Mitochondria-associated endoplasmic reticulum membranes participate mitochondrial dysfunction and endoplasmic
Junjun Peng1, Xueyan Dai1, Huiqin Fan1
1Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Economic and Technological Development District, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Nanchang, 330045, Jiangxi, People's Republic of China.
Abstract:
Copper (Cu) can be harmful to host physiology at high levels, although it is still unclear exactly how it causes nephrotoxicity. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are associated with heavy metal intoxication. Meanwhile, mitochondria and ER are connected via mitochondria-associated ER membranes (MAM). In order to reveal the crosstalk between them, a total of 144 1-day-old Peking ducks were randomly divided into four groups: control (basal diet), 100 mg/kg Cu, 200 mg/kg Cu, and 400 mg/kg Cu groups. Results found that excessive Cu disrupted MAM integrity, reduced the co-localization of IP3R and VDAC1, and significantly changed the MAM-related factors levels (Grp75, Mfn2, IP3R, MCU, PACS2, and VDAC1), leading to MAM dysfunction. We further found that Cu exposure induced mitochondrial dysfunction via decreasing the ATP level and the expression levels of COX4, TOM20, SIRT1, and OPA1 and up-regulating Parkin expression level. Meanwhile, Cu exposure dramatically increased the expression levels of Grp78, CRT, and ATF4, resulting in ER stress. Overall, these findings demonstrated MAM plays the critical role in Cu-induced kidney mitochondrial dysfunction and ER stress, which deepened our understanding of Cu-induced nephrotoxicity.
Insights
Excessive copper damages kidney cells by disrupting mitochondria-associated ER membranes (MAM), leading to mitochondrial dysfunction and endoplasmic reticulum stress in Peking ducks.
Area of Science:
- Toxicology
- Cell Biology
- Molecular Biology
Background:
- High copper levels can harm kidney function, but the exact mechanisms of nephrotoxicity are not fully understood.
- Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are known consequences of heavy metal exposure.
- Mitochondria and ER are interconnected through mitochondria-associated ER membranes (MAM), suggesting a role in cellular response to toxins.
Purpose of the Study:
- To investigate the role of mitochondria-associated ER membranes (MAM) in copper-induced nephrotoxicity.
- To elucidate the crosstalk between mitochondria and ER in the context of excessive copper exposure.
- To understand the molecular mechanisms underlying copper-induced kidney damage.
Main Methods:
- 144 Peking ducks were divided into control and three copper-exposed groups (100, 200, 400 mg/kg).
- Assessed MAM integrity, co-localization of key proteins (IP3R, VDAC1), and levels of MAM-related factors.
- Analyzed mitochondrial function markers (ATP, protein expression) and ER stress markers (protein expression).
Main Results:
- Excessive copper disrupted MAM integrity and altered MAM-related factor levels, indicating MAM dysfunction.
- Copper exposure led to mitochondrial dysfunction, evidenced by reduced ATP levels and altered expression of key mitochondrial proteins.
- Copper significantly increased ER stress markers, including Grp78, CRT, and ATF4.
Conclusions:
- Mitochondria-associated ER membranes (MAM) play a critical role in copper-induced kidney mitochondrial dysfunction and ER stress.
- Disruption of MAM integrity is a key mechanism in copper toxicity.
- These findings enhance the understanding of copper-induced nephrotoxicity at the molecular level.
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