| Abstract |
High-temperature (HT) stress induces female-to-male sex reversal (masculinization) in the teleost fish medaka (Oryzias latipes). Previous studies have shown that activation of peroxisome proliferator-activated receptor α (PPARα) signaling promotes masculinization and that experimentally induced oxidative stress elicits a similar response in a PPARα-dependent manner, suggesting that PPARα is a key mediator of temperature-induced sex reversal. Because PPARα is a lipid-sensing regulator of metabolic adaptation, it may translate oxidative stress into remodeling of metabolic organelles, including peroxisomes, thereby providing a cellular link to sex differentiation. However, how these stress responses are coordinated at the intracellular level remains unclear. Here, we show that HT-induced oxidative stress drives remodeling of metabolic organelles, with a prominent PPARα-dependent peroxisomal response. In medaka OLHE-131 cells, HT induced PPARα-related gene expression and increased reactive oxygen species (ROS) production, lipid peroxidation, and lipid droplet accumulation. Moreover, HT induced expansion of the peroxisomal compartment and disruption of the mitochondrial network, both of which were suppressed by the antioxidant vitamin E. In contrast, pharmacological inhibition of PPARα selectively suppressed the peroxisomal changes without affecting mitochondria. Furthermore, HT increased Pex14, a peroxisomal membrane protein, in wild-type female medaka during sex differentiation, whereas this response was abolished in pparaa-knockout medaka. To our knowledge, this study provides the first evidence in a vertebrate that HT induces PPARα-dependent peroxisomal remodeling. These findings identify peroxisomal remodeling as a novel cellular response to HT-induced oxidative stress and provide new insight into the cellular mechanisms of sex differentiation.
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