Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity

Area of Science:

• Mitochondrial biology
• Cellular stress response
• Protease function

Background:

• Mitochondrial proteases, like OMA1, are crucial for organelle dynamics and cellular function.
• OMA1 processes mitochondrial substrates, but its targets and stress-response mechanisms are not fully understood.

Purpose of the Study:

• To identify and characterize novel substrates of the mitochondrial metalloprotease OMA1.
• To elucidate the role of OMA1-mediated processing of AIFM1 in mitochondrial stress response and cellular energetics.

Main Methods:

• In vitro and in vivo multiproteomic analyses
• Biochemical assays to study protein processing and localization
• Assessment of mitochondrial respiration and cell growth

Main Results:

• AIFM1, an intermembrane space protein, is a novel substrate of OMA1 under mitochondrial stress.
• OMA1-dependent cleavage of AIFM1 leads to its dislocation from the inner mitochondrial membrane, reducing respiratory activity.
• AIFM1 also functions in maintaining the mitochondrial proteome, including import of respiratory complex I subunits, under steady-state conditions.
• Similar AIFM1 processing occurs in the lungs of virally infected mice.

Conclusions:

• OMA1 integrates mitochondrial stress signals by remodeling AIFM1.
• AIFM1 processing by OMA1 impacts cellular energetics and growth.
• These findings highlight a novel mechanism linking mitochondrial stress, proteostasis, and cellular metabolism.