Sirt3-dependent deacetylation of COX-1 counteracts oxidative stress-induced cell apoptosis

Area of Science:

• Cellular Biology
• Biochemistry
• Mitochondrial Function

Background:

• Mitochondrial sirtuins (Sirt3) regulate cellular responses to stimuli like oxidative stress through deacetylation.
• Cytochrome c oxidase (COX)-1, a key component of mitochondrial complex IV, is implicated in cellular survival under stress.

Purpose of the Study:

• To investigate the role of Sirt3 in the regulation of COX-1 acetylation and its impact on oxidative stress-induced apoptosis.
• To identify the specific acetylation sites on COX-1 and explore the therapeutic potential of the Sirt3/COX-1 axis.

Main Methods:

• Utilized NIH/3T3 cells and primary neuronal cells treated with oxidative stressors (2,2'-azobis(2-amidinopropane) dihydrochloride and hydrogen peroxide).
• Manipulated Sirt3 levels using small interfering RNA (siRNA) and overexpression.
• Assessed COX-1 acetylation, mitochondrial membrane potential, and apoptosis.
• Examined COX-1 acetylation in rat brain tissues following ischemia/reperfusion injury.

Main Results:

• Oxidative stress led to COX-1 acetylation and deactivation, promoting apoptosis.
• Sirt3 inhibition increased COX-1 acetylation, decreased mitochondrial membrane potential, and enhanced apoptosis.
• Sirt3 overexpression reversed these effects, inhibiting oxidative stress-induced apoptosis.
• Ischemia/reperfusion injury in rats showed inhibited Sirt3-induced COX-1 hyperacetylation.
• Identified K13, K264, K319, and K481 as critical acetylation sites on COX-1.

Conclusions:

• COX-1 is a novel deacetylation target of Sirt3.
• The Sirt3/COX-1 pathway plays a crucial role in counteracting oxidative stress-induced apoptosis.
• Targeting the Sirt3/COX-1 axis offers a promising therapeutic strategy for stress-related diseases.