Misfolding of a key enzyme disrupts energy production and balance in mitochondria

CBS deficiency due to the I278T variant leads to substantial impairment in mitochondrial respiration and ATP production.

• The I278T variant of the cystathionine beta-synthase gene is associated with unfolded protein response and oxidative stress in cellular models of homocystinuria.
• All three cellular models exhibited impaired cellular energy metabolism linked to mitochondrial dysfunction.
• Mitochondrial morphology changes included swelling and loss of cristae, correlating with decreased membrane potential and cytosolic mitochondrial DNA release.
• Compromised activation of mitophagy and dysfunctional lysosomes contributed to impaired clearance of damaged mitochondria.
• Methionine restriction was shown to reduce plasma total homocysteine and improve mitochondrial function in treated mouse hepatocytes.
• CBS knockout HEK293 cells maintained normal mitochondrial function and proteostasis, suggesting that misfolding of CBS I278T is a primary cause of the pathological phenotype.

Simplified