['Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Numerous studies have shown that APAP hepatotoxicity in mice involves mitochondrial dysfunction, and recent data suggest that this is also the case in humans. We have previously shown that glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA), and nuclear DNA (nDNA) fragments can be measured in circulation of overdose patients as mechanistic biomarkers of mitochondrial damage and damage-associated molecular patterns. In the present study, our aim was to determine whether these biomarkers are higher in serum from nonsurvivors of APAP-induced ALF (AALF), compared to survivors. GDH, mtDNA, and nDNA fragments were measured in serum from AALF patients who did (n\u2009=\u200934) or did not (n\u2009=\u200935) recover. Importantly, all three were significantly increased in patients who died, compared to those who survived (GDH: 450\u2009±\u200973 vs. 930\u2009±\u2009145 U/L; mtDNA: 21\u2009±\u20096 vs. 48\u2009±\u200913 and 33\u2009±\u200910 vs. 43\u2009±\u20097 ng/mL for two different genes; nDNA fragments: 148\u2009±\u200913 vs. 210\u2009±\u200913% of control). Receiver operating characteristic (ROC) curve analyses revealed that nDNA fragments, GDH, and mtDNA were predictive of outcome (area under the curve [AUC], study admission: 0.73, 0.70, and 0.71 or 0.76, respectively, P\u2009<\u20090.05; AUC, time of peak ALT: 0.78, 0.71, and 0.71 or 0.76, respectively, P\u2009<\u20090.05), and the results were similar to those from the Model for End-Stage Liver Disease (MELD; AUC, peak MELD: 0.77; P\u2009<\u20090.05).'] Are serum mitochondrial biomarkers and damage-associated molecular patterns higher in acetaminophen overdose patients with poor outcome?