How Biogenesis, Dynamics, and Mitophagy Fix Your Brain
Estimated reading time: 8 minutes
Some of you are beginning to understand that you need to focus on mitochondrial function to have a healthy brain that allows a good mood and rockin’ cognitive function. Some of you are just good with knowing mitochondria are key. And you may enjoy this simple blog post about these amazing organelles!
But some of you want to know more about mitochondria, and learning about them is important to you. You might be like me, who needs to really understand my scientific “why” for something to go all in and for my new behaviors to have a purpose. So if you are like that, this blog post is for you!
Let’s discuss the pathways that maintain mitochondrial health and then look at how ketogenic diets might influence those pathways to help you feel better. Shall we begin?
Mitochondrial Biogenesis
Mitochondrial biogenesis is the process by which new mitochondria are generated within a cell, and it plays a critical role in regulating cellular metabolism, maintaining energy homeostasis, and mitigating the effects of oxidative stress. This process is highly regulated and involves intricate coordination of gene expression, protein translation, and organelle assembly.
The primary driver of mitochondrial biogenesis is the transcriptional co-activator PGC-1α. Don’t get scared off by a little alphabet soup. This is easy to understand! I promise.
The PGC-1α gene codes for a protein called PGC-1α. Not surprising, as most genes provide instructions for making proteins.
PGC-1α is a protein that helps create and maintain healthy mitochondria in neurons by promoting the production of new mitochondria. It activates the expression of genes involved in mitochondrial biogenesis (creation!) and function, ultimately producing new mitochondria and enhancing the ability of existing mitochondria to produce energy!
Overall, the process of mitochondrial biogenesis involves the coordinated expression of many genes and the assembly of a large number of proteins and other molecules, culminating in the formation of new mitochondria within the cell. And if you don’t have this part of mitochondrial function going on in a healthy way, your brain is going to starve for the energy it needs to work and maintain itself. It causes a whole cascade of negative effects that cause problems with these other mitochondrial pathways.
So let’s learn more.
Mitochondrial Dynamics
Mitochondrial dynamics refers to the way mitochondria change their shape and size in response to different signals in our bodies. This process is controlled by two main processes: fusion and fission. Don’t be intimidated by these two terms (like I was), because I am going to explain them simply here.
Fusion is when two or more mitochondria come together to form a larger, more interconnected network, while fission is when a mitochondrion splits into two or more smaller units. Fusion of mitochondria can increase the amount of energy produced, while fission can decrease it. This allows the mitochondria to adapt to different energy demands in the cell.
By undergoing fusion and fission, mitochondria can adapt to changing energy demands and respond to cellular stressors. This is because when mitochondria fuse together, they share resources and can produce more energy than when they are separate. Conversely, when mitochondria undergo fission, they become smaller and more isolated, which can reduce energy production.
Changes in mitochondrial shape are important and can help them to respond to cellular stressors. For example, when cells are exposed to high levels of oxidative stress (which can damage cells and DNA), mitochondria may undergo fission to generate new, healthier mitochondria that can better cope with the stress. These changes in shape (morphology) can also help to facilitate communication between mitochondria and other parts of the cell. For example, the fusion of mitochondria can allow for the exchange of proteins and other molecules between mitochondria, which can be important for regulating cellular metabolism and energy production.
Mitochondrial Mitophagy
Mitochondrial mitophagy is a process by which cells selectively remove damaged or dysfunctional mitochondria, helping to maintain a healthy mitochondrial network and reduce oxidative stress. And you all know by now what that means for brain function!
The process of mitochondrial mitophagy involves several steps. First, the damaged or dysfunctional mitochondria are identified and marked for destruction by a process called ubiquitination. This fun word describes a process by which a protein called ubiquitin is added to the damaged mitochondria, marking them for removal.
Next, the marked mitochondria are surrounded by a membrane structure called an autophagosome, which forms a vesicle that engulfs the damaged mitochondria. The autophagosome then fuses with a lysosome, a specialized organelle that contains enzymes that can break down and degrade cellular waste.
Once the damaged mitochondria are inside the lysosome, the enzymes break them down into their component parts, which can be recycled by the cell. It’s a complex process involving several steps and coordinating various cellular components. Luckily, you don’t need to understand all the steps to know that this mitochondrial process is crucial to your brain health goals.
During periods of mitochondrial dysfunction and failure of mitochondrial quality control mechanisms (such as mitophagy) ROS/RNS can induce damage to cellular macromolecules and necrotic cell death. Proper control and coordination of mitophagy pathways are crucial to prevent cell death and inflammation.
Swerdlow, N. S., & Wilkins, H. M. (2020). Mitophagy and the brain. International journal of molecular sciences, 21(24), 9661. https://doi.org/10.3390/ijms21249661
This process of selective removal of damaged mitochondria helps to maintain a healthy mitochondrial network and reduce oxidative stress and basically is a huge component of your ability to recover your mood and cognitive function!
#MitochondriaMatter
In the brain, mitophagy is particularly important due to the high energy demands of brain cells and their susceptibility to oxidative stress. Impaired mitochondrial function and oxidative stress have been implicated in the development of a variety of neurodegenerative disorders and mental illness.
Ketogenic Diets and Mitochondria
I think it’s important for you to know that a ketogenic diet has profound positive effects on these mitochondrial pathways.
There is evidence that ketogenic diets can affect mitochondrial dynamics, including the processes of fusion and fission that shape mitochondrial morphology. Studies in both animals and humans have shown that ketogenic diets can increase the expression of genes involved in mitochondrial fusion, increasing mitochondrial size and network complexity.
Recent studies have shown that ketogenic diets can decrease the expression of genes involved in mitochondrial fission, which can promote mitochondrial fragmentation and dysfunction. Specifically, a ketogenic diet has been found to reduce the expression of the protein Drp1, which is involved in the process of mitochondrial fission.
KD may suppress ER [endoplasmic reticulum] stress and protect mitochondrial integrity by suppressing the mitochondrial translocation of Drp1 to inhibit NLRP3 inflammasome activation, thus exerting neuroprotective effects.
Why would we want to reduce mitochondrial fission? Because excessive mitochondrial fission can lead to mitochondrial fragmentation and dysfunction, which has been linked to a variety of diseases, including neurodegenerative disorders.
These changes in mitochondrial dynamics may contribute to the overall improvement in mitochondrial function observed with ketogenic diets.
Although the mechanisms through which a ketogenic diet may improve these conditions expand beyond mitochondrial function, the great extent to which nutritional ketosis increases reliance on mitochondrial metabolism strongly suggests that mitochondrial adaptation is a central factor.
Miller, V. J., Villamena, F. A., & Volek, J. S. (2018). Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health. Journal of nutrition and metabolism, 2018. https://doi.org/10.1155/2018/5157645
Conclusion
So yes, mitochondria are the powerhouses of our cells, responsible for producing the energy that our cells need to function properly. But the processes of mitochondrial dynamics, mitochondrial mitophagy, and mitochondrial biogenesis are also crucial for maintaining these vital organelles’ health and proper function.
Through these processes, cells can regulate energy production and metabolism in the brain. We need these pathways working well to adapt to changing energy demands, respond to cellular stressors, and prevent the accumulation of damaged or dysfunctional mitochondria. And what happens when these pathways are impaired in the brain? We see the development of mental illness and neurodegenerative disorders.
If that last statement sounds scandalous and unscientific, you need to catch up on the fields of metabolic psychiatry and neurology. I would recommend you check out Chris Palmer’s book Brain Energy (see references).
In this blog post, you have learned that recent research supports the assertion that a ketogenic diet can have important implications for mitochondrial dynamics and function. And we are not talking about ketogenic diets exerting wimpy effects. A ketogenic diet literally alters the expression of genes involved in mitochondrial fission and fusion and exerts neuroprotective effects.
If you want to work with me to have kick-ass mitochondrial functions like these, you are welcome to inquire about my online program below:
My hope is that this blog post has contributed to your understanding of the processes that regulate mitochondrial function and dynamics and how ketogenic diets can be a powerful intervention to treat metabolic disorders in the brain that manifest as mental illness and neurological disorders.
Because you have the right to know all of the ways that you can feel better.
References
Guo, M., Wang, X., Zhao, Y., Yang, Q., Ding, H., Dong, Q., … & Cui, M. (2018). Ketogenic diet improves brain ischemic tolerance and inhibits NLRP3 inflammasome activation by preventing Drp1-mediated mitochondrial fission and endoplasmic reticulum stress. Frontiers in Molecular Neuroscience, 11, 86. https://doi.org/10.3389/fnmol.2018.00086
Miller, V. J., Villamena, F. A., & Volek, J. S. (2018). Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health. Journal of nutrition and metabolism, 2018. https://doi.org/10.1155/2018/5157645
Palmer, C. D. (2014). Brain Energy. Academic Press. https://brainenergy.com/
Qu, C., Keijer, J., Adjobo-Hermans, M. J., van de Wal, M., Schirris, T., van Karnebeek, C., … & Koopman, W. J. (2021). The ketogenic diet as a therapeutic intervention strategy in mitochondrial disease. The International Journal of Biochemistry & Cell Biology, 138, 106050. https://doi.org/10.1016/j.biocel.2021.106050
Swerdlow, N. S., & Wilkins, H. M. (2020). Mitophagy and the brain. International journal of molecular sciences, 21(24), 9661. https://doi.org/10.3390/ijms21249661
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