The Role of Mitochondrial TNAP in Adaptive Thermogenesis

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Abstract Thermogenic adipocytes and adaptive thermogenesis are promising therapeutic targets for treating and preventing obesity and obesity-linked diabetes. We recently demonstrated that the mitochondrial tissue- nonspecific alkaline phosphatase, TNAP, plays a crucial role in the futile creatine cycle (FCC) and adaptive thermogenesis by hydrolyzing phosphocreatine. Pharmacological inhibition or genetic ablation of TNAP in mice reduces systemic energy expenditure. Genetic ablation of TNAP in mice also causes rapid-onset obesity. TNAP assumes a mitochondrial localization specifically in thermogenic adipocytes, which might ensure the cell- selectivity of the phosphocreatine hydrolysis events and the FCC operation. Here, we propose to study the metabolic effects of gain-of- function of TNAP in the adipose tissues in mice, as well as the molecular mechanism and regulation of its mitochondrial localization. Using a transgenic mouse strain that artificially expresses TNAP in the adipose tissues, we will investigate its effects on obesity, diabetes, fatty liver, and energy expenditure. To study the TNAP localization, we will test whether its cell specificity lies in the TNAP polypeptide or its trafficking pathway, or both. I will first determine whether there are any molecular elements (e.g., PTMs or amino acid sequences) on the TNAP polypeptide crucial for its mitochondrial localization. This will be done using a combination of biochemical and cell imaging approaches. In addition, we will investigate the cellular pathway of TNAP trafficking to mitochondria. We will interrogate the role of lipid rafts in TNAP localization. This might allow us to identify key regulators and mediators of the mitochondrial localization of TNAP. Finally, we will identify other mitochondrial proteins that share the localization pathway of TNAP and study their functions. The candidate, Dr. Yizhi Sun, has a strong track record of innovative research with a focus on the molecular mechanisms of diseases. The candidate’s career goal is to become an independent academic investigator with a research laboratory oriented towards understanding and reversing obesity and obesity-linked metabolic disorders. The proposed research will be conducted in the laboratory of Bruce Spiegelman, PhD at Dana-Farber Cancer Institute and Harvard Medical School, who is a leader in the fields of molecular metabolism and adipocyte biology. The proposed studies will also bring together leading laboratories of the advisory committee that have expertise in cell imaging, protein trafficking, and mitochondrial biology. All of these, together with the ideal research environment in the Longwood Medical Area, will maximize applicant’s potential to successfully transition to an independent investigator.