Abstract
Elevated bile acids, particularly hydrophobic secondary species, impair mitochondrial structure and function across multiple organs. In cardiomyocytes, pathologically elevated circulating bile acids impair mitochondrial biogenesis, diminish ATP generation, disrupt calcium homeostasis, and compromise myocardial energetics. These alterations promote oxidative stress and activate mitochondrial apoptotic pathways, culminating in systolic dysfunction, diastolic impairment, and heightened arrhythmogenic risk. Parallel mitochondrial injury in liver and skeletal muscle contributes to liver fibrosis and sarcopenia. Accumulating evidence suggests that elevated circulating bile acids are not merely biochemical epiphenomena in Fontan circulation, where chronic hepatic congestion is intrinsic to the physiology, or in metabolic dysfunction-associated steatotic liver disease (MASLD). Rather, bile acid excess may represent a mechanistic link between hepatic injury and the broader, multisystem dysfunction that characterizes both conditions. This review focuses on recognizing bile acids as systemic mitochondrial toxins that share a common pathogenic pathway to two distinct clinical settings, Fontan failure and MASLD.It also highlights emerging diagnostic opportunities and supports therapies aimed at reducing bile acid toxicity or improving mitochondrial resilience to enhance outcomes in these patients.