Maintenance and repair of mitochondrial protein complexes

• Applicant: Dr. Ilka Wittig
• Subject Area: Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515944830

The function of mitochondrial protein complexes is essential for the supply of energy, metabolites, cofactors and a variety of metabolic pathways. The assembly sequence of mitochondrial complexes was intensively investigated in proliferating cells. These studies mostly reflect the de-novo assembly and give only limited information on the protein complex dynamics in differentiated cells and tissues. The state of protein complexes in postmitotic tissues might rather be a balance between biosynthesis and degradation and is adapted to the energy requirements of the cell. However, this macro-regeneration process of mitochondria does not appear to be the only way that keeps functional mitochondrial protein complexes in tissues. In proteomic studies, we and others identified a heterogeneity in mitochondrial protein turnover rates. They span a few hours to months. These data suggest mechanisms that control the targeted degradation and exchange of individual proteins or assembly modules. We have so far identified the mitochondrial matrix protease ClpP and the heat shock protein DNAJC30 as service factors involved in microregeneration of complex I and defects lead to mitochondrial dysfunction and disease. With our recently developed method dynamic pulsed-SILAC Complexome Profiling, we can study exchange processes in protein complexes in a time-resolved manner. To better understand these microregeneration processes, we aim to determine whether (1) maintenance and repair of mitochondrial protein complexes are stress-inducible, (2) how and which factors are involved in the scheduled and inducible regeneration of complex I, and (3) which mitochondrial chaperones and proteases are additionally involved in routine checks and maintenance of mitochondrial complexes. With the investigation of regenerative processes within mitochondria, we will gain insights to better understand the degenerative sequence of aging and the pathomechanisms of mitochondrial diseases and help to develop future therapeutic concepts.

• DFG Programme: Research Grants