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

Julie Lavie, Román Serrat, Nadège Bellance, Gilles Courtand, Jean-William Dupuy, Christelle Tesson, Isabelle Coupry, Alexis Brice, Didier Lacombe, Alexandra Durr, Giovanni Stevanin, Fréderic Darios, Rodrigue Rossignol, Cyril Goizet, Giovanni Bénard
Hum. Mol. Genet.. 2016-12-22; : ddw425
DOI: 10.1093/hmg/ddw425

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1. Hum Mol Genet. 2017 Feb 15;26(4):674-685. doi: 10.1093/hmg/ddw425.

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

Lavie J(1)(2), Serrat R(2)(3), Bellance N(1)(2), Courtand G(2)(4), Dupuy
JW(2)(5), Tesson C(6)(7), Coupry I(1)(2), Brice A(6), Lacombe D(1)(2), Durr A(6),
Stevanin G(6)(7), Darios F(6), Rossignol R(1)(2), Goizet C(1)(2), Bénard G(1)(2).

Author information:
(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,
(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,
(7)Ecole Pratique des Hautes Etudes, PSL Research University, 75014 Paris,

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

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DOI: 10.1093/hmg/ddw425
PMID: 28007911 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus