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

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 Stepanova, Belem Yoval-Sanchez, Alexander Galkin, Hynek Wichterle and Estela Area-Gomez ()
Additional contact information
Delfina Larrea: Columbia University Irving Medical Center
Kirstin A. Tamucci: 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)
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-51578-1

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