LETM1 couples mitochondrial DNA metabolism and nutrient preference

EMBO Molecular Medicine
Romina DurigonAntonella Spinazzola

Abstract

The diverse clinical phenotypes of Wolf-Hirschhorn syndrome (WHS) are the result of haploinsufficiency of several genes, one of which, LETM1, encodes a protein of the mitochondrial inner membrane of uncertain function. Here, we show that LETM1 is associated with mitochondrial ribosomes, is required for mitochondrial DNA distribution and expression, and regulates the activity of an ancillary metabolic enzyme, pyruvate dehydrogenase. LETM1 deficiency in WHS alters mitochondrial morphology and DNA organization, as does substituting ketone bodies for glucose in control cells. While this change in nutrient availability leads to the death of fibroblasts with normal amounts of LETM1, WHS-derived fibroblasts survive on ketone bodies, which can be attributed to their reduced dependence on glucose oxidation. Thus, remodeling of mitochondrial nucleoprotein complexes results from the inability of mitochondria to use specific substrates for energy production and is indicative of mitochondrial dysfunction. However, the dysfunction could be mitigated by a modified diet-for WHS, one high in lipids and low in carbohydrates.

References

Jun 1, 1972·The Biochemical Journal·R M DentonB R Martin
Aug 1, 1995·Molecular and Cellular Biochemistry·B J Nichols, R M Denton
Jul 11, 2000·The Journal of Biological Chemistry·M Liu, L Spremulli
Mar 22, 2002·Molecular Biology of the Cell·Kai Stefan DimmerBenedikt Westermann
Sep 30, 2003·Molecular & Cellular Proteomics : MCP·Daniel F BogenhagenRyuji Kobayashi
May 21, 2005·Biochimica Et Biophysica Acta·Elisabeth FroschauerRudolf J Schweyen
Feb 16, 2006·The Journal of Cell Biology·Ann E FrazierPeter Rehling
Jun 13, 2008·Nature Protocols·Thomas D Schmittgen, Kenneth J Livak
Sep 11, 2008·Nucleic Acids Research·Joanna RorbachZofia M A Chrzanowska-Lightowlers
Dec 8, 2009·Biochimica Et Biophysica Acta·Martin Ott, Johannes M Herrmann
Dec 23, 2009·Human Molecular Genetics·Angus G McQuibbanKarin Nowikovsky
Apr 30, 2010·Molecular Biology of the Cell·Heike BauerschmittJohannes M Herrmann
Jun 8, 2011·Proceedings of the National Academy of Sciences of the United States of America·Angelika S RamboldJennifer Lippincott-Schwartz
Jan 13, 2012·Nucleic Acids Research·Joanna RorbachMichal Minczuk
Mar 12, 2013·Cell Metabolism·Alexis A JourdainJean-Claude Martinou
May 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Dawei JiangDavid E Clapham
Jul 4, 2013·Proceedings of the National Academy of Sciences of the United States of America·Reiko Ban-IshiharaNaotada Ishihara
Jul 31, 2013·The Journal of Biological Chemistry·Hassan HashimiJulius Lukeš
Oct 29, 2013·Biochimica Et Biophysica Acta·Abdulraheem AlmalkiZofia M A Chrzanowska-Lightowlers
Dec 18, 2013·The Journal of General Physiology·Ming-Feng TsaiChristopher Miller
Feb 14, 2014·Nutrition & Metabolism·Shuai ZhangElizabeth R Gilbert
Mar 13, 2014·Frontiers in Physiology·Karin Nowikovsky, Paolo Bernardi
Apr 8, 2014·Cell Metabolism·Daniel F BogenhagenAntonius Koller
Jun 21, 2014·Nucleic Acids Research·Ilaria Dalla RosaAntonella Spinazzola
Aug 1, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Patrick J DoonanMuniswamy Madesh
Mar 27, 2015·The Journal of Physiology·I Llorente-FolchJ Satrustegui
Aug 1, 2015·Nature·Brian GlancyRobert S Balaban
Jan 13, 2016·Trends in Endocrinology and Metabolism : TEM·Timothy Wai, Thomas Langer
Jan 14, 2016·PLoS Genetics·Ilaria Dalla RosaAntonella Spinazzola
Jul 13, 2016·Proceedings of the National Academy of Sciences of the United States of America·Gokhan AkmanIan J Holt
Jan 20, 2017·Journal of Inherited Metabolic Disease·Kalliopi SofouNiklas Darin

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Citations

May 3, 2019·Nucleic Acids Research·Ian J Holt
May 1, 2019·Human Molecular Genetics·Enrico BugiardiniAntonella Spinazzola
Sep 30, 2020·Nature Cell Biology·Timo ReySuliana Manley
Mar 21, 2021·Molecular Biology Reports·Alejandro HorgaHenry Houlden
Apr 6, 2021·Frontiers in Physiology·Gayathri K NatarajanWai-Meng Kwok
Sep 25, 2021·Science Advances·Giulia RossettiAleksandra Filipovska
Oct 27, 2021·Physiological Reviews·Joanne F Garbincius, John W Elrod

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Methods Mentioned

BETA
transfection
transmission electron microscopy
electron microscopy
PCR

Software Mentioned

ImageJ
Fiji ImageJ
GraphPad Prism

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