SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation
Ritam Naha,
Rebecca Strohm,
Yulia Schaumkessel,
Jennifer Urbach,
Ilka Wittig,
Andreas S. Reichert,
Arun Kumar Kondadi,
Ruchika Anand
Affiliations
Ritam Naha
Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany
Rebecca Strohm
Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany
Yulia Schaumkessel
Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany
Jennifer Urbach
Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany
Ilka Wittig
Functional Proteomics, Institute for Cardiovascular Physiology, Faculty of Medicine, Goethe-University, 60590 Frankfurt am Main, Germany; German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, 60590 Frankfurt am Main, Germany
Andreas S. Reichert
Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany
Arun Kumar Kondadi
Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany
Ruchika Anand
Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany; Corresponding author
Summary: The MICOS complex, essential for cristae organization, comprises MIC10 and MIC60 subcomplexes, with MIC13 as a crucial subunit. MIC13 mutations cause severe mitochondrial hepato-encephalopathy, cristae defects, and MIC10-subcomplex loss. We demonstrate that depletion of the mitochondrial protease YME1L in MIC13 KO stabilizes MIC10-subcomplex, restoring MIC60-MIC10 interaction and crista junction (CJ) defects, indicating MIC13 is crucial for MIC10-subcomplex stabilization rather than MIC60-MIC10 bridging. We identified stomatin-like protein 2 (SLP2) as a key MIC13 interaction partner, essential for cristae morphology and CJ formation. SLP2 serves as an interaction hub for MICOS subunits and stabilizes MIC26 by protecting it from YME1L-mediated degradation. Deleting both SLP2 and MIC13 impairs MIC60-subcomplex assembly and its nanoscale organization. Restoring the MIC10-subcomplex in MIC13-SLP2 double KO cells through YME1L depletion reinstates MIC60-subcomplex assembly and cristae morphology. Overall, we propose SLP2 and the MIC10-subcomplex act as a proteolytically controlled ‘seeder’ complex, facilitating MICOS-MIB complex assembly and maintaining mitochondrial integrity.
