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Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1
Julie Lavie1,2, Román Serrat2,3, Nadège Bellance1,2
1INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.
Abstract:
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.
Insights
Mitochondrial dysfunction contributes to SPG31, a rare neurological disorder. Mutations in the REEP1 gene cause abnormal mitochondrial shape and transport, impacting neuronal health.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Hereditary spastic paraplegia (SPG31) is a rare neurological disorder linked to mutations in the REEP1 gene.
- The precise mechanisms connecting REEP1 function to SPG31 pathogenesis remain largely unknown.
- REEP1 is known to influence organelle morphology and trafficking through microtubule interactions.
Purpose of the Study:
- To investigate mitochondrial morphology in patient-derived cells.
- To elucidate the role of REEP1 in regulating mitochondrial dynamics in SPG31.
- To identify molecular mechanisms underlying mitochondrial dysfunction in SPG31.
Main Methods:
- Analysis of mitochondrial morphology in primary fibroblasts from SPG31 patients.
- Investigation of DRP1 phosphorylation at serine 637.
- Examination of REEP1 interactions with PGAM5.
- Assessment of mitochondrial transport in neuronal cultures expressing mutated REEP1.
Main Results:
- SPG31 patient cells exhibit significantly more tubular mitochondrial morphology compared to controls.
- This tubular morphology is attributed to hyperphosphorylation of DRP1 at serine 637, inhibiting mitochondrial fission.
- Impaired interaction between REEP1 and PGAM5 leads to DRP1 hyperphosphorylation.
- Restoring normal DRP1-S637 phosphorylation levels ameliorates mitochondrial morphology defects.
- Mutated REEP1 sequesters mitochondria in the neuronal perinuclear region, hindering axonal transport.
Conclusions:
- Mitochondrial morphology and transport defects are implicated in SPG31 pathology.
- Dysfunctional REEP1 disrupts mitochondrial dynamics through DRP1 hyperphosphorylation and impaired transport.
- These findings highlight mitochondrial dysfunction as a key factor in SPG31.
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