Organelle teamwork: understanding how peroxisomes and mitochondria communicate in neuronal cell function

Our bodies are made up of trillions of cells, each of which contains an array of specialised compartments, known as organelles. Each type of organelle has its own important job to do, but must also cooperate with other types of organelles to form an integrated network that keeps cells alive and healthy. Efficient inter-organelle teamwork is particularly critical in the brain, where the unique properties and functions of nerve cells (neurons) place extra demands on organelles. Indeed, dysfunctional organelle cooperation has been implicated in many neurological and neurodegenerative diseases, which are a major socio-economic burden in the UK and beyond.

One way organelles within a network 'talk' to each other is by sharing information, signals and resources at points of physical contact called 'membrane contact sites'. Orchestrated cooperation between organelles at membrane contact sites is vital for cell function and survival. Despite this, how most organelles communicate at contact sites, and for what purposes, is still unclear. Because we do not yet understand this, we do not know which processes are compromised during disease, or how to correct these using medical treatment. This research project seeks to identify and characterise the machinery that mediates organelle communication, and reveal the cellular processes that benefit from this cooperation. This knowledge will significantly advance our understanding of cell biology and provide new insights into how detrimental changes in organelle communication cause disease, and might one day be targeted for new treatments.

Given the immense social cost of declining brain function in ageing populations, my research will focus on nerve cells, where my aim is to explain:

the mechanisms and functions of inter-organelle communication within nerve cells
how faulty organelle communication leads to disease
how organelle communication can be therapeutically targeted to improve nerve cell health
I will use my existing expertise to concentrate on two organelles, namely peroxisomes and mitochondria. Peroxisomes act as factories within the cell, making and breaking-down important cellular molecules, while mitochondria are 'power-houses' that generate most of the cell's energy. Both are essential for cell survival and play crucial roles in healthy brain function, with inherited defects in either organelle causing devastating diseases that are frequently associated with neurological decline.

Peroxisomes and mitochondria are closely linked because they act in concert to 1) process fat molecules within the cell and 2) control levels of potentially harmful 'free-radical' molecules that can damage cellular components. Peroxisome-mitochondria communication appears to be particularly important in the brain since nerve cells contain more peroxisome-mitochondria contacts than other cell types. Despite this, membrane contact sites between peroxisomes and mitochondria, their roles in nerve cell function, and their contribution to disease, are poorly understood.

I will use my expertise in a variety of cutting-edge cell biology, microscopy and large-scale screening techniques to address three specific objectives:

How do mitochondria and peroxisomes physically interact?
What is the function of peroxisome-mitochondria communication in nerve cells?
Can modulating peroxisome-mitochondria communication improve nerve cell health?
The insights generated will fundamentally advance our understanding of organelle communication in health and disease, and inform future studies on other crucial organelle interactions. Furthermore, in conjunction with my collaborators in the pharmaceutical industry, this knowledge will ultimately drive the development of treatments that improve nerve cell health in a variety of diseases where these processes are dysregulated.