Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria

The Journal of Cell Biology
Anne KorwitzThomas Langer

Abstract

Proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 in mitochondria is emerging as a central regulatory hub that determines mitochondrial morphology under stress and in disease. Stress-induced OPA1 processing by OMA1 triggersmitochondrial fragmentation, which is associated with mitophagy and apoptosis in vitro. Here, we identify OMA1 as a critical regulator of neuronal survival in vivo and demonstrate that stress-induced OPA1 processing by OMA1 promotes neuronal death and neuroinflammatory responses. Using mice lacking prohibitin membrane scaffolds as a model of neurodegeneration, we demonstrate that additional ablation of Oma1 delays neuronal loss and prolongs lifespan. This is accompanied by the accumulation of fusion-active, long OPA1 forms, which stabilize the mitochondrial genome but do not preserve mitochondrial cristae or respiratory chain supercomplex assembly in prohibitin-depleted neurons. Thus, long OPA1 forms can promote neuronal survival independently of cristae shape, whereas stress-induced OMA1 activation and OPA1 cleavage limit mitochondrial fusion and promote neuronal death.

References

Oct 17, 2003·The Journal of Biological Chemistry·Kathy PfeifferHermann Schägger
Oct 29, 2004·Proceedings of the National Academy of Sciences of the United States of America·Sara CipolatLuca Scorrano
Nov 5, 2004·Molecular Biology of the Cell·Takashi TatsutaThomas Langer
Jun 17, 2006·The EMBO Journal·Naotada IshiharaKatsuyoshi Mihara
Aug 22, 2007·The Journal of Cell Biology·Lorena GriparicAlexander M van der Bliek
Feb 9, 2008·Experimental Cell Research·Katsumi KasashimaHitoshi Endo
Apr 19, 2008·Journal of Neurochemistry·Vasudheva Reddy AkepatiChristiane Alexander
Oct 8, 2008·Proceedings of the National Academy of Sciences of the United States of America·G M CereghettiL Scorrano
Apr 11, 2009·The EMBO Journal·Daniel TonderaJean-Claude Martinou
Nov 6, 2009·Journal of Cell Science·Christof OsmanThomas Langer
Dec 30, 2009·The Journal of Cell Biology·Brian HeadAlexander M van der Bliek
Dec 30, 2009·The Journal of Cell Biology·Sarah EhsesThomas Langer
Jan 12, 2011·The Journal of Cell Biology·Christof OsmanThomas Langer
Aug 9, 2011·Journal of Neuroimmunology·Preeti J KhandelwalCharbel E-H Moussa
Jul 17, 2012·Antioxidants & Redox Signaling·Sang-Bing OngDerek J Hausenloy
Sep 1, 2012·Science·Richard J Youle, Alexander M van der Bliek
Oct 9, 2012·The Journal of Clinical Investigation·Eva R AlmajanElena I Rugarli
Dec 4, 2012·Biochimica Et Biophysica Acta·Michael Schlame
Jan 15, 2014·The International Journal of Biochemistry & Cell Biology·Ronald A Merrill, Stefan Strack
Jan 17, 2014·Nature·Jonathan R Friedman, Jodi Nunnari
Mar 13, 2014·The Journal of Cell Biology·Ruchika AnandThomas Langer
Mar 29, 2014·American Journal of Physiology. Renal Physiology·Xiao XiaoZheng Dong
Jul 13, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Apostolos PolykratisMichelle A Kelliher
Sep 23, 2014·Nature Reviews. Molecular Cell Biology·Prashant Mishra, David C Chan
Oct 3, 2014·Proceedings of the National Academy of Sciences of the United States of America·Xian JiangXiaodong Wang
Dec 10, 2014·Nature Reviews. Neurology·Florence BurtéPatrick Yu-Wai-Man
Feb 24, 2015·Current Opinion in Cell Biology·Madhuparna RoyHiromi Sesaki
May 15, 2015·Nature Reviews. Molecular Cell Biology·Pedro M QuirósCarlos López-Otín
Jun 4, 2015·Cell Metabolism·Gabriele CivilettoMassimo Zeviani

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Citations

May 4, 2016·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Roman M LevytskyyOleh Khalimonchuk
Jun 3, 2016·Cell Calcium·Prashant Mishra
Mar 14, 2017·Nature Cell Biology·Shotaro SaitaThomas Langer
May 24, 2017·Plant Signaling & Behavior·Nazmul H Bhuiyan, Klaas J van Wijk
Jan 21, 2018·Antioxidants & Redox Signaling·Petr JežekMartin Jabůrek
Apr 1, 2018·Annals of Neurology·Mindaugas JonikasGeorge K Tofaris
Feb 6, 2017·Journal of Cell Science·Kyle H Flippo, Stefan Strack
May 18, 2016·Journal of Cell Science·Thomas MacVicar, Thomas Langer
Jun 14, 2017·Molecular and Cellular Biology·Oluwaseun B OgunbonaSteven M Claypool
Sep 30, 2018·Antioxidants & Redox Signaling·Elianne P BulthuisWerner J H Koopman
Feb 2, 2019·Pflügers Archiv : European journal of physiology·Tomohiro TanakaMotohiro Nishida
Feb 5, 2019·International Journal of Cancer. Journal International Du Cancer·Marcel V Alavi
May 3, 2019·Antioxidants & Redox Signaling·Iryna BohovychOleh Khalimonchuk
Jun 24, 2019·The FEBS Journal·Emilie HollvilleMohanish Deshmukh
Nov 6, 2018·EMBO Molecular Medicine·Hans-Georg SprengerThomas Langer
Nov 27, 2019·American Journal of Physiology. Endocrinology and Metabolism·Hexirui WuJamie I Baum
Oct 23, 2019·Nature Reviews. Molecular Cell Biology·Florian J Bock, Stephen W G Tait
Dec 12, 2019·Journal of Biochemistry·Matthew J EramoMichael T Ryan
Feb 23, 2020·Annual Review of Biochemistry·Soni DeshwalThomas Langer
Mar 1, 2018·Physiological Reviews·Michael FrickerGuy C Brown
Feb 13, 2017·Cardiovascular Drugs and Therapy·Sang-Bing OngDerek John Hausenloy
Jan 24, 2019·Cold Spring Harbor Perspectives in Biology·Sofia AholaThomas MacVicar
Dec 11, 2019·Cell Death and Differentiation·Corey J AndersonCostantino Iadecola
Apr 3, 2020·Cardiovascular Drugs and Therapy·Dong HuDao Wen Wang
Dec 3, 2016·Biochemical Society Transactions·Carlo Viscomi
Jan 27, 2019·Life Science Alliance·Uwe RichterBrendan J Battersby
Dec 14, 2018·Antioxidants·Hakjoo Lee, Yisang Yoon
Dec 30, 2020·The Journal of Biological Chemistry·Emily H ClarkThomas Briston
Jan 30, 2021·FEBS Letters·Uwe RichterSarah J Pickett
Mar 5, 2021·Developmental Cell·Matthew Yoke Wui NgAnne Simonsen
Jan 8, 2021·The Journal of Biological Chemistry·Emily H ClarkThomas Briston
Apr 13, 2021·Frontiers in Cell and Developmental Biology·Robert GilkersonShaynah St Vallier
Jul 3, 2021·International Journal of Molecular Sciences·Javier RamónRamon Martí

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Methods Mentioned

BETA
GTPases
PCR
FACS
Flow cytometry
transmission electron microscopy
scraping
transfections

Software Mentioned

Volocity
AxioVision
ImageJ

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