MFN2-mediated remodelling of ER-mitochondria communication alleviates ochratoxin A-induced hepatocyte ferroptosis by enhancing mitophagy.

Abstract

Mycotoxins are ubiquitous environmental contaminants that widely occur throughout ecosystems and the food chain, posing persistent threats to environmental safety and public health. Ochratoxin A (OTA) is a widespread and chemically stable mycotoxin with recognized hepatotoxicity, yet the mechanisms linking OTA exposure to liver injury remain poorly defined. This study investigated the role of mitofusin 2 (MFN2)-mediated ER-mitochondria communication in OTA-induced hepatotoxicity, with particular emphasis on its regulation of mitophagy and ferroptosis. An OTA-exposed chicken model and primary chicken embryonic hepatocytes (CEHs) were examined using histopathological, ultrastructural, molecular, and fluorescence-based analyses together with MFN2 overexpression. Our findings indicated that OTA caused pronounced hepatic injury and mitochondrial and ER structural abnormalities. These changes were accompanied by reduced MFN2 expression, weakened ER-mitochondria contacts, disturbed Ca²⁺ homeostasis, and activation of ER stress. OTA exposure also suppressed mitophagy and mitophagic flux, which disrupted iron homeostasis and then induced ferroptosis. Importantly, MFN2 overexpression restored ER-mitochondria communication and mitophagic activity and markedly attenuated ferroptosis. Collectively, these findings indicate that disruption of MFN2-dependent ER-mitochondria communication promotes OTA-induced ferroptosis by impairing mitophagy and identify MFN2 as a potential target for mitigating mycotoxin-associated liver injury.