Ebert Adam C, Hepowit Nathaniel L, Martinez Thyandra A, Vollmer Henrik, Singkhek Hayley L, Frazier Kyrie D, Kantejeva Sophia A, Patel Maulik R, MacGurn Jason A
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States.
Department of Biological Sciences, Vanderbilt University, Nashville, United States.
bioRxiv. 2025 Feb 27:2025.02.26.640157. doi: 10.1101/2025.02.26.640157.
One of the hallmarks of aging is a decline in the function of mitochondria, which is often accompanied by altered morphology and dynamics. In some cases, these changes may reflect macromolecular damage to mitochondria that occurs with aging and stress, while in other cases they may be part of a programmed, adaptive response. In this study, we report that mitochondria undergo dramatic morphological changes in chronologically aged yeast cells. These changes are characterized by a large, rounded morphology, decreased co-localization of outer membrane and matrix markers, and decreased mitochondrial membrane potential. Notably, these transitions are prevented by pharmacological or genetic interventions that perturb sphingolipid biosynthesis, indicating that sphingolipids are required for these mitochondrial transitions in aging cells. Consistent with these findings, we observe that overexpression of inositol phospholipid phospholipase (Isc1) prevents these alterations to mitochondria morphology in aging cells. We also report that mitochondria exhibit similar sphingolipid-dependent morphological transitions following acute exposure to oxidative stress. These findings suggest that sphingolipid metabolism contributes to mitochondrial remodeling in aging cells and during oxidative stress, perhaps as a result of damaged sphingolipids that localize to mitochondrial membranes. These findings underscore the complex relationship between mitochondria function and sphingolipid metabolism, particularly in the context of aging and stress.
衰老的一个标志是线粒体功能衰退，这通常伴随着形态和动态变化。在某些情况下，这些变化可能反映了衰老和应激过程中线粒体发生的大分子损伤，而在其他情况下，它们可能是程序性适应性反应的一部分。在本研究中，我们报告了在按时间顺序老化的酵母细胞中线粒体经历了显著的形态变化。这些变化的特征是形态大且呈圆形，外膜和基质标记物的共定位减少，以及线粒体膜电位降低。值得注意的是，干扰鞘脂生物合成的药理学或基因干预可阻止这些转变，表明鞘脂是衰老细胞中这些线粒体转变所必需的。与这些发现一致，我们观察到肌醇磷脂磷脂酶（Isc1）的过表达可防止衰老细胞中线粒体形态的这些改变。我们还报告了急性氧化应激后线粒体表现出类似的依赖鞘脂的形态转变。这些发现表明，鞘脂代谢有助于衰老细胞和氧化应激期间的线粒体重塑，这可能是由于定位于线粒体膜的受损鞘脂所致。这些发现强调了线粒体功能与鞘脂代谢之间的复杂关系，特别是在衰老和应激的背景下。
