Prof. Dr. Thomas Langer

Research Area: Mitochondrial proteostasis

Website: http://cecad.uni-koeln.de/Prof-Dr-Thomas-Langer.98.0.html

1. Research Background:

Aging is defined by a decline in the functional capacity of cells, organs and organisms. Mitochondria are intimately linked to a wide range of processes associated with aging but how perturbations in mitochondrial activities contribute to aging remains ill-defined. Organ failure during aging is accompanied by a decline in the bioenergetics capacity of mitochondria and the accumulation of mtDNA mutations, raising the possibility that mitochondrial dysfunction causally contributes to aging. The devastating consequences of impaired mitochondrial activities are illustrated by numerous inherited encephalomyopathies that are associated with mutations affecting mitochondrial proteins. Since mitochondria are the primary site of cellular energy production and perform vital biosynthetic functions, mitochondrial research has been focused for decades on oxidative phosphorylation and the biogenesis of the organelle. However, the notion that mitochondria are highly plastic and dynamic organelles that constantly fuse and divide opened up new research avenues, which significantly altered the view on the role of mitochondria for cell function. It became clear that mitochondria do not represent disparate entities in a cell. Rather, they communicate in many ways with their cellular environment resulting in changes of their proteome and shape in response to physiological demands and stress. Mitochondria thus serve as intracellular signaling platforms and regulators of age-related processes.

2. Research questions addresses by the group:

Our group studies mechanisms that maintain mitochondrial proteostasis focusing on the role of proteases in mitochondria. Proteases conduct protein quality control and are emerging as central regulators of mitochondrial activities, shaping the mitochondrial proteome in response to physiological demands and modulating mitochondrial signaling. Proteolytic activities decline with age and numerous inherited diseases are associated with mutations in mitochondrial proteases, highlighting their central relevance for the functional integrity of mitochondria.

Combining mouse genetic approaches with biochemical and quantitative proteomic approaches, we succeeded to identify key roles of mitochondrial proteases for the regulation of mitochondrial dynamics (Ehses et al., J. Cell. Biol., 2009; Baker et al., EMBO J., 2014; Anand et al., J. Cell Biol., 2014; Wai et al., Science, 2015; Korwitz et al., J. Cell Biol., 2016), apoptosis (Saita et al., Nat. Cell Biol., 2017), phospholipid trafficking in mitochondria (Osman et al., J. Cell Biol., 2009; Osman et al., EMBO J., 2010; Connerth et al., Science, 2012; Potting et al., Cell Metab., 2013; Aaltonen et al., J. Cell Biol., 2016), and the assembly of multiprotein complexes in mitochondrial membranes that regulate cellular calcium signalling (König et al., Mol Cell, 2016).

These discoveries revealed new regulatory principles and are of fundamental importance for our understanding of age-related pathologies that are associated with a dysfunction of mitochondria.

3. Possible projects:

The rhomboid protease PARL resides in the mitochondrial inner membrane and is emerging as an important regulatory hub, controlling the communication between mitochondria and the cellular environment. Our recent proteomic experiments assign a critical role in the regulation of protein localization to the rhomboid-like protease PARL in the mitochondrial inner membrane (Saita et al., Nat. Cell Biol. 2017). PARLmediated processing allows the release of several novel PARL substrate proteins from mitochondria, including proteins that regulate mitophagy, apoptosis and lipid trafficking. PARL is part of a large proteolytic hub, termed the SPY complex, which is composed of the membrane scaffold SLP2 and the mitochondrial proteases PARL and YME1L, suggesting that these processes are regulated within spatially defined membrane domains in mitochondria.

The proposed project focusses on the lipid transfer protein StarD7 whose localization to the mitochondrial intermembrane space and the cytosol is regulated by PARL mediated processing. Our recent experiments revealed that StarD7 acts as a lipid transfer protein in the intermembrane space and preserve mitochondrial respiration and ultrastructure by shuttling phosphatidyl choline (PC) to the inner membrane (Saita et al., in revision). However, the role of the dual localization of StarD7 and the function of cytosolic StarD7 remain enigmatic and will be the focus of the proposed project.

Initial experiments in available human cell lines expressing StarD7 exclusively in the cytosol or mitochondria will characterize how the loss of cytosolic StarD7 affects cell functions and mitochondrial activities. Proteomic, lipidomic and immunofluorescence studies will be performed to assess how alterations in nutrient supply affect the cellular localization of StarD7 and to further characterize StarD7 containing foci at the mitochondrial surface.

4. Applied Methods and model organisms:

The group uses mice, cultured mammalian cells and yeast as model systems to examine mitochondrial function and dysfunction in aging and disease. Applied methods include biochemical and cell biological approaches, live cell imaging, as well as quantitative proteomics and lipidomics by quantitative mass spectroscopy.

5. Desirable skills and qualifications:

Standard biochemical and cell biological skills and experience in live cell imaging are desirable.

6. References:

  • Saita, S., Nolte, H., Fiedler, K.U., Kashkar, H., Venne, A.S., Zahedi, R.P., Krüger, M., and Langer, T. (2017) PARL mediates Smac/DIABLO proteolytic maturation in mitochondria to promote apoptosis. Nature Cell Biol. 19, 318-328. doi:10.1038/ncb3488.
  • Wai, T., Saita, S., Nolte, H., Müller, S., König, T., Richter-Dennerlein, R., Sprenger, H.-G., Madrenas, J., Mühlmeister, M., Brandt, U., Krüger, M., and Langer, T. (2016) The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i-AAA protease YME1L. EMBO Rep. 17, 1844-1856. doi: 10.15252/ embr.201642698