Functional and dynamic mitochondrial damage by chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) mixture...

Area of Science:

• Biochemistry
• Toxicology
• Neuroscience

Background:

• The biocide mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) and 2-methyl-4-isothiazolin-3-one (MIT) is widely used in consumer products.
• Adverse health outcomes linked to CMIT/MIT, particularly in cosmetics and humidifier disinfectants, are not fully understood.
• The brain microvascular endothelium, a critical interface, is particularly vulnerable to toxic insults.

Purpose of the Study:

• To investigate the effects of CMIT/MIT on cellular redox homeostasis and energy metabolism in brain microvascular endothelial cells.
• To elucidate the mechanisms underlying CMIT/MIT-induced endothelial dysfunction.
• To assess the in vivo impact of CMIT/MIT on mitochondrial function and endothelial barrier integrity in the brain.

Main Methods:

• Utilized in vitro cell lines (murine bEND.3 and human hCMEC/D3) to examine mitochondrial function and oxidative stress.
• Employed ex vivo rat models to evaluate CMIT/MIT effects on brain endothelium following intravenous administration.
• Assessed mitochondrial membrane potential, oxidative phosphorylation, mitochondrial dynamics (fission/fusion), and tight junction protein expression.

Main Results:

• Sub-lethal concentrations of CMIT/MIT amplified mitochondrial-derived oxidative stress, disrupting mitochondrial membrane potential and oxidative phosphorylation in endothelial cells.
• CMIT/MIT exposure led to an imbalance in mitochondrial fission and fusion dynamics.
• In vivo studies revealed significant mitochondrial damage and reduced tight junction proteins in the brain endothelium of CMIT/MIT-treated rats.
• Endogenous stressors potentiated CMIT/MIT-induced endothelial dysfunction.

Conclusions:

• CMIT/MIT significantly impairs mitochondrial function and dynamics in the brain microvascular endothelium.
• This mitochondrial damage results in endothelial barrier dysfunction.
• The findings provide insights into the role of mitochondrial impairment in CMIT/MIT-associated systemic health effects.