The mammalian NADH dehydrogenase (complex I), which is under dual genetic control, nuclear and mitochondrial, plays a central role in oxidative phosphorylation. This respiratory complex consists of 45 subunits and has been implicated in human genetic and acquired diseases. In previous studies, we have isolated several cell lines deficient in complex I assembly and mitochondrial function. We further identified a putative protein factor whose over-expression was associated with recovered complex I assembly.
The specific aims of the proposal are to 1) determine if the protein we identified is a complex I assembly factor 2) to develop a genetic approach to isolated genes that could compensate mitochondrial deficiency caused by complex I gene mutations. The success of this proposal will help us to understand the regulation of assembly and function of respiratory complex I, and also provide useful clues for developing a therapeutic approach for complex I deficiency.
We submit this grant application focusing on understanding the function and regulation of mitochondrial respiratory complex I. In particular, we will develop a novel approach to isolate important protein factors which regulate mitochondrial function. The success of this project will advance our understanding of mitochondrial function and shed light on the pathogenesis of human disease associated with complex I dysfunction.
|Porras, Christina Ann-Marie; Bai, Yidong (2015) Respiratory supercomplexes: plasticity and implications. Front Biosci (Landmark Ed) 20:621-34|
|Vartak, Rasika S; Semwal, Manpreet Kaur; Bai, Yidong (2014) An update on complex I assembly: the assembly of players. J Bioenerg Biomembr 46:323-8|
|Nie, Hezhongrong; Shu, Hongying; Vartak, Rasika et al. (2013) Mitochondrial common deletion, a potential biomarker for cancer occurrence, is selected against in cancer background: a meta-analysis of 38 studies. PLoS One 8:e67953|
|Li, Hongzhi; Kumar Sharma, Lokendra; Li, Youfen et al. (2013) Comparative bioenergetic study of neuronal and muscle mitochondria during aging. Free Radic Biol Med 63:30-40|
|Vartak, Rasika; Porras, Christina Ann-Marie; Bai, Yidong (2013) Respiratory supercomplexes: structure, function and assembly. Protein Cell 4:582-90|
|Chen, Liuh-Yow; Zhang, Yi; Zhang, Qinfen et al. (2012) Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. Mol Cell 47:839-50|
|Zhang, Chengkang; Huang, Vincent H; Simon, Mariella et al. (2012) Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions. FASEB J 26:4914-24|
|Sharma, Lokendra Kumar; Fang, Hezhi; Liu, Jiangtao et al. (2011) Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum Mol Genet 20:4605-16|