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
Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, USA.
Nat Commun. 2025 Jan 3;16(1):379. doi: 10.1038/s41467-024-51578-1.
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.
线粒体功能通过其与内质网（ER）的相互作用来调节。最近的研究表明，在肌萎缩侧索硬化症（ALS）的家族模型中，这些接触会被破坏。我们在此报告，线粒体与内质网之间串扰的这种损害阻碍了将葡萄糖衍生的丙酮酸用作线粒体燃料，导致转向脂肪酸以维持能量产生。随着时间的推移，这种缺陷会改变脊髓组织中线粒体电子流以及复合物I的活性/休眠状态，但不会影响大脑。这些发现表明，线粒体相关内质网膜（MAM结构域）在调节细胞葡萄糖代谢中起关键作用，并且MAM功能障碍可能是ALS中观察到的生物能量缺陷的基础。
