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Comparative functional analysis reveals differential nucleotide sensitivity between human and mouse UCP1.
Eva Musiol1, Tobias Fromme1,2, Julia Hau1
1Chair for Molecular Nutritional Medicine, TUM School of Life Sciences, Research Department of Molecular Life Sciences, Technical University of Munich, Freising, Germany.
Acta Physiologica (Oxford, England)
|July 29, 2024
Summary
Human and mouse UCP1 show similar fatty acid activation but differ in purine nucleotide inhibition. Key structural elements in human UCP1 were identified, aiding the search for metabolic disease activators.
Area of Science:
- Mitochondrial physiology
- Brown adipose tissue thermogenesis
- Metabolic disease research
Background:
- Mitochondrial uncoupling protein 1 (UCP1) is central to brown adipose tissue thermogenesis.
- UCP1 activity is regulated by fatty acids and purine nucleotides.
- Rodent models dominate current UCP1 research, necessitating human-specific studies.
Purpose of the Study:
- To analyze human UCP1 activity, regulation, and structure.
- To compare human UCP1 function with its murine ortholog.
- To identify structural determinants of human UCP1 uncoupling.
Main Methods:
- Established a doxycycline-inducible cell model for human and murine UCP1 expression.
- Performed functional studies using respirometry.
- Compared wild-type and mutant variants of human UCP1.
Main Results:
- Human and mouse UCP1 display comparable fatty acid-induced activity.
- Significant differences were observed in purine nucleotide inhibition between human and mouse UCP1.
- Mutagenesis identified key residues in α-helices 5 and 6 critical for human UCP1 uncoupling.
Conclusions:
- Comparative analysis of human UCP1 with orthologs offers insights into structure-function relationships.
- Identified structural features are crucial for UCP1 uncoupling function.
- Findings facilitate the search for novel activators targeting human UCP1 for metabolic disorders.
