Selected Grantee Publications
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- Invertebrate Models
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- Pediatrics
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
De Novo Variants in EMC1 Lead to Neurodevelopmental Delay and Cerebellar Degeneration and Affect Glial Function in Drosophila
Chung et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac053
Variants in EMC1, which encodes a subunit of the endoplasmic reticulum (ER)–membrane protein complex (EMC), are associated with developmental delay in children. Functional consequences of these variants are poorly understood. The investigators identified de novo variants in EMC1 in three children affected by global developmental delay, hypotonia, seizures, visual impairment, and cerebellar atrophy. They demonstrated in Drosophila that these variants are loss-of-function alleles and lead to lethality when expressed in glia but not in neurons. This work suggests the causality of EMC variants in disease. Supported by ORIP (R24OD022005, R24OD031447), NINDS, and NICHD.