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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
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    References listed on IDEAS

    as
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    2. 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.
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    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.
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