Mitochondrial retrograde signaling connects respiratory capacity to thermogenic gene expression

Scientific Reports
Minwoo NamMarcus P Cooper

Abstract

Mitochondrial respiration plays a crucial role in determining the metabolic state of brown adipose tissue (BAT), due to its direct roles in thermogenesis, as well as through additional mechanisms. Here, we show that respiration-dependent retrograde signaling from mitochondria to nucleus contributes to genetic and metabolic reprogramming of BAT. In mouse BAT, ablation of LRPPRC (LRP130), a potent regulator of mitochondrial transcription and respiratory capacity, triggers down-regulation of thermogenic genes, promoting a storage phenotype in BAT. This retrograde regulation functions by inhibiting the recruitment of PPARγ to the regulatory elements of thermogenic genes. Reducing cytosolic Ca2+ reverses the attenuation of thermogenic genes in brown adipocytes with impaired respiratory capacity, while induction of cytosolic Ca2+ is sufficient to attenuate thermogenic gene expression, indicating that cytosolic Ca2+ mediates mitochondria-nucleus crosstalk. Our findings suggest respiratory capacity governs thermogenic gene expression and BAT function via mitochondria-nucleus communication, which in turn leads to either a thermogenic or storage mode.

References

Jun 20, 2001·Nature Reviews. Molecular Cell Biology·M J BerridgeM D Bootman
Jan 31, 2002·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xing Xian YuSean H Adams
Aug 6, 2002·Science·Eric S BachmanBradford B Lowell
Jan 17, 2003·Proceedings of the National Academy of Sciences of the United States of America·Vamsi K MoothaEric S Lander
Jan 13, 2004·Physiological Reviews·Barbara Cannon, Jan Nedergaard
Apr 8, 2004·Molecular Cell·Ronald A Butow, Narayan G Avadhani
Apr 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·Takeshi ImaiDaniel Metzger
Dec 22, 2005·American Journal of Physiology. Endocrinology and Metabolism·Ken-ichi InokumaMasayuki Saito
Mar 3, 2006·The Journal of Clinical Investigation·Brian N Finck, Daniel P Kelly
May 2, 2007·Proceedings of the National Academy of Sciences of the United States of America·Lindsay M RohasBruce M Spiegelman
Aug 30, 2008·The Journal of Biological Chemistry·Marcus P CooperBruce M Spiegelman
Mar 12, 2010·The Journal of Biological Chemistry·Vishal M GohilVamsi K Mootha
Jul 17, 2010·Biochemical and Biophysical Research Communications·Fredrik H SterkyNils-Göran Larsson
Jul 24, 2010·Nature·Jang Hyun ChoiBruce M Spiegelman
Oct 6, 2011·The Journal of Biological Chemistry·Lijun LiuMarcus P Cooper
Jan 14, 2012·Journal of Molecular Cell Biology·Shuangtao MaZhiming Zhu
Oct 9, 2013·Nature Medicine·Matthew Harms, Patrick Seale
Oct 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Fenfen WangMitchell A Lazar
Jan 9, 2014·Human Molecular Genetics·Arnaud MourierNils-Göran Larsson
Jan 17, 2014·The Journal of Clinical Investigation·Lijun LiuMarcus P Cooper
Feb 25, 2014·Cell Metabolism·Jeanho Yun, Toren Finkel
Jul 10, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Cecile VernochetC Ronald Kahn
Jul 15, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Young-Kyoung LeeGyesoon Yoon
Oct 9, 2015·Biophysical Journal·Dania C Liemburg-ApersWerner J H Koopman
Feb 18, 2016·EMBO Reports·Wuping SunMakoto Tominaga

❮ Previous
Next ❯

Citations

Jun 27, 2018·Integrative and Comparative Biology·Pierre BizeGerald Heckel
Jul 10, 2019·International Journal of Molecular Sciences·Guglielmina ChimientiAngela Maria Serena Lezza
Jun 4, 2019·Applied Physiology, Nutrition, and Metabolism = Physiologie Appliquée, Nutrition Et Métabolisme·Hashim IslamBrendon J Gurd
Feb 18, 2020·Pflügers Archiv : European journal of physiology·Hashim IslamBrendon J Gurd
Mar 28, 2020·Oxidative Medicine and Cellular Longevity·Parameswaran G SreekumarRam Kannan
Jan 9, 2021·Journal of Cellular Biochemistry·Julia KöritzerSascha Beneke

❮ Previous
Next ❯

Methods Mentioned

BETA
ChIP
electron microscopy
PCR
Assay
immunoprecipitation

Software Mentioned

GraphPad Prism

Related Concepts

Related Feeds

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.