Sulfite Alters the Mitochondrial Network in Molybdenum Cofactor Deficiency

Abstract

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disorder belonging to the large family of inborn errors in metabolism. Patients typically present with encephalopathy and seizures early after birth and develop severe neurodegeneration within the first few weeks of life. The main pathomechanism underlying MoCD is the loss of function of sulfite oxidase (SO), a molybdenum cofactor (Moco) dependent enzyme located in mitochondrial intermembrane space. SO catalyzes the oxidation of sulfite (SO32–) to sulfate (SO42–) in the terminal reaction of cysteine catabolism, and in the absence of its activity, sulfurous compounds such as SO32–, S-sulfocysteine, and thiosulfate accumulate in patients. Despite growing evidence that these compounds affect neuronal and mitochondrial function, the molecular basis of neuronal dysfunction and cell death in MoCD is still poorly understood. Here we show that mitochondria are severely affected by the loss of SO activity. SO-deficient mouse embryonic fibroblasts display reduced growth rates and impaired ATP production when cultured in galactose, which is an indicator of mitochondrial dysfunction. We also found that mitochondria in SO-deficient cells form a highly interconnected network compared to controls while displaying a slight decrease in motility and unchanged mitochondrial mass. Moreover, we show that the mitochondrial network is directly influenced by SO32–, as a moderate elevation of SO32– lead to the formation of an interconnected mitochondrial network, while high SO32– levels induced fragmentation. Finally, we found a highly interconnected mitochondrial network in MoCD patient-derived fibroblasts, similar to our findings in mouse-derived fibroblasts. We therefore conclude that altered mitochondrial dynamics are an important contributor to the disease phenotype and suggest that MoCD should be included among the mitochondrial disorders.

Molybdenum Cofactor Deficiency in Humans

“…In aggregate, accumulating thiosulfate in MoCD and iSOD gives rise to the proposal that alterations in H 2 S homeostasis may contribute to a larger extent to mitochondrial dysfunction than initially anticipated, and recent data support this notion [ 124 , 125 ], being in line with other data showing sulfite-dependent changes in mitochondrial morphology [ 126 ].…”

Fosdenopterin: a First-in-class Synthetic Cyclic Pyranopterin Monophosphate for the Treatment of Molybdenum Cofactor Deficiency Type A

“…39 Sulphite can disrupt mitochondrial integrity and function, 40 and mitochondrial respiration was found to be impaired in a MOCS1 defective cell line 41 and in cells of SO-deficient mice. 42 In addition, a specific pathomechanism has been proposed that can explain the apparent peracute neuronal failure after birth: SSC is a strong N-methyl-D-aspartate (NMDA) receptor agonist, 43,44 and leads to excitotoxic neuronal cell death and seizures. [45][46][47] It is therefore likely that, in MoCD, the encephalopathic crisis after birth is caused by an excitotoxic storm that leads to widespread neuronal necrosis.…”

Differentiation of HSA and BSA and Instantaneous Detection of HSO3– Using Confined Space of Serum Albumins and Live Cell Imaging of Exogenous/Endogenous HSO3–

“…In physiological conditions, sulfites are formed by the reaction of SO 2 and water; SO 2 + H 2 O ↔ H 2 SO 3 – ↔ HSO 3 – + H + ↔ SO 3 2– + 2H + . The mitochondrial enzyme sulfite oxidase catalyzes the oxidative degradation of cysteine and methionine and also plays a vital role in detoxifying exogenously supplied sulfite from food, pharmaceutical products, and antimicrobial agents. , However, the deficiency in the sulfite oxidase enzyme or the error in the biosynthetic pathway results in the accumulation of sulfite in biological fluids or tissues. − The accumulation of sulfite affects the mitochondrial homeostasis in rat brain mitochondria and also induces mitochondrial swelling and reduces the mitochondrial membrane potential and Ca 2+ retention capacity . Bisulfite is associated with respiratory abnormalities and brain cancer .…”

“… 30 , 31 However, the deficiency in the sulfite oxidase enzyme or the error in the biosynthetic pathway results in the accumulation of sulfite in biological fluids or tissues. 32 − 34 The accumulation of sulfite affects the mitochondrial homeostasis in rat brain mitochondria and also induces mitochondrial swelling and reduces the mitochondrial membrane potential and Ca 2+ retention capacity. 35 Bisulfite is associated with respiratory abnormalities 36 and brain cancer.…”