Periodic Reporting for period 3 - SOLID (Suppression of Organelle Defects in Human Disease)
Okres sprawozdawczy: 2022-07-01 do 2023-12-31
Malfunctioning cellular organelles are a highly prevalent cause of severe human disease with unmet clinical need in many cases. This is particularly evident for mitochondria, which are best known for their role in ATP production through respiration but also play critical roles in cellular processes ranging from metabolism to signaling and apoptosis. Consequently, dysfunction of the organelle is at the heart of aging, age-related forms of neurodegeneration, cardiovascular defects and cancer. Formerly separate organisms, endosymbiotic mitochondria are constantly exposed to different types of stress and need to coordinate protective measures with the surrounding cell, which can fail in the face of overwhelming insults or advanced age. Efforts to mitigate organelle malfunction hinge on a solid understanding of the genetic inputs on the organelle in the steady-state and in the context of stress. Particularly, elucidation of relevant genetic interactions could inform therapeutic strategies for mitochondrial defects with a hereditary component, which make up the largest group of human inborn errors. Our objective is to systematically identify the genetic inputs on healthy and perturbed mitochondria in the human system and mechanistically clarify the pathways that maintain organelle homeostasis and cellular health. Using a unique genetic strategy, we seek to identify genetic interactions that could potentially be exploited for the restoration of homeostasis in the context of hereditary defects. Our approach is also meant to generate reagents and workflows that can be transferred to other cellular processes and disease-related scenarios.
We have conducted a series of genome-scale phenotypic genetic screens for mitochondrial and mitochondria-related parameters in healthy cells and such challenged with an exogenous insult or engineered genetic defect. This has led to a number of significant discoveries, including a pathway that relays a wide range of mitochondrial insults to the cytosol and nucleus in the human system. Perturbed mitochondrial proteostasis, protein import, respiration and other defects trigger the mitochondrial protease OMA1, which in turn cleaves a protein called DELE1. The C-terminal cleavage fragment subsequently relocalizes from mitochondria to the cytosol by an unknown mechanism, where it engages and activates the kinase HRI. Activated HRI attenuates cellular protein synthesis and starts a cellular recovery program.
The activation of the identified OMA1-DELE1-HRI pathway downstream of diverse type of cellular insults, including genetic defects derived from patients underscores its relevance for human health. Going forward, it will be critical to gain a deep understanding of the underlying mechanics of this new biology and how it can be modulated in disease-related settings.