COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.

Area of Science:

• Mitochondrial physiology
• Epigenetics
• Metabolic regulation

Background:

• Reversible protein acetylation regulates adaptive metabolic responses.
• The mechanisms of mitochondrial protein acetylation remain largely unknown.
• MOF (MYST family lysine acetyltransferase) is implicated in various cellular processes.

Purpose of the Study:

• To investigate the role of MOF in mitochondrial protein acetylation and energy metabolism.
• To identify MOF targets within mitochondria.
• To explore the therapeutic potential of targeting MOF in MOF syndrome.

Main Methods:

• Analysis of mitochondrial morphology and function in MOF-deficient cells.
• Identification and characterization of MOF acetylation targets.
• Functional rescue experiments using wild-type and mutant proteins.
• Assessment of patient-derived fibroblasts.

Main Results:

• Loss of MOF leads to mitochondrial defects, including fragmentation and impaired electron transport chain (ETC) complex IV.
• COX17 is identified as a direct acetylation target of MOF.
• Acetylation of COX17 is essential for complex IV integrity and function.
• Restoration of mitochondrial function in MOF syndrome patient cells was achieved through various interventions.

Conclusions:

• MOF plays a critical role in mitochondrial physiology through acetylation of mitochondrial proteins like COX17.
• Mitochondrial protein acetylation, particularly of ETC components, is essential for maintaining energy metabolism.
• Targeting MOF or its downstream effectors may offer therapeutic strategies for MOF syndrome.