Allicin Attenuates Mitochondrial Calcium (Ca2+) Overload Induced by Acrylamide in Hepatocytes via the NAD+/SIRT3-FoxO3 Axis

Acrylamide (AA) is a byproduct of the Maillard reaction, with mitochondrial damage playing a pivotal role in mediating its hepatotoxicity. Allicin, a potent dietary phytochemical, has been used to mitigate the hepatotoxicity of AA. This study confirmed that allicin attenuated mitochondrial structural damage in AA-treated livers and AML-12 cells. Liver RNA-seq analysis identified that CA²⁺ transport and nicotinamide adenine dinucleotide (NAD⁺) metabolism, which were associated with mitochondrial function, contributed to the hepatoprotective effects of allicin. Subsequent experiments demonstrated that allicin inhibited AA-caused excessive formation of the mitochondrial-associated endoplasmic reticulum membrane (MAM) and activation of the CA²⁺ channel components. Additionally, allicin restored AA-suppressed NAD⁺ content and the expression of its dependent deacetylase SIRT3, thereby promoting FoxO3 deacetylation and protecting hepatocytes from mitochondrial CA²⁺ overload. Deficiency of SIRT3 eliminated the protective effect of allicin, confirming that allicin antagonized AA-induced hepatotoxicity by regulating mitochondrial CA²⁺ homeostasis through the NAD⁺/SIRT3-FoxO3 axis.

FoxO3; SIRT3; acrylamide (AA); allicin; mitochondrial calcium (Ca2+).