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Luo, Chi

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Luo, Chi
Author's Publications: search.filters.isAuthorOfPublication.339a239a-8603-490b-bc6b-cb5f69ecdb9c

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    Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models
    (Springer Science and Business Media LLC, 2021-01-18) Perry, Elizabeth; Bennett, Christopher; Luo, Chi; Balsa Martinez, Eduardo; Jedrychowski, Mark; O'Malley, Katherine; Latorre Muro, Pedro Antonio; Ladley, Richard Porter; Reda, Kamar; Wright, Peter; Gygi, Steven; Myers, Andrew; Puigserver, Pere
    Mitochondrial diseases (MD) are a heterogeneous group of disorders resulting from genetic mutations in nuclear or mitochondrial DNA (mtDNA) genes encoding for mitochondrial proteins 1,2. MD cause pathologies with severe tissue damage and ultimately death 3,4. There are no cures for MD and current treatments are only palliative 5–7. To search for new drug-targeted therapies, we designed a chemical high-throughput screen using cells carrying human MD mutations to identify small molecules that prevent cellular damage and death under nutrient stress conditions. Top hits in the screen were a series of antibiotics that maintain survival of different human MD mutant cells. A sub-library of tetracycline analogs, including doxycycline, rescued cell death and inflammatory signatures in mutant cells through partial and selective mitochondrial translation inhibition, causing a mitohormetic response that was ATF4 independent. Remarkably, doxycycline treatment strongly promoted fitness and survival of Ndufs4-/- mice, a pre-clinical Leigh syndrome mouse model 8. Brain proteomic analysis showed that doxycycline treatment largely prevented neuronal death and the increases of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causality of these proteins in this brain pathology. These findings implicate tetracyclines as a potential therapeutic treatment for MD.
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    CDK6 inhibits white to beige fat transition by suppressing RUNX1
    (Nature Publishing Group UK, 2018) Hou, Xiaoli; Zhang, Yongzhao; Li, Wei; Hu, Alexander J.; Luo, Chi; Zhou, Wenhui; Hu, Jamie K.; Daniele, Stefano G.; Wang, Jinfeng; Sheng, Jinghao; Fan, Yongsheng; Greenberg, Andrew S.; Farmer, Stephen R.; Hu, Miaofen G.
    Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6−/− mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.