In a paper published in , a team of researchers from the Montreal Neurological Institute and Hospital of 平特五不中: Ayumu Sugiura, Sevan Mattie, Julien Prudent, and Heidi M. McBride, examined the origins of organelles called peroxisomes. They found that this very important organelle has two origins, which is unique in the field of cellular biology.
We spoke with McBride, the senior author of the study, to learn more about this discovery:
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What are peroxisomes?
Peroxisomes are small, membrane bound organelles inside of every cell. 听They get their name because they neutralize cellular peroxide, which is very toxic, into water. 听 This study looked at how peroxisomes may be born in mammalian cells - including humans. We made a surprising discovery: new peroxisomes are formed as a hybrid organelle. That means they come from two distinct sources, in this case the organelles endoplamic reticulum and mitochondria.
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Is it unusual for an organelle to have a hybrid nature like this?
Yes! It is really the first example of such a hybrid organelle within cell biology. 听 Only the mitochondria and peroxisomes were known to be isolated, self-sufficient organelles able to grow and divide on their own. 听These two organelles have always been unique in that way. 听Mitochondria have their own DNA that is a remnant from their early origins as an alpha-proteobacteria, and mitochondria still retain much of their autonomy. 听Peroxisomes have been more complicated to figure out, but it was generally accepted that in addition to their autonomous growth and division, that they could sometimes be generated as a sub-domain of the endoplasmic reticulum. 听Our works leads to a complete re-evaluation of this model.
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Do they do anything else besides break down peroxide?
In addition to enzymes that neutralize peroxide, they also have essential roles in breaking down complex fatty acids. 听Many human diseases are a result of mutations in this pathway, where there is an accumulation of very long chain and branched fatty acids, for example in X-linked adrenoleukodystrophy.听But peroxisomes also have specific functions in different tissues, for example in the liver they house enzymes that make bile, which is transported into the gut to break down food.听In the brain they are critical to make a specific protective lipid called plasmalogen, which makes up nearly 70 per cent of the myelin sheets that wrap around neurons. 听So these are very important organelles that are largely unstudied in the context of disease.
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Myelin 鈥� that makes me think of MS, where the myelin sheath around neurons is damaged. Could there be a link between peroxisome development and MS?
It is not clear how peroxisomal dysfunction may contribute to neurodegenerative disease, particularly in multiple sclerosis where the myelin is lost and axons become exposed. 听We are now looking at how peroxisomes behave in models of MS, and whether or not increasing their numbers may help combat the toxicity and work towards rebuilding the myelin sheets. 听This work provides a new framework to look at peroxisomal formation and growth, allowing us to move into more complex systems that are 听very relevant to disease.
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Are there any diseases where peroxisomes are already known to play a role?
Yes. There are many rare diseases where peroxisomes cannot form, or cannot perform their function. 听For example, a condition called Zellweger syndrome results in patients either completely lacking peroxisomes, or with peroxisomes that remain 鈥渆mpty鈥� and without function. 听These patients are extremely ill, as they cannot make myelin, nor bile, and they accumulate many toxic metabolites from peroxide to fatty acids. 听The lifespan of these patients is only a few months to about two years. 听There is currently no treatment for these patients, so learning how we may trigger new peroxisomal biogenesis could be important to develop new strategies for therapy.
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What role do mitochondria play in the formation of peroxisomes?
Mitochondria are well known as the 鈥渆nergy powerhouse of the cell鈥�, using the oxygen that we breathe to convert glucose and fat into cellular energy. 听However, mitochondria do a great deal more than this. 听Like peroxisomes, they perform many additional biochemical tasks. 听Some of these tasks are shared with peroxisomes, particularly the breakdown of fatty acids, but also in the generation of bile in liver and plasmalogen in the brain. 听Both organelles also play important roles in neutralizing toxic chemicals. However, mitochondria had not been implicated in the formation of new peroxisomes until our study. 听We found that in skin cells from Zellweger patients lacking peroxisomes, that some peroxisomal proteins are inserted into the mitochondria, while others targeted the endoplasmic reticulum. 听These proteins are then packaged into small membrane vesicles that are ejected from each organelle. 听When they fuse together, the proteins that had been separated within distinct organelles now come together and assemble into a larger protein complex that act like a gate allowing entry of a host of peroxisomal proteins and enzymes into the newly born peroxisome. 听We saw this occur also in normal, healthy cells where the number of peroxisomes was greatly reduced, suggesting that there is some kind of sensing mechanism that 鈥渒nows鈥� when to make peroxisomes from scratch, and when to just let them grow and divide from pre-existing peroxisomes. 听How this sensing system works in the brain or other organs is a major question for our future work.
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What implications does this have for future research?
We hope that this work may shine new light on this essential and understudied organelle. 听Mitochondrial dysfunction has been increasingly linked to many disease states, including Parkinson鈥檚, MS, Alzheimers, cancer and many others. 听Given the close links between mitochondria and peroxisomes, we wonder how dysfunctional mitochondria may impact peroxisomal activity and biogenesis, and how this may contribute to the worsening of disease. 听There are many new questions raised, as we must now gain a better understanding of the mechanisms and signals that initiate the formation of newly born peroxisomes, and their contribution to both rare and common disease. 听We believe this work will have a great impact on the field of peroxisomal biology, and in time, we will understand the impact on human disease progression.
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