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

Mitochondria are double-membrane enclosed organelles fulfilling essential metabolic and regulatory functions in eukaryotes. The inner membrane is subdivided into the inner boundary membrane and the cristae membrane both of which are connected by pore-like structures termed crista junctions. A pleiotropy of severe human diseases including Alzheimers and Parkinsons disease are associated with aberrant cristae membrane structures. Recent progress by others and us identified the MICOS complex as a protein complex crucial for cristae membrane organization. This complex consists of the following subunits: Mic60/mitofilin, Mic27, Mic26, Mic25, Mic19, Mic13/Qil1, Mic10, and CHCHD10. Formation of crista junctions, as shown in different organisms, depends on the central MICOS subunit Mic60. Subunits of the MICOS complex are linked to various human diseases such as Parkinsons disease, diabetes, cancer, and epilepsy. Still, it is unclear how aberrant cristae architecture could contribute to the pathogenesis of a diverse set of human diseases. Here we aim to solve this conundrum. To decipher the physiological role of Mic60 for crista junction formation in mammalian cells and its role in neuronal function and neurodegeneration, we plan to apply a combination of in vitro, ex vivo, and in vivo approaches. Our preliminary data show that whole-body deletion of Mic60 leads to embryonic lethality. We now plan to generate tissue-specific Mic60 knockout mouse models. Because of the intricate connection between mitochondria and neuronal dysfunction, we propose to generate and characterize conditional brain-specific Mic60 knockout mouse models. These mice will be the first knockout mouse models of the MICOS complex available. In addition, we will use primary murine neuronal cultures (ex vivo) to complement the in vivo studies. We further aim to decipher the mechanistic importance of different post-translational modifications of Mic60 and the role of individual domains of Mic60 by studying associated mutations and truncations using available in vitro cell culture based models. Overall, by using these complementary approaches we hope to better understand the physiological and pathophysiological role of Mic60 and altered cristae morphology in neurodegenerative disorders.

• DFG Programme: Research Grants