Associated Principal Investigator, Institute for Molecular Immunology
Dr. Hamid Kashkar and his group investigate how mitochondria control cellular death and immune signaling and coordinate tissue homeostasis. Mitochondrial dysfunction has been associated with a plethora of human diseases including cancer, degenerative and immune disorders. By exploiting the knowledge of how mitochondria interfere with cellular death and immune signaling the group aims to design novel therapeutic protocols for human diseases.
Our research: In an average human adult billions of cells die each day to counter mitosis and to maintain tissue function. Whereas the failure to execute death of irreparable cells contributes to cancer, excessive cell death precipitates degenerative states and causes aging. Within a renovating tissue there is an essential need for a dynamic crosstalk between a dying cell and the neighboring cells to avoid collateral tissue damage. Accumulating evidence showed that cellular death signaling is tightly coupled with immune regulatory cascades in order to prepare adjacent tissues and to promote the clearance of cellular debris arising from dying cells. Mitochondria represent one of the central regulatory nodes of cell death machinery. Dr. Hamid Kashkar and his group aim to elucidate the role of mitochondria in tissue immune surveillance under physiologic and pathologic conditions.
Our successes: The researchers in Dr. Kashkar’s group were able to show that mitochondria simultaneously control cellular death and immune signaling. Thereby, mitochondria impact on intercellular crosstalks and coordinate tissue homeostasis. The results obtained indicated that the therapeutic modalities initially designed to induce cell death also interfere with cellular immune signaling and impact on immunity.
Our goals: The research focuses on the role of mitochondria in cell death and immunity in the context of human diseases. This knowledge will be exploited to design novel therapeutic protocols for cancer, immune disorders and degenerative diseases.
Our methods/techniques: Protein biochemistry, cell biology and immunology.
Figure 1: Mitochondrial outer membrane permeabilization (MOMP) and the release of several intermembrane space (IMS) proteins including cytochrome c and IBM (IAP-binding motive)- containing proteins including SMAC are known to interfere with cellular death machinery by activating caspases (apoptosis or programmed cell death). Cytosolic cytochrome c induces the proteolytic activation of caspase cascade, whereas cytosolic SMAC antagonizes the inhibitor of apoptosis proteins (IAPs). IAPs have been additionally shown to interfere with cellular immune inflammatory signaling. Our recent data demonstrated that mitochondria impact on inflammation by releasing SMAC and antagonizing IAPs (see Andree et al, EMBO J 2014) and provide the first line evidence how cell death signaling interferes with cellular immune signaling. The dynamic crosstalk between cell death and inflammatory signaling cascades via mitochondria represents a central cellular regulatory circuit involved in immunity, aging and cancer.