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Autosomal dominant spinocerebellar ataxias (SCA) are a heterogeneous group of neurological disorders characterized by cerebellar dysfunction. We recently showed that AFG3L2 mutations cause dominant ataxia SCA28. AFG3L2 and its partner protein paraplegin, which causes recessive spastic paraparesis SPG7, are components of the m-AAA complex, involved in mitochondrial protein quality control. Since yeast functional studies showed that paraplegin coexpression can modulate AFG3L2 mutations, we investigated the possible coinheritance of AFG3L2 and SPG7 mutations in patients with spinocerebellar syndromes. We identified 3 probands with heterozygous mutations in both the AFG3L2 and the SPG7 genes. Two ataxic patients carry an AFG3L2 mutation affecting highly conserved amino acids located in the ATPase or in the proteolytic domains of the protein along with the parapleginA510V. The third proband carries a de novo AFG3L2 mutation in the highly conserved SRH region of the ATPase domain along with the inherited deletion of SPG7 exons 4-6. The clinical presentation of this patient is characterized by early onset optic atrophy and a L-dopa-responsive spastic-ataxic syndrome with extrapyramidal signs. A muscle biopsy revealed an isolated complex I deficiency. Moreover, evaluation of substrates processing in patient’s fibroblasts showed abnormal processing pattern of OPA1. In conclusion, our data indicate that the presence of a loss-of-function mutation in paraplegin may act as a disease modifier for heterozygous AFG3L2 mutations. Concurrent mutations in both components of the mitochondrial m-AAA complex may result in a complex phenotype, thus expanding the clinical spectrum of AFG3L2-associated mutations. Moreover, biochemical and cell biology studies revealed a crucial role of the m-AAA complex in the processing of OPA1 and the maintenance of mitochondrial morphology., TIRANTI, VALERIA, TARONI, FRANCO, 1692, open, open, Magri, Magri, S