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In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice
Published on: November 22, 2017
Comparative mitochondrial proteomic: PGAM5-mediated necroptosis through excessive mitophagy in sheep livers under
Zhiwei Xiong1, Fan Yang2, Xueyan Dai2
1Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China; Jiangxi Biotechnology Vocational College, No. 1636, Liantang North Road, Nanchang County, Nanchang 330200, Jiangxi, PR China.
Abstract:
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.
Insights
Excessive environmental molybdenum (Mo) and cadmium (Cd) cause liver damage. This study reveals Mo and Cd co-exposure induces liver cell death (necroptosis) via PGAM5-regulated mitochondrial self-degradation (mitophagy).
Area of Science:
- Environmental toxicology
- Mitochondrial biology
- Hepatopathology
Background:
- Molybdenum (Mo) and cadmium (Cd) accumulation causes environmental harm.
- Mechanisms of Mo and Cd-induced liver toxicity, particularly mitochondrial involvement, are unclear.
Purpose of the Study:
- To investigate the toxicological mechanisms of co-exposure to Mo and Cd in sheep livers.
- To elucidate the role of mitochondria in Mo and Cd-induced hepatotoxicity.
Main Methods:
- Sheep were exposed to Mo and Cd (45 mg Mo·kg⁻¹·B.W. and 1 mg Cd·kg⁻¹·B.W.).
- Liver function markers, histopathology, mitochondrial ultrastructure, and protein expression were analyzed.
- Bioinformatic analyses (GO, KEGG) were performed on isolated mitochondria.
Main Results:
- Co-exposure to Mo and Cd altered liver function markers, caused histopathological damage, and induced mitochondrial oxidative stress.
- 360 differentially expressed proteins were identified in isolated mitochondria.
- Mo and Cd affected mitochondria-mediated oxidation-reduction, metabolic processes, and the TNF signaling pathway, increasing mitophagy and necroptosis factors regulated by PGAM5.
Conclusions:
- Co-exposure to Mo and Cd induces hepatotoxicity through mitochondrial dysfunction.
- The study identifies PGAM5-mediated mitophagy as a key pathway in Mo and Cd-induced necroptosis.
- Findings provide insights into the combined toxicological effects of Mo and Cd.
