Role of the MICOS complex in regulating metabolite fluxes and dynamic changes of the mitochondrial inner membrane

• Applicant: Professor Dr. Andreas Reichert
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577554190

The MICOS (‘Mitochondrial Contact Site and Cristae Organizing System’) complex is a high-molecular weight membrane protein complex of the mitochondrial inner membrane forming crista junctions (CJs) which are proposed to act as a diffusion barrier between the inner boundary membrane (IBM) and the cristae membrane (CM). Using stimulated emission depletion (STED) super-resolution nanoscopy we showed that cristae membranes in mammalian cells remodel at a time scale of seconds in a MICOS-dependent manner and provided evidence that cristae transiently can even detach from the IBM before they reconnect by cristae fusion. We propose that transient formation of cristae vesicles primarily promotes oxidative phosphorylation via proton trapping. Cristae membrane fusion increases IM surface area and is expected to rather promote metabolite exchange. Net transport of ADP and reducing equivalents/electrons from the cytosol to mitochondria matrix as well as export of ATP are such fundamental processes determining cellular energy metabolism. They depend on the adenine nucleotide translocase (ANT, also termed ADP/ATP carrier), the malate-aspartate shuttle (MAS), and the glycerol-3-phosphate shuttle (G3PS). It is unclear how these membrane complexes are distributed within the inner membrane, whether this distribution is dynamically changing depending e.g. on the metabolic condition, how this depends on the MICOS complex, and how metabolite flux is influenced by these processes. Here, we aim to expand our recent findings to better understand how dynamic changes of the cristae membrane mediated by the MICOS complex regulate metabolite exchange in mitochondria. Specifically, we will focus our analysis on ANT2, MAS, and the G3PS in the inner membrane using biochemical approaches as well as STED-superresolution microscopy and electron microscopy. Overall, we hope to obtain detailed insights into the dynamics, the mechanisms and the physiological importance of MICOS-dependent cristae membrane dynamics and what roles these processes play in regulating metabolite fluxes in and out of mitochondria.

• DFG Programme: Research Grants