Age-dependent decline in plasmalogen biosynthesis impairs stress-induced mitochondrial fission in Drosophila

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.