We aim to unravel the regulation of mitochondrial homeostasis in health and disease.
Mitochondrial signalling: a matter of life and death
Mitochondria do it all. They carry the genetic signature of our maternal lineage, are critical to cell viability and produce the chemical energy required for our cells and tissues to survive. Their unique morphology reflects our bacterial past. It is now widely appreciated that mitochondria serve as essential signalling platforms for a variety of molecular reactions within our cells. Despite their static textbook depiction, these membrane-bound organelles form a remarkably dynamic network in our cells.
It is not surprising, therefore that mitochondrial damage and aberrant mitochondrial metabolism are associated with a diverse array of human diseases. These include neurodegeneration (Parkinson's disease, ALS), ageing, immune dysfunction, certain forms of cancer and inherited mitochondrial disorders. Consequently, our cells have evolved multiple mechanisms to cope with mitochondrial meltdown.
Mitophagy: selective delivery of damaged mitochondria to the lysosome for destruction
One way to deal with damaged mitochondria is to destroy them. Autophagy is an essential pathway that evolved to sustain cells during times of nutrient deprivation. During this process, our cells sense, encapsulate and deliver defective components to the lysosome for elimination. Loss of basal macroautophagy in animals leads to pronounced neurodegenerative disease.
We now recognise that autophagy can be both non-selective (macroautophagy) or selective in cells. Over the past decade, pioneering work from many laboratories has demonstrated that damaged mitochondria can be selectively eliminated, in a process known as "mitophagy". Recent advances have made it possible to visualise mitophagy in mammalian tissues. In contrast to the classical in vitro characterisation of mitophagy as an inducible 'stress response', it has emerged that mitophagy pathways operate constitutively in vivo. Indeed, different cells within the same organ can exhibit striking heterogeneity. In contrast to our understanding of mitophagy in vitro, the molecular regulation of mitophagy in vivo remains an open question.
Tackling a complex question in tissues: in vivo mitophagy
Understanding the regulation of mitophagy in vivo is particularly complex and could not be addressed until recently. The McWilliams lab combines sophisticated mouse genetics and cutting edge approaches in neuroscience, microscopy and biochemistry to understand the endogenous regulation of mitophagy pathways in vivo. A primary goal of our research is to both exploit and develop tools to understand mitochondrial homeostasis in health and disease.