Mitochondrial Disorders: Essential Functions Beyond Energy Dynamics. Part 2
Last week, you read about mitochondrial function--the basics of energy production using the Krebs cycle and some of the different diseases associated with mitochondrial dysfunction. This Substack is focusing on other essential roles of mitochondria in the body. Although some mitochondrial disorders are inherited (which you’ll read about next week), others arise from uncontrolled free radical stress which damages these sensitive cellular organelles. This can affect your immune system, detoxification systems, and hormone balancing as well as how you fight cancer cells in the body.
Immune Balance, Immune Cell Activation, Differentiation, and Survival
Any organs in the body with high energy demands, such as muscles, the heart, brain, liver, and kidneys will be adversely affected by mitochondrial dysfunction. Immune cells also have high energy demands. T cells responsible for controlling cancer cells and intracellular infections and orchestrating our immune response to ensure we don’t develop autoimmune diseases rely on healthy mitochondria to do their job. So do the B cells that make antibodies as well as macrophages, which play a crucial role in the immune system. Macrophages act as sentinels and defenders against intracellular pathogens (i.e. Borrelia, Bartonella, Mycobacteria, viruses) while clearing away cellular debris and regulating the production of other immune cells like Natural Killer (NK) cells.
These different immune cell types rely on different metabolic pathways, and mitochondria are needed for metabolic flexibility, so they function correctly. Mitochondria are also involved in immune cell activation and differentiation, and controlled production of mitochondrial reactive oxygen species (ROS) act as signaling molecules so the immune system can do its job.
The Cell Danger Response: Danger Associated Molecular Patterns (DAMPs) and Pathogen Associated Molecular Patterns (PAMPs)
When too many free radicals are present, whether due to infection, toxins, smoking, excessive alcohol consumption, a poor diet high in sugar or processed food, or even strenuous exercise, cells can become stressed or damaged. Mitochondria then release Danger Associated Molecular Patterns or DAMPs. These consist of molecules that are normally hidden within healthy cells but become exposed or released into the extracellular environment when cells are damaged, stressed, or die. They act as “danger signals” or “alarmins” to alert the innate immune system to tissue injury or sterile inflammation (inflammation not caused by pathogens). Think of them as internal alarm bells that ring when something is wrong inside the body’s own tissues, even in the absence of an infection.
This is in contrast to PAMPs (Pathogen-Associated Molecular Patterns), which are molecules associated with microbes (like bacterial cell wall components like lipopolysaccharides or viral nucleic acids) that alert the immune system to an invading pathogen. Both DAMPs and PAMPs are important signaling molecules that trigger immune responses and inflammation, activating cells like macrophages that damage tissues if the inflammation in not kept under control.
For example, cigarette smoke acts like a DAMP, informing B cells to activate macrophages, which cause tissue damage due to excessive inflammation. When the offending agent is no longer present, B cells can secrete an anti-inflammatory cytokine (IL-10) that decreases inflammation. See below:
DAMPs are a diverse and heterogeneous group of molecules, some of which are mitochondrial proteins, nucleic acids (DNA), and mitochondrial metabolites. This explains why mitochondria play an important role in ongoing inflammation in the body. Any increase in ROS which stresses or damages cells can release mitochondrial DNA (mtDNA), mitochondrial metabolites, or mitochondrial proteins into the extracellular environment, which act as DAMPs. When these stimulate the immune system, they are recognized by specific receptors on our immune cells (and sometimes non-immune cells) called Pattern Recognition Receptors (PPRs) which turn on inflammation.
You’ve previously read how some inflammation arises from turning on NFKappa B, a switch inside a nucleus, which releases inflammatory chemokines and cytokines (TNF-alpha, IL-1, IL-6). Another inflammatory mechanism is damaged cells which release mitochondrial components like mtDNA, damaged mitochondrial membrane components (cardiolipin), or parts of our Kreb cycle that makes energy into the surrounding environment (ATP, succinate, cytochrome C) where they don’t belong. When any of these damaged mitochondrial components are found outside our cells, they act as DAMPs, which bind to receptors called toll-like receptors (TLRs), turning on inflammation.
The Inflammasome Complex: An Internal Switch Turning on Inflammation
In some cases, instead of damaged mitochondrial components acting outside our cells to turn on inflammation via TLRs, they act inside our cells. Damaged mitochondrial DNA (mtDNA) can activate inflammasomes, protein complexes inside a cell’s cytoplasm that play a crucial role in initiating inflammatory responses. When inflammasomes are activated, whether by pathogens (PAMPs) or cellular damage (DAMPs), they too will trigger the release of inflammatory cytokines and turn on cell-death pathways (called apoptosis). Apoptosis, or programmed cell death, is generally a normal and beneficial process, but it can become abnormal, particularly when influenced by inflammation. Normally, apoptosis occurs to eliminate damaged, infected, or aged cells without causing inflammation—but in inflammatory conditions, cells can undergo apoptosis at inappropriate times or in excessive amounts. This contributes to the chronic disease process.
One of the important pathways involved in the pathogenesis of acute and chronic diseases is called the NLRP3 inflammasome. NLRP3 inflammasome activation was one of the inflammatory pathways that was responsible for the increase in mortality during Covid, but aberrant inflammasome activation has also been implicated in a broad range of diseases. These include autoimmune disorders, cardiovascular diseases, cancer, diabetes, and neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease (PD). That is in part how all these diseases are intricately linked to mitochondrial dysfunction.
If you want to stay healthy and avoid chronic illness, you need to control activation of these pathways outside and inside your cells. The illustration below discusses how DAMPs, PAMPs, and their TLRs, including receptors for AGEs (advanced glycation end products, discussed in Mitochondrial Dysfunction, Part 1), turn on enzymes and inflammatory pathways leading to persistent inflammation and in some cases, sepsis and death.
The Role of Mitochondria in Detoxification
Mitochondria are also essential players in detoxifying chemicals, toxins, and medications from your body. They provide energy for detoxification pathways and participate in neutralizing and eliminating harmful substances. Although mitochondria are major sites of ROS production, they also scavenge free radicals and have antioxidant enzymes to control excessive free radical production. The 3 primary antioxidant enzymes--superoxide dismutase (SOD), glutathione peroxidase (GPX), and peroxiredoxin 3 (PRX3) --are all found in mitochondria. One of your most dangerous and potent free radicals, superoxide radicals, produced during the process of making ATP, is converted into a less toxic substance by a mitochondrial enzyme called superoxide dismutase (SOD). This enzyme requires both manganese and copper to function properly, along with other antioxidants (which is why a healthy diet with the right vitamins and minerals and cofactors is essential for health). SOD converts superoxide radicals into hydrogen peroxide (H2O2), and then glutathione (GSH) peroxidase comes along and converts the H2O2 into H2O (water) using glutathione. Mitochondria have a high concentration of reduced glutathione to neutralize these free radicals, and that is why if glutathione is used up in the process of dealing with chronic infections or toxins, our mitochondria suffer. Most of this detoxification process takes place in the liver, in the endoplasmic reticulum, and is part of our phase 1 and phase 2 liver detoxification pathways. See below:
Mitochondria Are Needed for Other Important Metabolic Pathways, and They Regulate Cell Death
Apart from mitochondria’s role in our immune system and detoxification, they play an essential role in fatty acid oxidation and ketogenesis (other ways of producing energy), amino acid metabolism, getting rid of urea from our body, as well as regulating cell death.
Fatty acids provide energy to the mitochondria, which are shuttled inside the cell using the carnitine shuttle, which utilizes L-carnitine as a transporter. The mitochondria also produce energy via ketogenesis, where fatty acids are converted in Acetyl CoA (see the first image in this Substack), which is one of the first steps in energy production in the Krebs cycle. This energy production, under normal circumstances with adequate oxygen, takes place via a process called oxidative phosphorylation (OX PHOS). When oxygen is limited or when rapid ATP production is needed, then an alternative metabolic pathway called glycolysis is used. Glycolysis is a less efficient way of producing energy, but becomes more prominent in situations like hypoxia (low oxygen) or in rapidly contracting muscle cells where demand for ATP exceeds what OXPHOS can quickly supply. This takes place during heavy exercise (think marathon runners) where both aerobic and eventually anaerobic metabolism is needed to provide adequate energy. Under normal conditions with enough oxygen, glucose transforms into pyruvate which can directly enter the Krebs cycle and produce 32 ATP (30-34 depending on the efficiency of the electron chain). When inadequate oxygen is present, instead of going into the Krebs cycle, pyruvate produces lactate (the feeling of muscle heaviness and fatigue during heavy exercise is due to lactate accumulation), which then goes on to produce 2 ATP (not a very efficient form of energy production, but fills in the gap). This is called anaerobic glycolysis (making energy from sugar without oxygen).
There is, however, an exception to this rule in one major disease process. Cancer cells, even in the presence of oxygen, often utilize glycolysis, in a phenomenon known as aerobic glycolysis (called the Warburg effect) to meet their energy needs, while normal cells can utilize both glucose and ketone bodies. By limiting glucose availability and increasing ketone bodies, this approach can potentially lead to reduced proliferation and (potentially) cancer cell death. By reducing glucose and insulin levels, ketogenic diets also can inhibit signaling pathways that promote cancer growth and proliferation, such as the mTOR pathway (mammalian target of rapamycin pathway) discussed here:
Other Important Mitochondrial Metabolic Functions
You also need mitochondria for amino acid metabolism, and for the urea cycle in the liver. Amino acids can be used for energy production by being converted into molecules that enter the Krebs cycle (TCA cycle) or by being converted into glucose through gluconeogenesis in the liver. If you have inherited mitochondrial disorders, one of the ways of diagnosing them is measuring certain amino acids and their ratios in the blood.
The urea cycle is also an important mitochondrial metabolic process that removes excess nitrogen, a byproduct of protein breakdown, from the body. It converts toxic ammonia into urea, a less toxic substance that can be excreted in urine. This detoxification process is crucial for preventing ammonia from accumulating and causing harm, particularly to the brain. Again, in inherited mitochondrial disorders, where these pathways don’t work properly, by measuring plasma lactate/pyruvate ratios, plasma/urine amino acids, and plasma ammonia/carnitine ratios (i.e., the biochemical pathways mentioned above) these disorders can be diagnosed.
You may be wondering why I took you through a brief Biochemistry 101 course, but it’s the only way to understand how to diagnose (and in some cases treat) both inherited and acquired mitochondrial disorders.
Hopefully, you now have a much better understanding of why supporting mitochondrial function is so important! Part 3 will discuss mitochondrial disorders in more detail, and help you determine whether mitochondrial dysfunction is playing a role in your symptoms.