A Proteolytic Hub in Mitochondria Regulating Mitophagy and Cell Death

• Applicant: Professor Dr. Thomas Langer
• Subject Area: Biochemistry
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274447724

A dysfunction of mitochondria, essential cell organelles surrounded by two membranes, is associated with aging and causes various diseases including cardiomyopathies and prevalent neurodegenerative disorders. The integrity of mitochondria depends on evolutionarily conserved proteases that serve quality control functions and regulate the biogenesis and dynamic behavior of mitochondria. An increasing number of substrates are reported to undergo proteolytic processing In the inner membrane, often followed by their redistribution within mitochondria. These proteins have been shown to regulate mitochondrial membrane dynamics, mitophagy and cell death. We have identified a large proteolytic hub, termed the SPY complex, which is composed of the membrane scaffold SLP2 and the mitochondrial proteases PARL and YME1L. SPY complexes were found to be essential for mitophagy and apoptotic as well as necrotic cell death, suggesting that these processes are regulated within spatially defined membrane domains in mitochondria. We will combine studies in cells and mice with advanced proteomic approaches to characterize these proteolytic hubs, to unravel the function of proteolytic processing of key regulatory proteins, and reveal how SPY complexes coordinate the activity of its resident oteases to modulate cell survival-cell death decisions.

• DFG Programme: Reinhart Koselleck Projects