Mitochondrial Dynamics in Drug-Induced Liver Injury

Abstract

Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

Membrane Vesicles of Toxigenic Clostridioides difficile Affect the Metabolism of Liver HepG2 Cells

“…In addition, the L. pneumophila T4SS effector MitF (also called LegG1) induced a DRP1-dependent mitochondrial fragmentation [ 64 ]. This increased mitochondrial fission may be involved in the development of the NAFLD spectrum and DILI, as suggested by several studies [ 65 , 66 ]. Although the mitochondrial fission profile is increased, toxigenic C. difficile -derived MVs slightly, but not significantly, decreased PGC1A mRNA expression, corroborating that mitochondrial biogenesis would not be modified after the treatment with these MVs.…”

Changes in PGC-1α-Dependent Mitochondrial Biogenesis Are Associated with Inflexible Hepatic Energy Metabolism in the Offspring Born to Dexamethasone-Treated Mothers

“…The present study also reveals that increased content of PGC-1α concurs with higher relative mitochondrial DNA, a key readout of mitochondrial biogenesis. Importantly, mitochondrial biogenesis has been reported to act as an adaptive response of the liver to drug-induced injury [33].…”

Emerging mechanistic insights of selective autophagy in hepatic diseases

“…On the one hand, various stimulants, such as nutrient scarcity, hypoxia and viral infection induce mitophagy ( Zhang et al, 2018 ; Ke, 2020 ; Malpartida et al, 2021 ). On the other hand, deregulated mitophagy can block the regeneration of healthy mitochondria causing the accumulation of defective mitochondria, which is associated with several pathological conditions ( Malpartida et al, 2021 ) including inflammation ( He et al, 2021 ; Onishi et al, 2021 ), cancer ( Panigrahi et al, 2020 ; Rodrigues et al, 2020 ), liver injury ( Aman et al, 2020 ; Ramachandran et al, 2021 ) and metabolic disorders ( Su et al, 2021 ).…”