The Role Of Mitochondria Associated Membranes Structure In Autophagy Induced By Molybdenum And Cadmium In Heart Of Sheep

To investigate whether the Mo or/and Cd could cause endoplasmic reticulum stress,mitochondrial dysfunction,MAMs structural changes,and ultimately lead to autophagy in sheep hearts,a total of 48 sheep were randomly divided into 4 groups:control group,Mo group(45 mg Mo·kg^-1·BW),Cd group(1 mg Cd·kg^-1·BW)and Mo+Cd group(45 mg Mo·kg^-1·BW+1 mg Cd·kg^-1·BW).The intragastric administration lasted for 50 days.Cardiac histopathology,microstructure and LC3 aggregation were observed,oxidative stress indices and ATP content were detected,and the expression levels of genes and proteins related to endoplasmic reticulum stress,mitochondrial function,MAMs structure and autophagy were detected.The results were as follows:1.Mo or/and Cd exposure caused trace element imbalance,granular degeneration of myocardial cells,and elevated H₂O₂ and MDA levels and reduced T-SOD,GSH-Px and CAT activities in the cardiac.2.Mo or/and Cd exposure up-regulated the m RNA expression levels of endoplasmic reticulum（ER）stress-related genes（Grp78,Grp94,IRE-1,PERK,ATF6,HERP and CRT）and the protein expression levels of Grp78,Grp94 and p-PERK/PERK.3.Mo or/and Cd exposure reduced cardiac ATP content,leading to mitochondrial vacuolation,and down-regulated the m RNA expression levels of mitochondrial biogenesis-related genes（SIRT1,SIRT3,FOXO1 and FOXO3）and the protein expression levels of SIRT1 and SIRT3.4.Mo or/and Cd exposure resulted in reduced MAMs structure in the heart,increased distance between ER and mitochondria,and down-regulated the m RNA expression levels of MAMs structure-related genes（Mfn1,Mfn2,IP3R,FUNDC1,VDAC1,MCU,MICU1 and MICU2）and the protein expression levels of Mfn1,Mfn2,IP3R,FUNDC1 and VDAC1,and up-regulated the m RNA expression level of Grp75.5.Mo or/and Cd exposure led to the formation of autophagosomes in the heart,increased the expression of LC3 fluorescent spots,and up-regulated the m RNA and protein expression levels of autophagy-related genes（Beclin1,Atg5,Atg14 and LC3II/LC3I）.In summary,our results revealed that Mo or/and Cd exposure could cause imbalance of trace elements,myocardial tissue damage,oxidative stress,ER stress and mitochondrial dysfunction,led to structural disturbance of MAMs,and induced autophagy in sheep heart,and the effects of Mo and Cd co-exposure were more obvious.