The Mighty Mitochondria

You have probably heard that mitochondria are called the “powerhouse of the cell” and yes, that’s true! These organelles produce ATP, which is the main energy supply that runs our cells. But their job doesn’t end there. Mitochondria are involved in metabolism, cell signaling, immunity, and homeostasis. However, as we age, mitochondria may not always be as efficient, and the processes through which they fuse, divide and transit can be negative impacted.

In this post, I will explain how mitochondria are formed (also known as mitochondrial biogenesis), how mitochondria functioning affects redox balance, the key to mitochondrial flexibility, and how exercise can improve the deterioration of mitochondrial function that is associated with aging. We will also explore some new peptides that have emerged recently, such as MOTS-C and SHMOOSE that are providing new insights into the protection and possibly enhancement of mitochondrial function and longevity.

The Story Behind Mitochondria

Mitochondria were first identified in 1890 by German pathologist Richard Altmann who referred to them as “bioblasts.” It was not until 1967 that scientist Lynn Margulis (then Sagan) suggested a revolutionary theory: mitochondria are the result of a capture of ancient bacteria, which explains why they have their own DNA and ribosomes.

We now know that there are more than 10 billion mitochondria present throughout the cells in the form of complex and dynamic network that control energy production, cellular efficiency, and stress protection. As a result, researchers continue to explore how mitochondrial dysfunctions are associated with diseases such as type 2 diabetes, cancer and neurodegenerative diseases.

One thing to note: Mitochondrial derived microproteins (MDPs) are similar to nuclear encoded microproteins, but they are not the same. These differences will enable us to identify new potential targets for supporting mitochondrial function, as our patients grow older and encounter age-related conditions.

Mitochondria at a Quick Glance

Mitochondria are referred to as the “power houses of the cell” and are involved in several primary functions that affect cell functioning and health span.

Mitochondria:

• Produce adenosine triphosphate (ATP) by oxidative phosphorylation and thus supplies the cell with energy
• Control a number of metabolic functions including the citric acid cycle and fatty acid oxidation
• Assist in the control of calcium concentrations within the cell compartments, which is necessary for cell signaling
• Secrete Ca2+ into the cytoplasm, stimulating cell growth, apoptosis (programmed cell death) and gene expression
• Help in the production of hormones like testosterone and estrogen
  Play a role in some cellular signaling processes and thus in cellular communication

In my upcoming Mastermind, we will delve deeper into these two main functions of mitochondria and how you can help support and optimize mitochondrial health for your patients.

Mitochondrial Biogenesis: How Your Cells Make More Powerhouses

Mitochondrial biogenesis refers to the process of cells producing more mitochondria. But new mitochondria don’t simply appear. Instead, existing mitochondria proliferate and divide, increasing their numbers by importing proteins and lipids from the parent cell. This process is very important because it enables the maintenance of the correct energy homeostasis, especially when energy demands change.

So how does this all get started? Through the cooperation between nuclear DNA (the main genetic material in the cell) and mitochondrial DNA (the small DNA in the mitochondria). This process entails the replication of Mitochondrial DNA (mtDNA); the synthesis of new proteins; the formation of membranes; and the assembly of important components of the energy producing apparatus. The chief regulator of this process is a protein, PGC-1α, which can be regarded as the chief executive responsible for driving mitochondrial biogenesis. PGC-1a is activated in response to various stimuli, including exercise, fasting, oxidative stress, as well as hormones.

Mitochondrial biogenesis enables cells to meet the energy requirements that are demanded of them. Mitochondrial biogenesis also coordinates with mitophagy, the process of degrading old or damaged mitochondria to allow new and efficient ones to take their place.

Mitochondria: The Key to Metabolic Flexibility

Mitochondria are indeed power houses of the cell, but that is not the only role they play. They are the organelles that enable the cell to switch from one energy source to another depending on what is available. This metabolic flexibility enables the body to respond to changing energy needs.

For instance, when one is fasting or on a keto diet, the mitochondria utilize fat as the source of energy through β-oxidation to produce acetyl-CoA, which is then used in the TCA cycle. But when there is enough glucose available in the blood, mitochondria switch to sugar mode and use pyruvate dehydrogenase (PDH) to oxidize glucose. This is possible because certain enzymes like CPT1 are used to regulate the uptake of fat into the mitochondria.

Key Point: Mitochondria do not only regulate the type of fuel used; they regulate the use of fuel as well, depending on the need. When engaging in intense exercise or training, mitochondria increase ATP production by increasing the rate of electron transport chain (ETC) electron flow. In situations where high energy demands are expected to persist for some time, the body even goes as far as stimulating mitochondrial biogenesis to create new mitochondria to support the muscles and enhance their fuel utilization.

When food is not readily available, the mitochondria in the liver convert fatty acids to ketone bodies that the brain and muscles can use as an alternative fuel source. In brown fat cells, however, mitochondria play one more role: producing heat instead of ATP with the help of a particular protein, UCP1, which is how babies and some animals such as hibernating ones stay warm.

In addition, mitochondria function as energy sensors that monitor the level of ATP in the cell. When the energy is low, they signal AMPK to activate energy-producing processes and suppress mTOR, which controls cell growth and metabolism. Also, the mitochondria’s ability to fuse and divide allows them to rearrange enzymes, DNA, and fuel to use resources effectively or to remove damaged parts when necessary.

So keep in mind that mitochondria are not merely the organelles that produce ATP: they are active, versatile, and vital for the proper functioning of the cells and the entire body.

Redox Balance and Mitochondrial Health: Age Better

In my second book, The Redox Promise, I delve into why it’s so important to maintain the correct balance between reducing and oxidizing agents in cellular metabolism, immune modulation, and microbiome homeostasis – to me redox is the key to helping you (and your patients) age better and maximize your healthspan.

In its simplest form, redox reactions can be defined as the gain or loss of electrons by a molecule, which in turn determines its oxidation state. Both cellular respiration and the breakdown of fats to produce energy rely on redox. But when the body’s antioxidant defense system is disturbed, it can result in an overload of reactive oxygen species (ROS) — very reactive molecules that can induce oxidative stress, inflammation, and thus, a deterioration of cellular metabolism – pushing redox out of balance.

Mitochondria are directly involved in these redox processes since these organelles generate ROS as a byproduct of respiration. For years, ROS production was understood to be purely a deleterious side effect, but recent studies indicate that some level of mitochondrial ROS is required for appropriate cell signaling, particularly in response to insulin.

Of course, there is such a thing as having too much ROS. Damage to the mitochondria can also lead to the generation of more ROS, thus creating a negative feedback loop of oxidative stress that can affect the function of cells, bringing about their death (apoptosis) or their complete destruction (necrosis). Mitochondrial DNA (mtDNA) is particularly sensitive to this sort of damage because it is located very close to the electron transport chain (ETC), the part of mitochondria that is responsible for energy production. Nuclear DNA is protected by histones and has better repair mechanisms than mtDNA, which is why it’s more prone to oxidative damage.

ROS can mutate the mtDNA to alter the generation of crucial proteins required for the proper functioning of the ETC, which in turn led to more electron leakage and the generation of more ROS, furthering the negative cycle.

But the problems from ROS don’t stop there.

High ROS levels can also react with nitric oxide (NO) to form reactive nitrogen species (RNS), such as peroxynitrite, that further damage mitochondrial proteins by altering their function. Prolonged oxidative stress decreases the activity of PGC-1α, the master regulator of mitochondrial biogenesis, which reduce the body’s capacity to replace and create new mitochondria. This can lead to generalized mitochondrial dysfunction, making it difficult for cells to rid themselves of and remove damaged mitochondria.

In order for mitochondria to be able to rely on their own antioxidant defenses, they have to keep ROS in check and to maintain redox balance.

Again, I am emphasizing the significance of mitochondria being redox organisms that cannot exist without proper redox regulation of their environment. In my upcoming Mitochondria Mastermind, we will discuss the key cellular relationships between redox balance and mitochondrial activity in detail – I will see you there!

MOTS-c: A Peptide Powerhouse for Mitochondrial Health

MOTS-c, a small but powerful 16 amino acid peptide that is a product of the mitochondrial 12S rRNA gene, has recently come into the limelight to play an important role in mitochondrial function. Scientists have discovered that in case of chronic stress or nutrient deprivation, MOTS-c translocates to the nucleus to stimulate the expression of genes that have protective role for the cell, particularly through the antioxidant pathway. This makes it a good potential for treatment.
So what is the effect of MOTS-c? It has been observed to positively impact metabolic homeostasis and insulin sensitivity in skeletal muscle by triggering the AMPK pathway, which assists the body in the management of glucose and renders the cells less sensitive to metabolic stress. MOTS-c also promotes antioxidant activity through the up-regulation of Nrf2, a master regulator of antioxidant genes, while at the same time reducing the formation of ROS.

MOTS-c is not only good for metabolism but also has a direct impact on mitochondrial functioning.

It does this by:

• Enhancing mitochondrial fusion (through MFN2 and OPA1)
• Improving mitochondrial quality control
• Possibly enhancing mitochondrial biogenesis (up regulating markers such as TFAM, COX4, and NRF1)

My point? MOTS-c could be a very useful agent in enhancing energy production, reducing cellular stress and possibly even extending lifespan.

SHMOOSE: A New Clue in the Fight Against Alzheimer’s

Another new and interesting player in the mitochondrial peptide family is SHMOOSE, a newly identified mitochondrial DNA-encoded microprotein. Recently, scientists have established that a mutation in the SHMOOSE gene increases the risk of Alzheimer’s disease by 30% – a significant discovery that may change the way we view brain aging.

So what is the function of SHMOOSE?

It is involved in energy signaling and metabolism in the brain. The authors of a recent article argued that this microprotein influences the inner mitochondrial membrane and, therefore, mitochondrial function in neuronal cells. Moreover, it also appears to increase the rate of oxygen consumption by mitochondria, which is very important for brain cells’ function and health.

In addition to contributing to the understanding of the disease, SHMOOSE may also be useful for detection purposes. Current studies are focusing on the level of SHMOOSE in cerebral spinal fluid (CSF) and how it changes with age, brain white matter volume and Alzheimer’s biomarkers (CSF tau). This means that one day SHMOOSE may be employed as a biomarker for the diagnosis of Alzheimer’s disease.

Why This Matters

The discovery of peptides like MOTS-c and SHMOOSE highlight the important role of mitochondria in aging, metabolism, and brain function. These microproteins may represent potential for developing new treatments for metabolic disorders, neurodegenerative diseases, and even longevity, or as I like to say, the optimization of healthspan. The better we understand how the mitochondria control the health of the cell, the more likely mitochondrial-based therapies will be developed. Are tiny peptides the key to better aging and disease prevention? It looks like science is slowly moving towards this conclusion.

Boosting Mitochondrial Health With Supplements

If you are looking for ways to support mitochondrial biogenesis (a fancy way of saying ‘help your body make more mitochondria’) there are several well researched supplements that may help.

Here are some of the top contenders:

1. Resveratrol – This polyphenol found in red wine activates the AMPK-SIRT1-PGC-1α pathway that initiates mitochondrial biogenesis.
2. Coenzyme Q10 (CoQ10) – A component of the electron transport chain, CoQ10 supports mitochondrial energy production.
3. Alpha-Lipoic Acid (ALA) – A potent antioxidant that enhances mitochondrial function and may be useful for various conditions associated with mitochondrial dysfunction.
4. L-Carnitine – Facilitates the transport of fatty acids into the mitochondria to produce energy.
5. Creatine – Well known for its benefits in high intensity exercise, creatine improves mitochondrial efficiency.
6. B-Vitamins – B3, B6, B12, and folic acid, which serve as essential cofactors in mitochondrial function.
7. Magnesium – Important in ATP production and over 300 biochemical reactions in the body including those occurring in the mitochondria.
8. Berberine – A natural product that stimulates mitochondrial biogenesis through the AMPK-SIRT1-PGC-1α pathway.
9. Epigallocatechin-3-gallate (EGCG) – An antioxidant from green tea that stimulates mitochondrial biogenesis.

These supplements vary in their effect from individual to individual, but most of them activate PGC-1α, which is the master regulator of mitochondrial biogenesis. When you are educating your patients on how they can help support mitochondria health and redox balance through supplements, check out my second book, The Redox Promise, where I discuss numerous other supplements that can benefit cellular health. Look for it!

References:
https://pmc.ncbi.nlm.nih.gov/articles/PMC4350682/
https://www.mdpi.com/2076-3921/13/5/613
https://www.nature.com/articles/s41380-022-01769-3
https://pmc.ncbi.nlm.nih.gov/articles/PMC10027624/