PMID:28282614

Citation	Yang, X, Wang, H, Ni, HM, Xiong, A, Wang, Z, Sesaki, H, Ding, WX and Yang, L (2017) Inhibition of Drp1 protects against senecionine-induced mitochondria-mediated apoptosis in primary hepatocytes and in mice. Redox Biol 12:264-273
Abstract	Pyrrolizidine alkaloids (PAs) are a group of compounds found in various plants and some of them are widely consumed in the world as herbal medicines and food supplements. PAs are potent hepatotoxins that cause irreversible liver injury in animals and humans. However, the mechanisms by which PAs induce liver injury are not clear. In the present study, we determined the hepatotoxicity and molecular mechanisms of senecionine, one of the most common toxic PAs, in primary cultured mouse and human hepatocytes as well as in mice. We found that senecionine administration increased serum alanine aminotransferase levels in mice. H&E and TUNEL staining of liver tissues revealed increased hemorrhage and hepatocyte apoptosis in liver zone 2 areas. Mechanistically, senecionine induced loss of mitochondrial membrane potential, release of mitochondrial cytochrome c as well as mitochondrial JNK translocation and activation prior to the increased DNA fragmentation and caspase-3 activation in primary cultured mouse and human hepatocytes. SP600125, a specific JNK inhibitor, and ZVAD-fmk, a general caspase inhibitor, alleviated senecionine-induced apoptosis in primary hepatocytes. Interestingly, senecionine also caused marked mitochondria fragmentation in hepatocytes. Pharmacological inhibition of dynamin-related protein1 (Drp1), a protein that is critical to regulate mitochondrial fission, blocked senecionine-induced mitochondrial fragmentation and mitochondrial release of cytochrome c and apoptosis. More importantly, hepatocyte-specific Drp1 knockout mice were resistant to senecionine-induced liver injury due to decreased mitochondrial damage and apoptosis. In conclusion, our results uncovered a novel mechanism of Drp1-mediated mitochondrial fragmentation in senecionine-induced liver injury. Targeting Drp1-mediated mitochondrial fragmentation and apoptosis may be a potential avenue to prevent and treat hepatotoxicity induced by PAs.
Links	PubMed PMC5344326 Online version:10.1016/j.redox.2017.02.020
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:DNM1L		GO:0008637: apoptotic mitochondrial changes	ECO:0000314:		P		MOUSE DNM1L (DRP1) // Mdivi, a specific inhibitor for Drp1, inhibited Sene-induced mitochondrial fragmentation (Fig. 5A).	complete CACAO 12391
MOUSE:DNM1L		GO:0051882: mitochondrial depolarization	ECO:0000314:		P		MOUSE DNM1L (DRP1) // Mdivi, a specific inhibitor for Drp1, inhibited Sene-induced mitochondrial depolarization (Fig. 5C-G).	complete CACAO 12413

References

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