Comparative mitochondrial proteomic: PGAM5-mediated necroptosis through excessive mitophagy in sheep livers under molybdenum and cadmium co-exposure.

Accumulation of excessive molybdenum (Mo) and cadmium (Cd) in the environment poses detrimental effects on organisms. The precise mechanisms of hepatotoxicity that are involved with mitochondria, resulting from the co-exposure to Mo and Cd, remain poorly understood and elusive. To fill the gap, a total of 24 sheep were stratified into two groups: control group and Mo + Cd group (45 mg Mo·kg⁻¹·B.W. and 1 mg Cd·kg⁻¹·B.W.). Results showed that exposure to Mo and Cd adversely co-induced the liver function related biochemical marker alterations in serum, histopathological abnormalities, mitochondrial ultrastructure damage and oxidative stress in the livers of sheep. Sequencing results from isolated mitochondria indicated that a total of approximately 4788 mitochondria-localized proteins were identified, of which 360 exhibited significant differential expression. GO and KEGG database analysis demonstrated excessive Mo and Cd primarily induced hepatotoxicity by affecting mitochondria-mediated oxidation-reduction processes, single-organism metabolic processes, and enhancing the TNF signaling pathway. Mo and Cd co-exposure increased the levels of mitophagy- and necroptosis- related factors regulated by PGAM5 in the livers. Consistently, our findings highlight the co-exposure of Mo and Cd induced necroptosis triggered by PGAM5-mediated mitophagy, which offers valuable insights into the toxicological mechanisms underlying the combined effects of Mo and Cd.