Proteolytic Control of Mitochondrial Membrane Homeostasis
Thomas Langer Max-Planck-Institute for Biology of Ageing, Cologne; Institute for Genetics and CECAD Research Center, University of Cologne, Germany
Mitochondria are emerging as cellular signaling platforms deeply integrated into various cell survival and cell death cascades. Proteolytic events at the inner membrane (IM) represent central regulatory steps in these processes, emphasizing the importance of mitochondrial IM proteases beyond their roles as gatekeepers of protein quality. The m-AAA protease degrades EMRE in the IM, an essential subunit of the mitochondrial Ca2+ uniporter MCU. This ensures the assembly of gatekeeper subunits with MCU and prevents Ca2+ overload, opening of the membrane permeability transition pore and neuronal death. The IM proteases YME1L and OMA1 mediate the processing of the dynamin-like GTPase OPA1, balancing fusion and fission of mitochondrial membranes. YME1L also catalyzes the regulatory turnover of PRELID1, a lipid transfer protein in the intermembrane space that is required at an early stage in the synthesis of the mitochondrial phospholipid cardiolipin. OMA1 is a stress-activated peptidase, which ensures protein quality control, fine-tunes mitochondrial bioenergetic function and controls cellular apoptotic resistance. The rhomboid protease PARL cleaves the PTEN-induced kinase PINK1 in the IM, which regulates the activity of respiratory complex I and the clearance of damaged mitochondria by mitophagy. Moreover, PARL processes Smac/DIABLO allowing its release from mitochondria in apoptotic cells and ensuring the progression of apoptosis. IM proteases thus have a pivotal role in determining the form and function of mitochondria as well as the regulation of cell signaling and survival.