OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Biochemistry

Background:

• Mitochondrial membrane potential (Δψm) reduction signals dysfunction and triggers adaptive responses.
• Maintaining Δψm is crucial for iron-sulfur cluster (ISC) synthesis, vital for mitochondrial function.
• The precise mechanisms cells use to maintain Δψm under stress are not fully understood.

Purpose of the Study:

• To investigate how yeast cells maintain Δψm and ISC biosynthesis despite mitochondrial dysfunction.
• To identify the adaptive responses involved in preserving mitochondrial function under stress.

Main Methods:

• Utilized yeast oxidative phosphorylation mutants (deficient in complexes III, IV, V, and mtDNA).
• Performed extensive omics analyses (genomics, transcriptomics, proteomics) to profile cellular responses.
• Investigated metabolic rewiring, protein import, and chaperone activity.

Main Results:

• Mutants showed activated stress responses and progressive Δψm reduction.
• Observed downregulation of ATP synthase inhibitor (Inh1) and OXPHOS subunits.
• Detected upregulation of import receptor Mia40, mitochondrial biogenesis, glycolysis, and cytoplasmic chaperones.
• Identified Snf1/AMPK pathway activation for metabolic adaptation.

Conclusions:

• Yeast cells employ coordinated adaptive strategies to maintain Δψm and ISC biosynthesis.
• These adaptations involve metabolic rewiring, proteome remodeling, and enhanced protein quality control.
• These processes are essential for cell proliferation under conditions of mitochondrial stress.