Mitochondrial myopathy with mitochondrial DNA (mtDNA) depletion is an important and newly recognized class of mitochondrial disease that causes metabolic myopathy as well as intellectual and developmental disabilities. Deficiency of ADP-specific succinyl-CoA synthetase (SCS), a component of the TCA cycle, has been identified as one of the causes of mitochondrial myopathy with mtDNA depletion. A gene trap mutant clone of Sucla2, the gene encoding the beta-subunit of SCS, has been isolated. This mutant mouse ES cell line has been used to generate transgenic mice and mouse embryonic fibroblast (MEF) cell lines deficient for Sucla2. Mutant MEFs as well as mutant embryonic skeletal muscle and brain demonstrate mtDNA depletion. This proposal is based on the hypothesis that SCS is an important protein component of the mtDNA nucleoid complex required for mtDNA maintenance and stability. Cells deficient for SUCLA2 will be utilized to investigate the functional and structural components of SUCLA2 required for mtDNA maintenance. Genetic studies to determine proteins that interact with SCS and are potential components of the mtDNA nucleoid complex will also be pursued. Mice mutant for Sucla2 will be generated to study the pathophysiology of SCS deficiency as a model for mtDNA depletion and myopathy. These studies will provide new insights into fundamental mechanisms of mtDNA biology as well as provide a novel model of mtDNA depletion to facilitate the development of new therapeutic strategies for an important subset of metabolic myopathies.
Depletion or reduction of total content of mitochondrial DNA (mtDNA) is a feature of a subset of mitochondrial diseases and has also been observed in breast cancer. The development of cell and animal models of mtDNA depletion is important for understanding the pathological mechanisms of mtDNA depletion as well as for understanding fundamental mechanisms of mtDNA biology. This project establishes a model to study mtDNA depletion and to explore basic mechanisms of mtDNA maintenance in order to ultimately develop novel therapeutic strategies for diseases with mtDNA depletion.
|Burrage, Lindsay C; Miller, Marcus J; Wong, Lee-Jun et al. (2016) Elevations of C14:1 and C14:2 Plasma Acylcarnitines in Fasted Children: A Diagnostic Dilemma. J Pediatr 169:208-13.e2|
|Donti, Taraka R; Masand, Ruchi; Scott, Daryl A et al. (2016) Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant. Mol Genet Metab 119:68-74|
|Sadat, Roa; Barca, Emanuele; Masand, Ruchi et al. (2016) Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency. Mol Genet Metab 118:28-34|
|Besse, Arnaud; Wu, Ping; Bruni, Francesco et al. (2015) The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism. Cell Metab 21:417-27|
|Liu, Lucy; Zhang, Ke; Sandoval, Hector et al. (2015) Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 160:177-90|
|Sandoval, Hector; Yao, Chi-Kuang; Chen, Kuchuan et al. (2014) Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production. Elife 3:|
|Burrage, Lindsay C; Tang, Sha; Wang, Jing et al. (2014) Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene. Mol Genet Metab 113:207-12|
|Donti, Taraka R; Stromberger, Carmen; Ge, Ming et al. (2014) Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion. Dis Model Mech 7:271-80|
|Bonnen, Penelope E; Yarham, John W; Besse, Arnaud et al. (2013) Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am J Hum Genet 93:471-81|