Ultrastructural Pathology and Interorganelle Cross Talk in Hepatotoxicity

Abstract

Mitochondria, endoplasmic reticulum (ER), cytoplasmic lipid droplets (CLD), and Golgi vesicles use cross talk to control hepatocyte metabolism, growth, and stress. Interpretation of ultrastructural change requires knowledge of how cross talk pathways function, how differential activation of hepatocellular signals influences organelle structure, and how organelles position themselves to become central hubs for stress responses. Mitochondria, by coupling energy production to pathways for protection, form critical platforms for innate signaling. Mitochondrial outer and inner membranes activate channels and signals to translocate peptides that drive oxidative phosphorylation, b-oxidation of fatty acids, and calcium ion (Ca 2þ ) flux. In cell stress, mitochondrial signals initiate fusion and fission, reactive oxygen species (ROS) control, autophagy, apoptosis, and senescence. Specialized tethering proteins tie mitochondria to ER to support translocation of metabolites. For Ca 2þ translocation, ER pores are connected to mitochondrial voltage-dependent anion channels, and for mitochondrial fission, unique membrane proteins pull ER to mitochondria. In toxic injury, cytosolic cytokines translocate to alter metabolism. Toxic effects on ER lipid synthesis lead to Golgi vesicle reduplication and transport of perilipin and other protein cargos into CLDs. How cellular proteostasis, oxidative homeostasis, and ion balance are maintained depend upon the effectiveness of mitochondrial ROS defense responses, unfolded protein responses in mitochondria and ER, and other organelle defenses.

Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo

“…Here, we found dilated cristae in Chga -KO mice, which may represent mitochondrial dysfunction resulting in the production of less ATP as has been reported by others in optic nerve head astrocytes (Noh et al 2013) and by us in the adrenal gland of Chga -KO mice (Mahapatra et al 2005). In addition to dilated cristae, we found dilated ER lumen in Chga -KO mice, which indicates ER stress (Cheville 2013; Oakes and Papa 2015). The increase in number of ribosomes is indicative of increased protein synthesis and has been reported earlier (Montesinos et al 2008).…”

“…The increase in number of ribosomes is indicative of increased protein synthesis and has been reported earlier (Montesinos et al 2008). Increased protein synthesis demands increased packaging of proteins for regulated secretion (Cheville 2013; Sengupta and Linstedt 2011). Consistent with this hypothesis, we found dilated Golgi lumen, presumably allowing increased packaging of proteins and alleviation of oxidative stress.…”

Hepatoprotective activity of chrysin is mediated through TNF-α in chemically-induced acute liver damage: An in vivo study and molecular modeling

“…Located primarily in centrlobular hepatocytes, cytochrome P450 enzymes are associated with drug-induced sER proliferation (39). In the present study, sER proliferation was evident in electron microscopy micrographs of the CCl 4 treated group.…”

“…In addition, the 5-OH group of chrysin forms a hydrogen bond with the carboxylate oxygen of Glu-406 in TACE, which acts as a base during catalysis (41). Furthermore, the 7-OH group of chrysin forms a hydrogen bond with Pro-437 of TACE, which serves a key role in reversing the Met-turn produced by Tyr-433, Val-434, Met-435 and Tyr-436 to form the outer wall of the S1 crevice (39). The hydrogen bonding seen positioned the outer wall loop of the S1 sub-pocket in such a way that it essentially blocked the cavity opening.…”

Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA)

“…MFN2 is a tethering protein that recruits DRP1 from the cytosol to its receptor on the mitochondrial outer membrane (MOM). Altered conformations of DRP1 can promote mitochondrial fission and inhibit fusion reactions, resulting in elongated mitochondria (Cheville 2013). …”