Physiological roles of Mic60/Mitofilin in formation of crista junctions and neuronal function

• Applicant: Professor Dr. Andreas Reichert
• Subject Area: Biochemistry ; Cell Biology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 386168927

• Final Report Year: 2024

Final Report Abstract

The project aimed to better understand how altered cristae morphology contributes to neuronal dysfunction and neurodegeneration. In particular, we aimed to obtain a fundamental understanding on the role of Mic60, a central subunit of the MICOS (‘mitochondrial contact site and cristae organising system’) complex, for neuronal function in vivo. Another aim was to dissect the molecular mechanism of crista junctions (CJ) formation in mammalian cells and the physiological function of the MICOS complex. We obtained preliminary results in the mouse model that indicate a critical role of Mic60 in neuronal function, yet further experiments are needed in the future to validate this and to dissect it in more detail. We focused on the fundamental role of the MICOS complex and its subunits generating several cellular models. We obtained additional insight into the roles of the MICOS subunits MIC26, MIC27, and MIC13. We revealed that Mic26 and Mic27 play a critical role in mitochondrial lipid metabolism and oxidative phosphorylation. Moreover, we could show for that cristae are highly dynamic entities that remodel in a MICOS-dependent manner at a timescale of seconds.

Publications

• Functional Interplay between Cristae Biogenesis, Mitochondrial Dynamics and Mitochondrial DNA Integrity. International Journal of Molecular Sciences, 20(17), 4311.
  Kondadi, Arun Kumar; Anand, Ruchika & Reichert, Andreas S.
  
• Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent. The EMBO Journal, 38(22).
  Wolf, Dane M.; Segawa, Mayuko; Kondadi, Arun Kumar; Anand, Ruchika; Bailey, Sean T.; Reichert, Andreas S.; van der Bliek, Alexander M.; Shackelford, David B.; Liesa, Marc & Shirihai, Orian S.
  
• Cristae Membrane Dynamics – A Paradigm Change. Trends in Cell Biology, 30(12), 923-936.
  Kondadi, Arun Kumar; Anand, Ruchika & Reichert, Andreas S.
  
• Cristae undergo continuous cycles of membrane remodelling in a MICOS ‐dependent manner. EMBO reports, 21(3).
  Kondadi, Arun Kumar; Anand, Ruchika; Hänsch, Sebastian; Urbach, Jennifer; Zobel, Thomas; Wolf, Dane M.; Segawa, Mayuko; Liesa, Marc; Shirihai, Orian S.; Weidtkamp‐Peters, Stefanie & Reichert, Andreas S.
  
• MIC26 and MIC27 cooperate to regulate cardiolipin levels and the landscape of OXPHOS complexes. Life Science Alliance, 3(10), e202000711.
  Anand, Ruchika; Kondadi, Arun Kumar; Meisterknecht, Jana; Golombek, Mathias; Nortmann, Oliver; Riedel, Julia; Peifer-Weiß, Leon; Brocke-Ahmadinejad, Nahal; Schlütermann, David; Stork, Björn; Eichmann, Thomas O.; Wittig, Ilka & Reichert, Andreas S.
  
• Conserved GxxxG and WN motifs of MIC13 are essential for bridging two MICOS subcomplexes. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1863(12), 183683.
  Urbach, Jennifer; Kondadi, Arun Kumar; David, Céline; Naha, Ritam; Deinert, Kim; Reichert, Andreas S. & Anand, Ruchika
  
• Emerging Roles of the MICOS Complex in Cristae Dynamics and Biogenesis. Biology, 10(7), 600.
  Anand, Ruchika; Reichert, Andreas S. & Kondadi, Arun Kumar
  
• Linking transport and translation of mRNAs with endosomes and mitochondria. EMBO reports, 22(10).
  Müntjes, Kira; Devan, Senthil Kumar; Reichert, Andreas S. & Feldbrügge, Michael
  
• The relevance of mitochondrial morphology for human disease. The International Journal of Biochemistry & Cell Biology, 134, 105951.
  Navaratnarajah, Tharsini; Anand, Ruchika; Reichert, Andreas S. & Distelmaier, Felix