Ultrastructural pathology and interorganelle cross talk in hepatotoxicity.
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, β-oxidation of fatty acids, and calcium ion (Ca(2+)) 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(2+) 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.
Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50010, USA. nfcheville@msn.com
Norman F
NF
Cheville
D000818:Animals; D001343:Autophagy; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D008107:Liver Diseases / Q000473:pathology* / Q000503:physiopathology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure