Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater...

Area of Science:

• Environmental Toxicology
• Biochemistry
• Cell Biology

Background:

• Excessive manganese (Mn) exposure poses health risks, yet its toxic mechanisms in vertebrates, particularly concerning liver function, remain poorly understood.
• Hepatic lipotoxicity and mitochondrial dysfunction are critical indicators of environmental pollutant impact.

Purpose of the Study:

• To elucidate the mechanisms underlying manganese-induced hepatic lipotoxicity in vertebrates.
• To investigate the role of mitochondrial dysfunction, oxidative stress, and specific molecular pathways in manganese toxicity.

Main Methods:

• Dietary manganese overload model in vertebrates.
• Analysis of hepatic lipid and manganese content.
• Measurement of superoxide dismutase 2 (Sod2) activity and acetylation levels.
• Assessment of mitochondrial function and oxidative stress markers.
• Investigation of Mtf1, Sirtuin 3 (Sirt3), Heat shock factor 1 (Hsf1), and Peroxisome proliferator-activated receptor gamma (Pparg) involvement.

Main Results:

• Dietary manganese overload increased hepatic lipid and Mn levels, reduced Sod2 activity, and elevated Sod2 acetylation.
• Manganese induced mitochondrial dysfunction via Mtf1/Sirt3-mediated Sod2 acetylation at K55 and K70 sites.
• Mitochondrial oxidative stress was implicated in manganese-induced lipotoxicity.
• Manganese-induced lipotoxicity occurred through an oxidative stress-dependent Hsf1/Pparg pathway, enhancing lipogenic gene transcription.

Conclusions:

• Manganese-induced hepatic lipotoxicity is mediated by a mitochondrial oxidative stress-dependent Hsf1/Pparg pathway.
• Mtf1/Sirt3-mediated Sod2 acetylation contributes to manganese-induced mitochondrial dysfunction.
• This research offers novel insights into manganese toxicology and its environmental assessment, particularly regarding lipid metabolism in aquatic environments.