Abstract
Mitochondrial dynamics, maintained by balanced fission and fusion, are essential for organelle quality control and cellular homeostasis, yet this process becomes disrupted during aging. The upstream cues underlying age-associated fission defects remain poorly defined. Here, using Drosophila oenocytes (hepatocyte-like cells), we show that aging drives progressive mitochondrial enlargement and morphological abnormalities. Live-cell imaging analysis demonstrated that young oenocytes rapidly undergo mitochondrial fission in response to paraquat-induced oxidative stress, whereas aged oenocytes fail to fragment, resulting in persistently enlarged mitochondria. This age-dependent fission defect correlates with a marked decline in mitochondrial plasmalogen levels, a class of ether phospholipids enriched in mitochondrial membranes. In addition, genetic disruption of plasmalogen biosynthesis using a hypomorphic mutation in the plasmanylethanolamine desaturase Kua (TMEM189) recapitulated the aging phenotype. These findings establish that an age-dependent decline in plasmalogen biosynthesis impairs mitochondrial fission, leading to persistent mitochondrial enlargement. Thus, loss of plasmalogen-dependent membrane dynamics represents a novel mechanism driving mitochondrial dysfunction during aging in metabolic tissues.
