Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits inSPG7but NotSPASTPatient-Derived Stem Cells

Mutations inSPG7andSPASTare common causes of hereditary spastic paraplegia (HSP). While someSPG7mutations cause paraplegin deficiency, otherSPG7mutations cause increased paraplegin expression. Mitochondrial function has been studied in models that are paraplegin-deficient (human, mouse, andDrosophilamodels with large exonic deletions, null mutations, or knockout models) but not in models of mutations that express paraplegin. Here, we evaluated mitochondrial function in olfactory neurosphere-derived cells, derived from patients with a variety ofSPG7mutations that express paraplegin and compared them to cells derived from healthy controls and HSP patients withSPASTmutations, as a disease control. We quantified paraplegin expression and an extensive range of mitochondrial morphology measures (fragmentation, interconnectivity, and mass), mitochondrial function measures (membrane potential, oxidative phosphorylation, and oxidative stress), and cell proliferation. Compared to control cells,SPG7patient cells had increased paraplegin expression, fragmented mitochondria with low interconnectivity, reduced mitochondrial mass, decreased mitochondrial membrane potential, reduced oxidative phosphorylation, reduced ATP content, increased mitochondrial oxidative stress, and reduced cellular proliferation. Mitochondrial dysfunction was specific toSPG7patient cells and not present inSPASTpatient cells, which displayed mitochondrial functions similar to control cells. The mitochondrial dysfunction observed here inSPG7patient cells that express paraplegin was similar to the dysfunction reported in cell models without paraplegin expression. The p.A510V mutation was common to all patients and was the likely species associated with increased expression, albeit seemingly non-functional. The lack of a mitochondrial phenotype inSPASTpatient cells indicates genotype-specific mechanisms of disease in these HSP patients.