Understanding molecular mechanisms driving cadmium-induced mitochondrial dysfunction in human metabolic liver disease

Cadmium (Cd) is an anthropogenic toxic heavy metal pollutant with a biological half-life on the order of decades. Chronic Cd exposures through industrial sources, cigarette smoke (1° and 2°), and contaminated food and/or water sources lead to progressive bioaccumulation, particularly in the human liver and kidneys. In hepatocytes, Cd is a potent inducer of mitochondrial dysfunction and oxidative stress. Cd exposures initiate a cascade of reactive oxygen species (ROS) production, triggering redox imbalances, acute and chronic inflammation, and, in extreme exposures, cellular death. While mitochondria are well recognized as central targets of Cd toxicity, the precise mechanisms linking Cd-induced mitochondrial damage driving chronic liver and metabolic diseases remains incompletely understood. Emerging evidence implicates Cd exposure as a direct inhibitor of the mitochondrial electron transport chain (ETC) complexes and disruption of calcium homeostasis as key, converging pathways of hepatocellular injury. And yet, their specific molecular underpinnings are still unknown. This review focuses on how Cd exposures perturb mitochondrial bioenergetics, calcium signaling, and lipid signaling and metabolism within the hepatocytes specifically. Subsequently, we examine how these molecular-level alterations may contribute to the pathogenesis of chronic liver disease. In this review article, we present a cohesive framework to highlight Cd exposures as a critical (and a model) environmental heavy metal driver of chronic hepatocellular mitochondrial injury. Prolonged heavy metal exposures (such as Cd) have significant implications for long-term human hepatic health and metabolic disorders, such as metabolic (dysfunction) associated liver injury (MASLD), a key emerging pandemic of chronic human liver disease.