A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function

Area of Science:

• Cellular Biology
• Molecular Biology
• Genetics

Background:

• Mitochondrial function relies on proteins encoded by both nuclear and mitochondrial DNA.
• Identifying key regulators of mitochondrial homeostasis is crucial for understanding cellular health and disease.

Purpose of the Study:

• To identify a novel regulator of mitochondrial homeostasis.
• To elucidate the molecular mechanism by which this regulator impacts mitochondrial function.

Main Methods:

• Mice models with Sirt7 deficiency were analyzed for mitochondrial dysfunction.
• Human fibroblasts with specific mutations were used to test the translational relevance of Sirt7.
• Biochemical assays were performed to investigate the interaction between Sirt7 and GABPβ1.

Main Results:

• Sirt7 deficiency in mice led to multisystemic mitochondrial dysfunction, including increased blood lactate, reduced exercise capacity, cardiac issues, liver steatosis, and hearing loss.
• SIRT7 overexpression rescued mitochondrial defects in human fibroblasts with NDUFSI mutations.
• SIRT7 deacetylation of GABPβ1 promotes GABPα/GABPβ heterotetramer formation and transcriptional activation of nuclear-encoded mitochondrial genes.

Conclusions:

• Sirt7 is a critical nuclear regulator of mitochondrial homeostasis.
• SIRT7 regulates mitochondrial function by targeting GABPβ1, a key transcription factor for nuclear-encoded mitochondrial genes.
• These findings establish a direct link between SIRT7 and mitochondrial health with potential therapeutic implications.