S, Bris C, Aranyi T, Stockholm D, Inisan A, Renaud A, Barth M, Simard G, Reynier P, Letournel F, Lenaers G, Bonneau D, , Procaccio V, Chevrollier A. Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure. Biomedicines. 2022 ;10(7):1665. doi: 10.3390/biomedicines10071665.

• Philippe Codron Neurologist : Codron P, Letournel F, Marty S, Renaud L, Bodin A, Duchesne M, Verny C, Lenaers G, Duyckaerts C, Julien JP, Cassereau J, Chevrollier A. STochastic Optical Reconstruction Microscopy (STORM) reveals the nanoscale organization of pathological aggregates in human brain. Neuropathol Appl Neurobiol. 2021 47(1):127-142. doi: 10.1111/nan.12646

• Charlène Lhuissier PhD student co-supervision Dr. Naïg Gueguen : Lhuissier C, Desquiret-Dumas V, Girona A, Alban J, Faure J, Cassereau J, Codron P, Lenaers G, Baris O, Gueguen N, Chevrollier A. Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission, iScience 2024 Apr 24;27(5). https://doi.org/10.1016/j.isci.2024.109808

• Charlotte ORRE PhD student co-supervision Dr. Valérie Desquiret Dumas : Orre C, Dieu X, Guillon J, Gueguen N, Ahmadpour ST, Dumas JF, Khiati S, Reynier P, Lenaers G, Coqueret O, Chevrollier A, Mirebeau-Prunier D, Desquiret-Dumas V. The Long Non-Coding RNA SAMMSON Is a Regulator of Chemosensitivity and Metabolic Orientation in MCF-7 Doxorubicin-Resistant Breast Cancer Cells. Biology (Basel). 2021 Nov 9;10(11):1156. doi: 10.3390/biology10111156. 

• Alexia Bodin : Bodin A, Greibill L, Gouju J, Letournel F, Pozzi S, Julien JP, Renaud L, Bohl D, Millecamps S, Verny C, Cassereau J, Lenaers G, Chevrollier A, Tassin AM, Codron P. Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells. Brain. 2023 Sep 1;146(9):3624-3633. doi: 10.1093/brain/awad228.

Publications

https://orcid.org/0000-0002-5135-6643

https://www.scopus.com/authid/detail.uri?authorId=6508331963

• Chevrollier A, Bonnard AA, Ruaud L, Gueguen N, Perrin L, Desquiret-Dumas V, Guimiot F, Becker PH, Levy J, Reynier P, Gaignard P. Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria Brain. 2024 Jan 4;147(1):91-99. doi: 10.1093/brain/awad347.
• Vovard B, Bodin A  Gouju J, Derkinderen  P, Etcharry-Bouyx F, Chauvire V, Guillet-Pichon V, Verny C, Cassereau J, Letournel F, Lenaers G, Chevrollier A, Codron P. STORM Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α-synuclein Aggregation. Movement Disorders, 2024 Apr;39(4):723-728 https://doi.org/10.1002/mds.29744
• Bureau J, Manero F, Baris O, Bodin A, Verny C, Chevrollier A, Lenaers G, Codron P, Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models. Brain Communications 2024 https://doi.org/10.1093/braincomms/fcae404
• Joaquim M, Altin S, Bulimaga B, Simões T, Nolte H, Bader V, Franchino C, Plouzennec S, Szczepanowska K, Marchesan E, Hofmann K, Krueger M, Elen Ziviani E, Trifunovic A, Chevrollier A, Winklhofer K, Elia Motori E, and Odenthal M, Escobar-Henriques M. Mitofusin 2 displays fusion-independent roles in proteostasis surveillance. Nature Communications 2025 10;16(1):1501 doi: 10.1038/s41467-025-56673-5
• Teixeira P, Galland R, Chevrollier A. Super-resolution microscopies, technological breakthrough to decipher mitochondrial structure and dynamic.  Seminars in Cell and Developmental Biology, 2024, Vol 159–160, P 38-51  doi.org/10.1016/j.semcdb.2024.01.006