Mutations in SLC25A26, encoding the mitochondrial S-adenosylmethionine (SAM) transporter, were identified in patients in three families though homozygosity mapping and exome sequencing. Clinical manifestations ranged from foetal hydrops to episodes of lactic acidosis and cardiopulmonary collapse in childhood with chronic progressive muscle weakness.
The authors showed that the defect of SAM import into mitochondria causes an intramitochondrial methylation deficiency, which in turn affects mitochondrial RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid. This a novel and fascinating mechanism of mitochondrial disease.
Interestingly, the group found that intramitochondrial methylation was not entirely abolished, suggesting the existence of alternative mechanisms, such as other forms of methylation or recycling of methyl groups originating from imported methylated proteins. To me, this underlines the fact that intramitochondrial methylation is still incompletely explored, and implies that a better understanding of these alternative mechanisms might lead to potential treatment options for this condition.
This study also highlights the physiological importance of intramitochondrial methylation. I think it might be interesting to speculate on the role that a secondary deficiency in intramitochondrial methylation might play in the pathophysiology of remethylation disorders that result in a global deficiency of SAM (e.g. MTHFR deficiency).
Kishita Y, Pajak A, Bolar NA, et al (2015) Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. Am J Hum Genet 97: 761-768.