Mitochondrial dysfunction in SPG31 HSP

Function restored in cell samples

The mechanism behind the impaired structure and function of mitochondria in SPG31 HSP cells derived from human tissue samples is explained in this study. Restoration of mitochondrial structure by genetic and drug means was also achieved.

Mitochondria are the energy factories in cells and their impairment is one of the defined mechanisms causing certain types of HSP. In this study, tissue samples were taken from HSPers with SPG31 HSP caused by mutations in the REEP1 gene.


Hereditary spastic paraplegia, SPG31, is a rare neurological disorder caused by mutations in REEP1 gene encoding the microtubule-interacting protein, REEP1. The mechanism by which REEP1-dependent processes are linked with the disease is unclear. REEP1 regulates the morphology and trafficking of various organelles via interaction with the microtubules.

In this study, we collected primary fibroblasts from SPG31 patients to investigate their mitochondrial morphology. We observed that the mitochondrial morphology in patient cells was highly tubular compared with control cells. We provide evidence that these morphological alterations are caused by the inhibition of mitochondrial fission protein, DRP1, due to the hyperphosphorylation of its serine 637 residue. This hyperphosphorylation is caused by impaired interactions between REEP1 and mitochondrial phosphatase PGAM5.

Genetically or pharmacologically induced decrease of DRP1-S637 phosphorylation restores mitochondrial morphology in patient cells. Furthermore, ectopic expression of REEP1 carrying pathological mutations in primary neuronal culture targets REEP1 to the mitochondria. Mutated REEP1 proteins sequester mitochondria to the perinuclear region of the neurons and therefore, hamper mitochondrial transport along the axon.

Considering the established role of mitochondrial distribution and morphology in neuronal health, our results support the involvement of a mitochondrial dysfunction in SPG31 pathology.

SOURCE: Hum Mol Genet. 2016 Dec 22. pii: ddw425. doi: 10.1093/hmg/ddw425. [Epub ahead of print] PMID: 28007911 [PubMed – as supplied by publisher] © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation.

Lavie J1,2, Serrat R2,3, Bellance N1,2, Courtand G2,4, Dupuy JW2,5, Tesson C6,7, Coupry I1,2, Brice A6, Lacombe D1,2, Durr A6, Stevanin G6,7, Darios F6, Rossignol R1,2, Goizet C1,2, Bénard G8,2.

1 INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.

2 University of Bordeaux, 33077 Bordeaux, France.

3 INSERM U1215, NeuroCentre Magendie, 33077 Bordeaux, France.

4 INCIA, Université de Bordeaux, CNRS UMR5287, Bordeaux, France.

5 Plateforme Protéome, Centre de Génomique Fonctionnelle, F-33000 Bordeaux, France.

6 INSERM U1127, CNRS UMR 7225, UPMC Université Paris 06 UMR S1127, Sorbonne Université Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.

7 Ecole Pratique des Hautes Etudes, PSL Research University, 75014 Paris, France.

8 INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France [email protected].

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