Scales of Mitochondrial Stress Response

forthcoming

The increase in human life expectancy and associated rise in late-life morbidities will be a key societal challenge of this century. Cellular homeostasis dwindles over time and the cellular structure tied to aging and age-related diseases like no other is the mitochondrion. As the sole endosymbiotic organelles of the human cell, mitochondria must elaborately interface with their environment—inside the cell and beyond—for the effective detection, communication and resolution of mitochondrial dysfunction. Until recently, a systematic and in-depth study of mitochondrial stress responses was infeasible in the human system, but our work has now created an opportunity for their decryption. Combining genome-wide screening, synthetic biology and biochemistry, we have discovered and begun to molecularly characterize the key signaling pathway engaged by human cells in the wake of a wide range of mitochondrial perturbations: the OMA1-DELE1-HRI ‘mitoISR’. At the level of the organelle, mitoSCALES will identify the molecular triggers of this pathway, the biochemical interplay of its components and how this relates to their other cellular functions. Molecular understanding of these processes will be paramount for decoding their role in human pathologies. At the cellular level, we will elucidate the functional remodeling of the cell in the wake of mitochondrial stress and how this shapes cell fate decisions. We will particularly examine the crosstalk with a secondary mitochondrial stress response we term ‘mitoHSR’ and how this can be tuned to bolster cell viability. At the highest level of complexity, we will create new paradigms for studying cell non-autonomous mitochondrial stress signaling and mitohormesis in the human system via genomics for the first time. Altogether, mitoSCALES will decipher mitochondrial stress responses at the molecular, cellular and inter- cellular level to inspire tomorrow’s biomedical solutions for longer, healthier lives across the population.