Mitochondria in Acetaminophen-Induced Liver Injury and Recovery: A Concise Review

Abstract

Mitochondria are critical organelles responsible for the maintenance of cellular energy homeostasis. Thus, their dysfunction can have severe consequences in cells responsible for energy-intensive metabolic function, such as hepatocytes. Extensive research over the last decades have identified compromised mitochondrial function as a central feature in the pathophysiology of liver injury induced by an acetaminophen (APAP) overdose, the most common cause of acute liver failure in the United States. While hepatocyte mitochondrial oxidative and nitrosative stress coupled with induction of the mitochondrial permeability transition are well recognized after an APAP overdose, recent studies have revealed additional details about the organelle’s role in APAP pathophysiology. This concise review highlights these new advances, which establish the central role of the mitochondria in APAP pathophysiology, and places them in the context of earlier information in the literature. Adaptive alterations in mitochondrial morphology as well as the role of cellular iron in mitochondrial dysfunction and the organelle’s importance in liver recovery after APAP-induced injury will be discussed.

Transcriptomic signature, bioactivity and safety of a non-hepatotoxic analgesic generating AM404 in the midbrain PAG region

“…Male CD1 mice fasted overnight with only access to water ad libitum were dosed with either ApAP, or SRP-001 or vehicle (0.9% saline) (n = 5 for each treatment group) via PO dosing at concentrations of 600 mg/kg (for both ApAP and SRP-001) with an injection volume of 10 mL/kg body weight. We selected this dosage based on its well-documented characterization in previous research as an effective measure for evaluating ApAP-induced hepatotoxicity in preclinical rodent models 33 – 35 , 59 , 72 , 73 .…”

Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury

“…Hence, provided that glucuronidation and sulfation are active and hepatic glutathione stores are adequately maintained, therapeutic doses of APAP do not produce liver injury since all NAPQI generated is efficiently scavenged. However, the presence of preexisting conditions such as acute viral hepatitis, treatment with antitubercular drugs, or chronic alcoholism could cause liver injury even with therapeutic doses of APAP (8), though there are nuances to be considered in these scenarios (8).…”

“…A relatively early change detected after exposure to an APAP overdose is an alteration in mitochondrial morphology to a donut-like topology in response to a decrease in mitochondrial membrane potential without compromised respiratory chain function (21). This is a reversible process once APAP is removed, and it has been reported that the donut topology maintains mitochondrial membrane potential and helps mitochondria resist autophagy (8). Thus, the second level of adaptation to formation of APAPprotein adducts once autophagic removal has been overwhelmed seems to be at the level of the mitochondria, which attempt to alter morphology and maintain respiratory function to tide over the functional deficits caused by mitochondrial protein adduct formation.…”

Sex differences in glutathione metabolism and acetaminophen toxicity

“…Many experimental studies have shown that female mice are less susceptible to APAP hepatotoxicity than males and that the sex differences are substantial [17,18,35] . Many of the mechanisms have been elucidated by the Jaeschke group in Kansas [18,36,37] .…”