IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-024-51578-1.html
   My bibliography  Save this article

Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)

Author

Listed:
  • Delfina Larrea

    (Columbia University Irving Medical Center)

  • Kirstin A. Tamucci

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Khushbu Kabra

    (Columbia University Irving Medical Center)

  • Kevin R. Velasco

    (Columbia University Irving Medical Center)

  • Taekyung D. Yun

    (Columbia University Irving Medical Center)

  • Marta Pera

    (Columbia University Irving Medical Center)

  • Jorge Montesinos

    (Centro de Investigaciones Biológicas Margarita Salas (CSIC)
    Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED))

  • Rishi R. Agrawal

    (Columbia University Irving Medical Center)

  • Carmen Paradas

    (Hospital Universitario Virgen del Rocío)

  • John W. Smerdon

    (Columbia University Irving Medical Center)

  • Emily R. Lowry

    (Columbia University Irving Medical Center)

  • Anna Stepanova

    (Weill Cornell Medical College)

  • Belem Yoval-Sanchez

    (Weill Cornell Medical College)

  • Alexander Galkin

    (Weill Cornell Medical College)

  • Hynek Wichterle

    (Columbia University Irving Medical Center)

  • Estela Area-Gomez

    (Columbia University Irving Medical Center
    Centro de Investigaciones Biológicas Margarita Salas (CSIC)
    Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED))

Abstract

Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.

Suggested Citation

  • Delfina Larrea & Kirstin A. Tamucci & Khushbu Kabra & Kevin R. Velasco & Taekyung D. Yun & Marta Pera & Jorge Montesinos & Rishi R. Agrawal & Carmen Paradas & John W. Smerdon & Emily R. Lowry & Anna S, 2025. "Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-51578-1
    DOI: 10.1038/s41467-024-51578-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-51578-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-51578-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Inmaculada Martínez-Reyes & Navdeep S. Chandel, 2020. "Mitochondrial TCA cycle metabolites control physiology and disease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Edward T. Chouchani & Victoria R. Pell & Edoardo Gaude & Dunja Aksentijević & Stephanie Y. Sundier & Ellen L. Robb & Angela Logan & Sergiy M. Nadtochiy & Emily N. J. Ord & Anthony C. Smith & Filmon Ey, 2014. "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS," Nature, Nature, vol. 515(7527), pages 431-435, November.
    3. Olga Martins de Brito & Luca Scorrano, 2008. "Mitofusin 2 tethers endoplasmic reticulum to mitochondria," Nature, Nature, vol. 456(7222), pages 605-610, December.
    4. Radu Stoica & Kurt J. De Vos & Sébastien Paillusson & Sarah Mueller & Rosa M. Sancho & Kwok-Fai Lau & Gema Vizcay-Barrena & Wen-Lang Lin & Ya-Fei Xu & Jada Lewis & Dennis W. Dickson & Leonard Petrucel, 2014. "ER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43," Nature Communications, Nature, vol. 5(1), pages 1-12, September.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Eunbyul Cho & Youngsik Woo & Yeongjun Suh & Bo Kyoung Suh & Soo Jeong Kim & Truong Thi My Nhung & Jin Yeong Yoo & Tran Diem Nghi & Su Been Lee & Dong Jin Mun & Sang Ki Park, 2023. "Ratiometric measurement of MAM Ca2+ dynamics using a modified CalfluxVTN," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Isshin Shiiba & Naoki Ito & Hijiri Oshio & Yuto Ishikawa & Takahiro Nagao & Hiroki Shimura & Kyu-Wan Oh & Eiki Takasaki & Fuya Yamaguchi & Ryoan Konagaya & Hisae Kadowaki & Hideki Nishitoh & Takehito , 2025. "ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    3. Gautham Yepuri & Lisa M. Ramirez & Gregory G. Theophall & Sergei V. Reverdatto & Nosirudeen Quadri & Syed Nurul Hasan & Lei Bu & Devi Thiagarajan & Robin Wilson & Raquel López Díez & Paul F. Gugger & , 2023. "DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    4. Chris G. Faulkes & Thomas R. Eykyn & Jan Lj. Miljkovic & James D. Gilbert & Rebecca L. Charles & Hiran A. Prag & Nikayla Patel & Daniel W. Hart & Michael P. Murphy & Nigel C. Bennett & Dunja Aksentije, 2024. "Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Tuğçe Beyazay & Kendra S. Belthle & Christophe Farès & Martina Preiner & Joseph Moran & William F. Martin & Harun Tüysüz, 2023. "Ambient temperature CO2 fixation to pyruvate and subsequently to citramalate over iron and nickel nanoparticles," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    6. Yu Jin Chung & Zoe Hoare & Friedrich Baark & Chak Shun Yu & Jia Guo & William Fuller & Richard Southworth & Doerthe M. Katschinski & Michael P. Murphy & Thomas R. Eykyn & Michael J. Shattock, 2024. "Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Katelyn C. Cook & Elene Tsopurashvili & Jason M. Needham & Sunnie R. Thompson & Ileana M. Cristea, 2022. "Restructured membrane contacts rewire organelles for human cytomegalovirus infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    8. Maithily S. Nanadikar & Ana M. Vergel Leon & Jia Guo & Gijsbert J. Belle & Aline Jatho & Elvina S. Philip & Astrid F. Brandner & Rainer A. Böckmann & Runzhu Shi & Anke Zieseniss & Carla M. Siemssen & , 2023. "IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    9. Rania El-Botty & Ludivine Morriset & Elodie Montaudon & Zakia Tariq & Anne Schnitzler & Marina Bacci & Nicla Lorito & Laura Sourd & Léa Huguet & Ahmed Dahmani & Pierre Painsec & Heloise Derrien & Soph, 2023. "Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Hao Wu & Xiufeng Zhao & Sophia M. Hochrein & Miriam Eckstein & Gabriela F. Gubert & Konrad Knöpper & Ana Maria Mansilla & Arman Öner & Remi Doucet-Ladevèze & Werner Schmitz & Bart Ghesquière & Sebasti, 2023. "Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    11. Hongming Su & Hong Guo & Xiaoxue Qiu & Te-Yueh Lin & Chao Qin & Gail Celio & Peter Yong & Mark Senders & Xianlin Han & David A. Bernlohr & Xiaoli Chen, 2023. "Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    12. Joy Edwards-Hicks & Huizhong Su & Maurizio Mangolini & Kubra K. Yoneten & Jimi Wills & Giovanny Rodriguez-Blanco & Christine Young & Kevin Cho & Heather Barker & Morwenna Muir & Ania Naila Guerrieri &, 2022. "MYC sensitises cells to apoptosis by driving energetic demand," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    13. Marine Lanfranchi & Sozerko Yandiev & Géraldine Meyer-Dilhet & Salma Ellouze & Martijn Kerkhofs & Raphael Dos Reis & Audrey Garcia & Camille Blondet & Alizée Amar & Anita Kneppers & Hélène Polvèche & , 2024. "The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    14. Qiqi Liu & Zhanxia Gao & Xiangyun Zhang & Qiannan Duan & Yue Zhang & Adam C. Midgley & Li Jiao & Ruming Liu & Mingsheng Zhu & Deling Kong & Jie Zhuang & Xinglu Huang, 2025. "Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    15. Vaibhav Sidarala & Jie Zhu & Elena Levi-D’Ancona & Gemma L. Pearson & Emma C. Reck & Emily M. Walker & Brett A. Kaufman & Scott A. Soleimanpour, 2022. "Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Cesare Granata & Nikeisha J. Caruana & Javier Botella & Nicholas A. Jamnick & Kevin Huynh & Jujiao Kuang & Hans A. Janssen & Boris Reljic & Natalie A. Mellett & Adrienne Laskowski & Tegan L. Stait & A, 2021. "High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    17. Foozhan Tahmasebinia & Yinglu Tang & Rushi Tang & Yi Zhang & Will Bonderer & Maisa Oliveira & Bretton Laboret & Songjie Chen & Ruiqi Jian & Lihua Jiang & Michael Snyder & Chun-Hong Chen & Yawei Shen &, 2025. "The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    18. Kai Shen & Hao Zhou & Qiang Zuo & Yue Gu & Jiangqi Cheng & Kai Yan & Huiwen Zhang & Huanghe Song & Wenwei Liang & Jinchun Zhou & Jiuxiang Liu & Feng Liu & Chenjun Zhai & Weimin Fan, 2024. "GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    19. Jiayi Wang & Mengke Zhao & Meina Wang & Dong Fu & Lin Kang & Yu Xu & Liming Shen & Shilin Jin & Liang Wang & Jing Liu, 2024. "Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    20. Tao Zhang & Sarah E. Noll & Jesus T. Peng & Amman Klair & Abigail Tripka & Nathan Stutzman & Casey Cheng & Richard N. Zare & Alexandra J. Dickinson, 2023. "Chemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-51578-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.