Background <p>Acute mitochondrial disorders, characterized by oxidative stress, bioenergetic failure, and cellular damage, are insufficiently studied due to the scarcity of preclinical models that capture their rapid progression. Aluminum phosphide (AlP) poisoning, which causes mitochondrial dysfunction by releasing phosphine gas (PH₃), shares key features with both genetic and toxin-induced mitochondrial diseases, presenting a promising approach to fill this gap.</p> Objective <p>This review considers AlP poisoning a translational model for acute mitochondrial disorders. It aims to explore its mechanistic similarities with known mitochondrial pathologies and assess its value in therapeutic testing.</p> Methods <p>We examined how AlP affects mitochondrial pathways, including inhibition of the electron transport chain (notably Complex IV), ATP depletion, and increased reactive oxygen species (ROS) production. Its multi-target toxic effects were compared with single-mechanism inducers like rotenone and antimycin A.</p> Results <p>AlP poisoning effectively mimics acute mitochondrial failure by inducing oxidative stress, disrupting the electron transport chain, and permeabilizing mitochondrial membranes. Unlike single-target toxins, AlP activates multiple pathways simultaneously, paralleling human disease progression. Preclinical AlP models have successfully tested interventions, such as ROS scavengers and ETC stabilizers, demonstrating their translational relevance.</p> Conclusion <p>AlP poisoning is a clinically relevant, mechanistically robust model for studying acute mitochondrial disorders. Its capacity to replicate multi-organ damage and rapid bioenergetic failure advances research into disease mechanisms and therapies, filling an urgent gap in mitochondrial medicine.</p>