SLC25A26 – SLC25A26-related Mitochondrial Disease

SLC25A26 encodes the mitochondrial inner membrane carrier responsible for importing S-adenosylmethionine (SAM) in exchange for S-adenosylhomocysteine (SAH). Proper SAM/SAH exchange is essential for intramitochondrial methylation of proteins and nucleic acids, supporting respiratory chain function. Pathogenic, biallelic SLC25A26 variants have been established as a cause of early-onset mitochondrial disease in children and have now been linked to a milder, adult-onset mitochondrial disease phenotype.

Autosomal recessive inheritance is confirmed by compound heterozygous or homozygous variants in unrelated families presenting with exercise intolerance (HP:0003546) and mitochondrial myopathy (HP:0003737). In two independent adult probands, biallelic SLC25A26 variants—including the canonical splice-site change c.190+4A>G—were identified, supporting loss of function as the disease mechanism (PMID:35024855).

Muscle biopsies in these patients revealed marked respiratory chain deficiencies and characteristic mitochondrial histopathology comparable to previously described neonatal-onset cases (PMID:35024855). In vitro transport assays demonstrated that SAH export, rather than SAM import, is preferentially impaired by these variants, pinpointing SAH transport deficiency as the critical molecular defect (PMID:35024855).

In vivo models strengthen this mechanistic link: both mouse and Drosophila engineered to carry analogous SLC25A26 mutations exhibit impaired mitochondrial respiration, altered methylation profiles, and histological abnormalities mirroring the human phenotype (PMID:35024855). These findings underscore disrupted SAH transport across the mitochondrial membrane as the proximate cause of mitochondrial dysfunction.

Collectively, the genetic and experimental data establish a moderate-to-strong association between SLC25A26 deficiency and mitochondrial disease, with autosomal recessive inheritance, a spectrum of onset ages, and a well‐defined mechanistic basis. Incorporation of SLC25A26 into diagnostic mitochondrial gene panels is recommended for patients with exercise intolerance and mitochondrial myopathy.

Key Take-home: Biallelic SLC25A26 variants impair SAH transport, leading to a variable-onset mitochondrial disease amenable to genetic diagnosis and functional confirmation.

References

• Human molecular genetics • 2022 • Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease. PMID:35024855

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