The Role Of FUNDC1-mediated Mitophagy On Mitochondrial Quality Control Disorders In Sheep Kidneys Under Molybdenum And Cadmium Combined Stress

The objective of this research was to investigate the effects of molybdenum（Mo）and cadmium（Cd）combined treatment on mitochondrial quality control in sheep kidney.Forty-eight 60-day-old sheep,half male and half female,were randomly divided into 4groups,as shown below:control group,Mo[45 mg/kg body weight（BW）]group,Cd（1mg/kg BW）group and Mo（45 mg/kg BW）+Cd（1 mg/kg BW）group.Ammonium molybdate(（NH₄）₆Mo₇O₂₄4H₂O)and cadmium chloride（Cd Cl₂）were selected as the sources of Mo and Cd respectively.The experimental group was given corresponding drugs and the control group was given normal saline.Kidney tissues were collected on the 25th and 50th days of the experiment.The levels of trace elements,oxidative stress-related indexs,ATP content and the expression levels of genes and proteins related to mitochondrial quality control in kidney tissues were detected,and histopathological and ultrastructural observations were made,and COX IV and LC3 were co-located.The results were as follows:1.Mo and Cd alone and combined treatment resulted in an imbalance of trace elements in the kidney and renal impairment,resulting in vacuolar degeneration and granular degeneration of renal tubular epithelial cells,and significantly increased the contents of MDA and H₂O₂ in the kidney.2.Mo and Cd alone and combined treatment increased the number of mitochondrial autophagosomes and vacuolated mitochondria,and significantly reduced the content of ATP in the kidney.3.Mo and Cd alone and combined treatment up-regulated the m RNA and protein expression levels of renal mitochondrial fission-related genes（DRP1,FIS1 and MFF）,and down-regulated the m RNA and protein expression levels of renal mitochondrial fusion-related genes（MFN1,MFN2 and OPA1）.4.Mo and Cd alone and combined treatment down-regulated the m RNA expression levels of renal mitochondrial biosynthesis-related genes（PGC-1α,SIRT1,SIRT3,FOXO1 and FOXO3）and the protein expression level of PGC-1α.5.Mo and Cd alone and combined treatment increased the m RNA expression levels of FUNDC1,LC3A,LC3B and PGAM5,and the protein expression levels of p-FUNDC1,FUNDC1 and LC3II/LC3I,and significantly increased the recruitment of LC3 in mitochondria.Conclusion:In summary,the accumulation of Mo and Cd in sheep kidneys caused kidney trace element imbalance,renal impairment and oxidative stress,and jointly induced mitochondrial quality control disorder in sheep kidneys through FUNDC1-mediated mitophagy.Moreover,there was a synergistic effect between Mo and Cd.