Genetic ablation of Sfxn5 induces mitochondrial dysfunction and precipitates lethal metabolic crisis in mice

Mitochondrial disorders frequently manifest with life-threatening hepatic metabolic crises. Using a global Sfxn5-knockout mouse model, we investigated the systemic consequences of disrupting this mitochondrial inner-membrane transporter through integrated biochemical, metabolomic, histological, and ultrastructural analyses. Sfxn5 deficiency resulted in complete postnatal lethality accompanied by severe metabolic collapse and progressive multi-organ dysfunction. The liver emerged as the primary site of pathology, exhibiting marked mitochondrial structural damage and widespread disruption of central metabolic pathways, including the tricarboxylic acid cycle, fatty acid β-oxidation, and ammonia detoxification, leading to hyperammonemia and systemic metabolic stress. Importantly, liver-specific reconstitution of Sfxn5 partially restored mitochondrial metabolic function, substantially reduced hyperammonemia, and alleviated multi-organ pathology. Altogether, these findings identify hepatic mitochondrial dysfunction as the central driver of Sfxn5-dependent lethality and establish a critical role for Sfxn5 in maintaining mitochondrial metabolic homeostasis during early postnatal life.