Molybdenum and Cadmium Co-induce Mitochondrial Quality Control Disorder via FUNDC1-Mediated Mitophagy in Sheep Kidney

Abstract

Molybdenum (Mo), fundamental trace mineral for animals and plants, but undue Mo damages animal health. Cadmium (Cd) is a toxic heavy metal that exists in the environment. Nevertheless, the mechanism of Mo and Cd on mitochondrial quality control are still indistinct. The objective of this research was to explore the effects of mitophagy on mitochondrial quality control via the FUNDC1-mediated by Mo and Cd in sheep kidney. Forty-eight 2-month-old sheep were stochastically divided into four groups, as shown below: control group, Mo [45 mg/kg body weight (BW)] group, Cd (1 mg/kg BW) group and Mo (45 mg/kg BW)+Cd (1 mg/kg BW) group, with 50 days feed technique. The results showed that Mo or/and Cd attract an unbalance of trace minerals and vacuoles and granular degeneration of renal tubular epithelial cells, and increase the number of mitophagosomes and vacuole-mitochondria and LC3 puncta and MDA and H2O2 contents, and decrease ATP content in the kidney. Moreover, Mo or/and Cd treatment could upregulate the mRNA levels of FUNDC1, LC3A, LC3B, PGAM5, DRP1, FIS1 and MFF, and the protein levels of FUNDC1, p-FUNDC1, LC3II/LC3I, DRP1, MFF and FIS1, downregulate the mRNA levels of MFN1, MFN2, OPA1, PGC-1α, SIRT1, SIRT3, FOXO1 and FOXO3, and the protein levels of MFN1, MFN2, OPA1 and PGC-1α. Notably, variations of above-mentioned factors in Mo and Cd group were more obvious than in Mo or Cd groups. Taken together, these results displayed that Mo and Cd co-treatment might induce mitochondrial quality control disorder via FUNDC1-mediated mitophagy in sheep kidney.

Cadmium induces mitochondrial dysfunction via SIRT1 suppression‐mediated oxidative stress in neuronal cells

“…Increasing evidence has shown that Cd‐induced mitochondrial dysfunction is associated with the reduced expression and activity of SIRT1 40–42 . To determine whether SIRT1 is involved in Cd‐induced mitochondrial dysfunction in PC12 and cerebral cortical neurons, we examined MMP and intracellular ATP levels, which are markers of mitochondrial function.…”

Mitochondrial sirtuin 3 and various cell death modalities

“…It was speculated that Cd caused mitochondrial disfunction, decreased Sirt3, and increased oxidative stress, which led to activation of BNIP3dependent mitophagy as well as PINK1/Parkin-dependent mitophagy (Zhang et al, 2021b). It was observed that the level of another mitophagy receptor-FundC1-could also be elevated, together with a decrease in the Sirt3 mRNA level after Cd and Mo intoxication (Wu et al, 2022). However, a decline in Sirt3 could only be a consequence of the accumulation of damaged mitochondria and not cause mitophagy on its own.…”

Environmentally relevant levels of Cd and Mo coexposure induces ferroptosis and excess ferritinophagy through AMPK/mTOR axis in duck myocardium

“…Environmental Mo and Cd levels are rapidly increasing due to industrial production and human activities. Numerous previous reports have suggested that Mo and Cd have adverse effects on animal and human health 11,12 . However, the underlying toxicological mechanisms of Cd and/or Mo in poultry have not been fully clarified.…”

“…Numerous previous reports have suggested that Mo and Cd have adverse effects on animal and human health. 11,12 However, the underlying toxicological mechanisms of Cd and/or Mo in poultry have not been fully clarified.…”