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Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) characterised by progressive degeneration of motor neurons, leading to death of patients 3–5 years after the onset of symptoms. Around 90% occur randomly and are considered as sporadic amyotrophic lateral sclerosis (sALS), whereas the remaining 10% of ALS are classified as familial amyotrophic lateral sclerosis (fALS). Among all factors involved in ALS pathogenesis, mitochondrial dysfunction has always been recognised as a key player, despite a causative role of mitochondria having always been debated.1 Recently, Cheng and colleagues identified a mitochondrial DNA (mtDNA) deletion (‘6692delA’) in 20 out of the 40 patients with sALS they analysed, suggesting a causal role in sALS.2 This variant, in a gene coding for a subunit of complex IV (CIV) of the respiratory chain, was present at 1% heteroplasmy in the blood of patients. They then demonstrated that CIV deficiency in rat motor neurons induces an ALS phenotype, thus confirming that a mitochondrial defect can trigger MND. Indeed, we previously showed that mutations in the CHCHD10 gene, coding for a mitochondrial protein, are responsible for mitochondrial disease associated with fALS.3