Mitochondria are like the batteries of our bodies. They are vital sources of energy and ultimately regulate the function of almost all cell types. Healthy mitochondria are especially crucial in energy-demanding organs such as the brain and muscle. Like any battery, they ‘burn out’ and need to be replaced with newly synthesized mitochondria. When this process does not happen efficiently, the ensuing stress can contribute to cell death. Notably, this mechanism of mitochondrial degradation is disrupted in many neurodegenerative diseases, including Parkinson’s, leading to the death of vulnerable neurons.
Researchers in the Department of Laboratory Medicine and Pathobiology at the Temerty Faculty of Medicine have now discovered how mitochondrial turnover is initiated, which not only develops our understanding of the basic science but could also open therapeutic avenues for many diseases where mitochondrial stability is lost.
The mitochondrial Nod-like receptor (NLR), NLRX1, is a protein Dr. Stephen Girardin has been interested in since he established his lab at the University of Toronto in 2006. While NLRX1 has been implicated in diverse cellular processes, the true, underlying function of NLRX1 remained elusive. Vanier Scholar, Dr. Samuel Killackey, who completed his PhD last year with Dr. Girardin, has finally uncovered it, which they report in their latest paper published in Molecular Cell.
Mitochondria must be replaced once they stop functioning at an optimal level. For the most part, mitophagy research has revolved around depolarization, i.e. the loss of electric potential across the inner mitochondrial membrane, as the major signal for mitochondrial removal. The Girardin lab has discovered that it is the inability of the mitochondria to transport nuclear encoded proteins into the mitochondria that leads to their removal, and that depolarisation is merely one upstream cause of restricted mitochondrial protein import.
“Mitochondrial depolarisation is not the problem, it’s the lack of protein import. The cell receives a signal from the faulty import of the mitochondrial protein, NLRX1, and this is the cue to initiate destruction of the mitochondria, a process known as mitophagy,” explains Girardin.
They were able to demonstrate that the established science on this issue wasn’t the whole picture, by looking at the process from a fresh perspective. “We took a step back and connected some of the dots in the literature – which helped us identify that disrupted protein import was a common denominator across many mitochondrial stressors that trigger mitophagy,” explains Killackey.
The discovery enables researchers to further investigate the role of mitochondrial dysfunction in diseases, particularly in metabolically active organs. “We’ve seen a role for NLRX1-driven mitophagy in muscle function measured through endurance capacity, which could have implications for diseases involving muscle atrophy or functional deficits. Modifying the extent and efficiency of mitochondrial protein import could also offer therapeutic benefit for neurodegenerative disease, a disease category where disrupted mitophagy has already been implicated.” says Killackey.
This has been the culmination of 15 years of research and is a bittersweet moment for Girardin. “I am a lover of fundamental questions. What happens next with the knowledge is a question of physiology, translational medicine, or drug development, which we are not experts in. It’s now time to pass the baton on to others, or to partner with enthusiastic collaborators,” Girardin says with a smile. “We’re proud because not only have we identified the problem, but we’ve made very good progress in understanding and characterising the molecular players and pathways and how this is all integrated in a cell, in some surprising ways”.
The Vanier Canada Graduate Scholarships programis designed to attract and retain world-class doctoral students by offering them a significant financial award to assist them during their studies at Canadian universities. Vanier Scholars demonstrate leadership skills and a high standard of scholarly achievement in the social sciences and humanities, natural sciences and engineering, and health-related fields.
