SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation

Area of Science:

• Mitochondrial biology
• Cellular structure and dynamics
• Protein complex assembly

Background:

• The Microlipoprotein Particle (M বিপ) complex (MICOS) is essential for organizing mitochondrial inner membrane cristae.
• Mutations in MIC13, a MICOS subunit, lead to severe mitochondrial diseases and cristae defects.
• The precise roles of MIC13 and its interaction partners in MICOS assembly and function remain unclear.

Purpose of the Study:

• To elucidate the function of MIC13 in MICOS complex assembly and cristae organization.
• To identify MIC13 interaction partners and their roles in mitochondrial integrity.
• To understand the regulatory mechanisms governing MICOS complex stability.

Main Methods:

• Mitochondrial protease YME1L depletion in MIC13 knockout cells.
• Identification of MIC13 interaction partners using co-immunoprecipitation.
• Analysis of MICOS subunit interactions and crista junction formation.
• CRISPR-Cas9 mediated gene deletions of MIC13 and SLP2.

Main Results:

• Depletion of YME1L in MIC13 knockout cells stabilizes the MIC10 subcomplex, restoring MIC60-MIC10 interactions and crista junction defects.
• Stomatin-like protein 2 (SLP2) was identified as a crucial MIC13 interaction partner essential for cristae morphology.
• SLP2 stabilizes MIC26 and acts as an interaction hub, with combined deletion of MIC13 and SLP2 impairing MICOS assembly.
• Restoring the MIC10 subcomplex via YME1L depletion in double knockout cells rescues MICOS assembly and cristae morphology.

Conclusions:

• MIC13 is critical for MIC10 subcomplex stabilization, not direct bridging of MIC60 and MIC10.
• SLP2 acts as a key regulator, stabilizing MICOS subunits and facilitating complex assembly.
• The MIC10 subcomplex and SLP2 function as a proteolytically controlled 'seeder' complex for MICOS assembly, maintaining mitochondrial integrity.