Proteasomal degradation induced by DPP9-mediated processing competes with mitochondrial protein import

Area of Science:

• Cell Biology
• Molecular Biology
• Proteostasis

Background:

• Proteome plasticity is essential for cellular adaptation.
• Mitochondrial protein import is a key regulatory point for proteome plasticity.
• Understanding the mechanisms controlling mitochondrial protein levels is crucial.

Purpose of the Study:

• To identify pathways regulating mitochondrial protein import.
• To investigate the role of N-terminal processing in mitochondrial protein homeostasis.
• To elucidate the function of dipeptidyl peptidases 8/9 (DPP8/9) in mitochondrial protein regulation.

Main Methods:

• Proteomic analysis to identify substrates of DPP8/9.
• Biochemical assays to study protein processing and degradation.
• Mitochondrial import assays.
• Western blotting to assess protein levels.

Main Results:

• Dipeptidyl peptidases 8/9 (DPP8/9) were identified as mediators of N-terminal processing for mitochondrial proteins, including adenylate kinase 2 (AK2).
• AK2, lacking a canonical mitochondrial targeting sequence, is processed by DPP9, leading to its rapid proteasomal degradation and preventing cytosolic accumulation of active AK2.
• Over 100 mitochondrial proteins with potential DPP8/9 recognition sites were identified, and DPP8/9 were shown to influence the cellular levels of several of these proteins.

Conclusions:

• Regulated cytosolic processing by DPP8/9 controls the levels of mitochondrial proteins.
• This mechanism impacts protein dual localization and cellular adaptation.
• DPP8/9-mediated processing represents a novel regulatory pathway for mitochondrial protein import and homeostasis.