Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• SLC25A26 encodes a mitochondrial carrier protein crucial for S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) transport.
• Pathogenic SLC25A26 variants cause severe, early-onset mitochondrial disease due to impaired SAM transport.
• The precise role of SAH transport in mitochondrial function and disease is less understood.

Purpose of the Study:

• To investigate the genetic and molecular basis of a milder, late-onset mitochondrial myopathy.
• To characterize the phenotype associated with biallelic SLC25A26 variants in adult patients.
• To elucidate the pathomechanism underlying this late-onset mitochondrial disorder.

Main Methods:

• Clinical case description of two unrelated adult patients with mitochondrial myopathy.
• Genetic analysis to identify biallelic SLC25A26 variants.
• Biochemical and histopathological analysis of skeletal muscle tissue.
• In vivo studies using mouse and fruit fly models to assess mitochondrial transport function.

Main Results:

• Identified two adult patients with exercise intolerance, metabolic decompensation, and mitochondrial myopathy linked to SLC25A26 variants.
• Observed severe respiratory chain deficiencies and muscle histopathology comparable to early-onset cases.
• Demonstrated in model organisms that impaired SAH transport, not SAM transport, is associated with the milder, late-onset phenotype.

Conclusions:

• Biallelic SLC25A26 variants can cause a milder, late-onset mitochondrial disease in adults.
• Impairment of S-adenosylhomocysteine (SAH) transport across the mitochondrial membrane is the likely pathomechanism for this phenotype.
• Findings highlight the importance of SAH transport and offer insights for precision medicine approaches in mitochondrial disorders.