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- Title
Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS).
- Authors
Larrea, Delfina; Tamucci, Kirstin A.; Kabra, Khushbu; Velasco, Kevin R.; Yun, Taekyung D.; Pera, Marta; Montesinos, Jorge; Agrawal, Rishi R.; Paradas, Carmen; Smerdon, John W.; Lowry, Emily R.; Stepanova, Anna; Yoval-Sanchez, Belem; Galkin, Alexander; Wichterle, Hynek; Area-Gomez, Estela
- 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. The bioenergetic deficits observed in Amyotrophic Lateral Sclerosis result from the disruption of mitochondria-associated ER membranes. Here, the authors show that this disruption impairs the use of glucose-derived pyruvate, which over time hinders mitochondrial electron flow.
- Subjects
AMYOTROPHIC lateral sclerosis; MEDICAL sciences; SPINAL cord; GLUCOSE metabolism; NEUROSCIENCES
- Publication
Nature Communications, 2025, Vol 16, Issue 1, p1
- ISSN
2041-1723
- Publication type
Academic Journal
- DOI
10.1038/s41467-024-51578-1