SIRT3 mediates multi-tissue coupling for metabolic fuel switching

Area of Science:

• Biochemistry
• Metabolomics
• Mitochondrial Biology

Background:

• Sirtuin 3 (SIRT3) is a key NAD(+)-dependent deacetylase involved in metabolic regulation.
• The tissue-specific functions and coordinating role of SIRT3 in inter-tissue metabolic homeostasis remain largely unknown.

Purpose of the Study:

• To comprehensively investigate the role of SIRT3 in regulating the mitochondrial acetyl-proteome across multiple tissues.
• To elucidate the coordinating function of SIRT3 in maintaining metabolic homeostasis between distinct tissues.

Main Methods:

• Multi-tissue quantitative proteomics in fasted wild-type and SIRT3-knockout mice.
• Innovative bioinformatic analysis of proteomic data.
• Biochemical validation of key findings.

Main Results:

• SIRT3 regulates mitochondrial acetylation in core processes common to brain, heart, kidney, liver, and skeletal muscle.
• SIRT3 differentially impacts metabolic pathways in fuel-producing (liver) versus fuel-utilizing (brain, muscle) tissues.
• SIRT3 plays a maintenance role in liver and kidney, reducing acetate load, and impacts brain ketone body utilization.

Conclusions:

• SIRT3 is a crucial regulator of mitochondrial acetylation, with both common and tissue-specific effects.
• SIRT3 coordinates inter-tissue metabolic communication, essential for maintaining overall metabolic homeostasis.
• Findings reveal novel roles for SIRT3 in fuel utilization and metabolic adaptation.