Mitochondria and cell death regulation following toxic injury

Our organs comprise millions of cells that work together in concert for those tissues to carry out their functions. In each cell, there are tiny structures called mitochondria that act as powerhouses.
They carry out many fundamental jobs, from turning the food we eat into energy, to killing cells when they have become old or damaged. As a result, a wide range of diseases can occur when they go wrong. Mitochondrial disorders appear in almost any organ, can occur at any age, and are incurable. Their social and economic impact is enormous.
Mitochondrial defects can be modelled in animals such as the fruit fly. We use flies engineered to carry mitochondrial defects. We found that defective mitochondria send-out messages to another tiny structure in the cell called the endoplasmic reticulum (ER). The outcome of this process is cell death. We want to understand the nature of the signal transmitted between the mitochondria and the ER that causes cell death. Understanding this process will lead to new strategies, designed to alter this communication, restoring cell heath. This can be important to protect certain tissues and organs with high energetic demands such as the brain and heart.

Mitochondria are cellular organelles that provide the main source of energy to cells. They are critical to the health of tissues with high energetic demand such as the brain and heart. Mitochondrial toxicity, resulting from both genetic and environmental factors leads to tissue damage and diseases in humans. Our aim is to increase mechanistic knowledge of adverse outcome pathways (AOPs) linked to mitochondrial toxicity. We use the fruit fly (Drosophila melanogaster) as an in vivo model system to study AOPs associated with mitochondrial liability. Fruit flies have short lifespan and powerful genetics. Further, the majority of human disease-causing genes have functional homologs in flies. Using a systems-based approach, combining transcriptomics, proteomics and metabolomics, we have identified new AOPs triggered by mitochondrial toxicity. These activate stress in the endoplasmic reticulum and immunity pathways. Our current work focuses on increasing knowledge on the mechanism through which mitochondrial toxicity triggers these adverse outcomes and how their manipulation can restore mitochondrial health. This knowledge, derived from in vivo studies, is essential to improve drug safety and human health.
Our work is unravelling two novel AOPs identified by our team: activation of endoplasmic reticulum stress caused by direct contacts with mitochondria and activation of innate immune response pathways.