Universität zu Köln

Mellis, Anna-Theresa, Roeper, Juliane, Misko, Albert L., Kohl, Joshua and Schwarz, Guenter ORCID: 0000-0002-2118-9338 (2021). Sulfite Alters the Mitochondrial Network in Molybdenum Cofactor Deficiency. Front. Genet., 11. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-8021

Full text not available from this repository.

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mellis, Anna-Theresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Roeper, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Misko, Albert L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kohl, Joshua UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-578703
DOI:	10.3389/fgene.2020.594828
Journal or Publication Title:	Front. Genet.
Volume:	11
Date:	2021
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-8021
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MUTATION; NEURODEGENERATION; HOMEOSTASIS; INCREASES; MOTILITY; ENERGY; ETHE1; GENE Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57870