P07 - Stress-responsive signaling pathways converging at the inner mitochondrial membrane

Mitochondria are major players in the regulation of immune and inflammatory signaling pathways and act both as a source and target of these pathways. Due to their bacterial ancestry, mitochondria can elicit immune responses when mitochondrial components, such as mitochondrial DNA (mtDNA) or cardiolipin, are exposed to the cytoplasm upon mitochondrial damage. These components are sensed as danger-associated molecular patterns (DAMPs) by innate immune receptors, for example Toll-like receptors (TLRs), inflammasomes, or cyclic GMP-AMP synthase (cGAS). On the other hand, various immune pathways signal to mitochondria in order to induce metabolic reprogramming, to increase the formation of reactive oxygen species, or to regulate apoptosis.We previously identified a link between tumor necrosis factor (TNF) signaling and the mitochondrial inner membrane via OPA1 that is transcriptionally regulated by NF-κB-responsive elements in its promoter. Our most recent unpublished research provided evidence for a fast, transcription-independent TNF signaling pathway that protects mitochondria from apoptosis. These data confirmed that signaling via TNF, a physiologically and pathophysiologically highly relevant cytokine, targets mitochondria. By using complementary approaches from cell biology, super-resolution imaging, and biochemistry we will elucidate the impact of fast and delayed TNF signaling on the architecture and function of the mitochondrial inner membrane.

In this context we will focus on components of cristae morphogenesis and the regulatory role of the mitochondrial kinase PINK1 in mediating anti-apoptotic effects at mitochondria. It has been shown recently that apoptotic stress conditions can induce herniation of the inner membrane through Bax/Bak pores at the outer membrane, resulting in exposure of inner membrane components to the cytoplasm and release of mtDNA by inner membrane permeabilization. We will therefore explore the immunogenic potential of the mitochondrial inner membrane exposed to the cytoplasm in this paradigm. Recruitment and activation of innate immune sensors at sites of inner membrane herniation will be studied as well as possible mechanisms implicated in mitochondrial inner membrane extrusion and permeabilization.In conclusion, this proposal is focused on the impact of TNF signaling on the architecture and function of the mitochondrial inner membrane and on the role of the inner membrane in eliciting innate immune responses with the overarching aim to explore mitochondria as both a target and source of immune signaling.