AFB₁-induced mice liver injury involves mitochondrial dysfunction mediated by mitochondrial biogenesis inhibition

Aflatoxin B1 (AFB₁) pollutes foodstuffs and feeds, causing a food safety problem and seriously endangering human and animal health. Liver is the principal organ for AFB₁ accumulation and biotransformation, during which AFB₁ can cause acute and chronic liver damage, however, the specific mechanism is not completely clear. Mitochondria are the primary organelle of cellular bio-oxidation, providing 95% energy for liver to execute its multiple functions. Therefore, we speculated that mitochondrial dysfunction is involved in AFB₁-induced liver injury. To verify the hypothesis, a total of eighty healthy male mice were randomly divided into four groups on average, and exposed with 0, 0.375, 0.75 and 1.5 mg/kg body weight AFB₁ by intragastric administration for 30 d. The results displayed that AFB₁ triggered liver injury accompanied by oxidative stress. AFB₁ exposure also damaged mitochondria structure, decreased mitochondrial membrane potential (MMP), as well as increased cytoplasmic cytochrome c (Cyt-c) protein expression, Bax, p53, Caspase-3/9 protein and/or mRNA expression levels and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine-5'-triphosphate (dUTP) nick end labeling (TUNEL) staining positive cells in mice liver. Meanwhile, AFB₁ exposure elevated pyruvate content, inhibited tricarboxylic acid (TCA) cycle rate-limiting enzymes and electron transport chain (ETC) complexes I-V activities, disturbed ETC complexes I-V subunits mRNA expression levels and reduced adenosine triphosphate (ATP) level in mice liver. These results indicated that AFB₁ destroyed mitochondrial structure, activated mitochondrion-dependent apoptosis and induced mitochondrial dysfunction. In addition, AFB₁ disrupted mitochondrial biogenesis, presented as the abnormalities of protein and/or gene expression levels of voltage dependent anion channel protein 1 (VDAC1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (Nrf1) and mitochondrial transcription factor A (Tfam). This may contribute to hepatic and mitochondrial lesions induced by AFB₁. These results provide a new perspective for elucidating the mechanisms of AFB₁ hepatotoxicity.