Research
Defects in mitochondrial respiratory complexes in brain tissues from ALS model transgenic mice. Cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activities are shown by double staining in sections of the cerebellum from mutant (SOD1G93A) and control (NTg) mice. In control sections, the purple stain representing SDH activity is masked by the brown stain representing COX activity, whereas the purple stain is prominently visible in mutant tissues. This suggests that COX activity is reduced in mutant samples, enabling visualization of the SDH stain. [Adapted from Nature Communications 16, 379 (2025)]
23 Jan 2025
The mechanism by which the alteration of the function of the endoplasmic reticulum membrane associated with mitochondria modifies mitochondrial metabolism in ALS is revealed
A study published in Nature Communications by Dr. Estela Area-Gómez's group at the Margarita Salas Center for Biological Research (CSIC) shows how alterations in the interaction between mitochondria and the MAM domains of the endoplasmic reticulum (ER) affect mitochondrial metabolism in amyotrophic lateral sclerosis (ALS). The work, performed in collaboration with Columbia University, CIBERNED, the Seville Institute of Biomedicine, and Weill Cornell Medical College, highlights the importance of these MAM domains in cellular metabolism and suggests that MAM dysfunction may contribute to the bioenergetic alterations observed in ALS.
ALS is a fatal neurological disorder characterized by the selective loss of motor neurons (MNs), resulting in muscle atrophy, paralysis, and respiratory failure. In about 10% of people with ALS, a genetic cause can be identified (familial ALS). In the remaining cases, the etiology is unknown (sporadic ALS).
The interaction between mitochondria and the endoplasmic reticulum (ER) domain called MAM (mitochondria-associated ER membranes) is essential for maintaining mitochondrial function. Recent studies have shown that these connections are disrupted in familial ALS models.
Larrea et al. demonstrate in this work that defects in the contacts established between mitochondria and MAM domains impede mitochondria's ability to utilize glucose-derived pyruvate, forcing cells to rely on fatty acids for energy production.
This study used ALS model transgenic mice, human and mouse embryonic stem cell-derived motor neurons, human induced pluripotent stem cells, and primary fibroblasts from patients and human brain samples. With this methodology, the researchers demonstrate that, over time, this observed metabolic change affects mitochondrial electron transport and the activity of respiratory complexes in the spinal cord, but not in the brain.
This work has been funded by the Fundación Sanitaria La Caixa and the Luzon Foundation (HR23-00124), the Spanish Ministry of Science and Innovation (PID2021-126818NB-I00), the ALS Project, the U.S. National Institutes of Health (NIH, R01-AG056387, R21NS125466, R01NS112381, T32-DK007647 and F31NS095571), and the US Department of Defense (FA9550-11-C-0028, W81XWH2210404 and W81XWH2110370).
Reference: 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 & Estela Area-Gomez (2025) Nature Communications 16, 379 (2025). https://doi.org/10.1038/s41467-024-51578-1