Villena 2018 MiP2018
Villena JA, Castillo A, Pedriza I, Vila M, Pardo R, Camara Y, Nogueiras R (2018)
Mitochondrial biogenesis is regulated at the transcriptional level by a well-defined network of transcription factors that coordinate the expression genes encoded by the nuclear (nDNA) and mitochondrial (mtDNA) genomes. However, little is known about the molecular components that control mitochondrial protein translation. Recently, Mitochondrial Transcription Termination Factor 4 (MTERF4) has been suggested to be a critical factor required for the assembly of mitochondrial ribosomes in heart. MTERF4 is highly expressed in brown adipocytes, but its role has not been explored.
To study the role of MTERF4 in brown adipose tissue (BAT), we generated adipose-specific knockout mice devoid of MTERF4 specifically in adipocytes (MTERF4-FAT-KO). Lack of MTERF4 in BAT leads to reduced steady-state levels of OxPhos mitochondrial proteins and to impaired assembly of OxPhos complexes I, III and IV as a consequence of deficient translation of mtDNA-encoded proteins. The reduced OxPhos protein content correlated with an impaired respiratory capacity of isolated brown adipocytes in response to norepinephrine. In vivo, MTERF4-FAT-KO mice exhibited a blunted thermogenic response upon acute treatment with a specific β3-receptor agonist and were unable to maintain body temperature when exposed to cold. Despite the strong association described between reduced BAT mass/activity and impaired glucose homeostasis in humans, MTERF-FAT-KO mice did not develop insulin resistance, glucose intolerance or obesity when fed with a high fat diet. Still, MTERF-FAT-KO mice became resistant to the insulin sensitizing effects induced by the long-term treatment with the β3-receptor agonist CL316,243.
Our results demonstrate that MTERF4 regulates mitochondrial protein translation and is essential for proper mitochondrial function in brown adipocytes, as well as for the thermogenic activity of BAT. These findings support the notion that pharmacological activation of brown adipocytes could be a useful therapeutic approach for the treatment of insulin resistance.
• Bioblast editor: Plangger M, Kandolf G
Labels: MiParea: mtDNA;mt-genetics, nDNA;cell genetics, Genetic knockout;overexpression
Organism: Mouse Tissue;cell: Fat
Villena JA(1), Castillo A1, Pedriza I(1), Vilà M(1), Pardo R(1), Cámara Y(1), Nogueiras R(2)
- Lab Metabolism Obesity, Vall d’Hebron Research Inst, Barcelona
- Univ Santiago de Compostela; Spain. - [email protected]