A long time ago I looked into the functions of the VCP gene. The core functions are as below:
Core Functions of VCP (as summarised by ChatGPT)
- Protein Degradation & Quality Control
- Extracts misfolded or damaged proteins from membranes or complexes so they can be degraded by the ubiquitin–proteasome system (UPS).
- Works in ER-associated degradation (ERAD), where it helps remove misfolded proteins from the endoplasmic reticulum.
- Autophagy
- Regulates autophagosome maturation and clearance.
- Important in removing defective organelles (like mitochondria via mitophagy).
- DNA Damage Response
- Helps in the repair of DNA double-strand breaks.
- Involved in chromatin remodeling to allow repair machinery access.
- Cell Cycle Regulation
- Participates in spindle disassembly during mitosis.
- Helps control progression through different cell cycle stages.
- Organelle Maintenance
- Involved in Golgi and ER membrane fusion and reassembly after mitosis.
- Maintains mitochondrial homeostasis.
- Stress Response
- Acts as a “segregase,” using ATP to remodel protein complexes during stress.
- Plays a role in clearing stress granules.
Okay great, we all gotta watch those Golgi and ER membrane fusions :S But what does this all mean in relation to VCP-ALS and the symptoms I experience, especially fatigue and exercise intolerance?
Several years ago I began a “mitochondrial cocktail” after research led me to suspect that my mitochondria (which everyone in the know seems to call the “powerhouse of the cell”) were likely somehow, somewhat dysfunctional.
This consisted of CoEnzymeQ10, B-Vitamins, L-Carnetine, Alpha Lipoic Acid and Creatine.
Nothing much really changed except perhaps a year of two I bought a brand of CoEnzymeQ10 that had twice the amount i.e 200mg vs 100mg. A few weeks later I realised that my energy was better and, as per usual I wracked my brain trying to figure out why. Thankfully I landed on the CoQ10. Since then I have been upping my daily dosage as my disease has progressed, and as energy demands require.
I am now on 1200mg daily which is quite a high (not to mention expensive) dose. I will up this to 1500mg+ before, during and after a day that requires more energy e.g. a day trip.
I strongly believe I would be bed-bound and far more progressed if I did not take this little miracle supplement. I do educate people I come across on CoQ10, it is widely well-tolerated with no real contraindications, but of course, chat to your team if you are considering supplementing. No one seems to have quite the same positive response as I have.
VCP, ALS, and Fatigue – diving deeper into processes at play
1. Mitochondria Dysfunction
- Normal role of VCP: regulates mitochondrial quality control through mitophagy (removal of defective mitochondria) and keeps the fusion/fission balance needed for energy.
- With VCP mutations (like my R155H): damaged mitochondria accumulate, produce less ATP and more ROS (reactive oxygen species – more on this below), leading to muscle fatigue, exercise intolerance, and “energy crashes.”
This could well explain why Coenzyme Q10 helps me so much: it acts as a powerful antioxidant. It supports the electron transport chain (ETC) inside mitochondria which means a boost in ATP availability, and reduction in oxidative stress. It also stabilises mitochondrial membranes.
2. Oxidative Stress & Sun Sensitivity
- Sunlight (UV exposure) increases oxidative stress.
- With impaired VCP function, cells are less able to clear damaged mitochondria and proteins.
- This pushes the body over its already fragile energy threshold, already vulnerable mitochondria cannot keep up, leading to disproportionate fatigue after sun exposure.
- This can result in more muscle fatigue, brain fog / buzzing sensation, feeling “energy poisoned” after sunlight exposure
I used to be an absolute sun junkie. I’m part Indonesian and have always felt I look and feel better with tanned skin and after sun-exposure (I know, I know). In the last two years I’ve noticed my tolerance to the heat and sun exposure isn’t what it used to be. Even 15 minutes in the winter sun here in Queensland this year can leave me feeling noticeably fatigued. Good for my skin, not so good for me and my love for the sun! 🙁
3. Protein Quality Control & Energy Drain
- Misfolded proteins that aren’t cleared properly (because of defective VCP) create cellular stress.
- Cells burn extra ATP trying to manage this, leaving less energy for muscles and brain function.
- This creates a constant background energy drain.
4. Neuro-Muscular Transmission
- VCP dysfunction disrupts synaptic vesicle recycling and motor neuron health.
- Neuromuscular junctions become “energy-poor,” so even small activity feels exhausting.
Free Radicals and Oxidative Stress
I want to touch on oxidative stress and free radicals here, as I think it’s a real kicker in regard to the fatigue I have experienced for decades:
Free radicals and other oxidants have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. Free radicals are molecules with unpaired electrons, making them highly reactive and unstable. Free radicals are the products of normal cellular metabolism. The odd number of electron(s) of a free radical makes it unstable, short lived and highly reactive. Because of their high reactivity, they seek electrons from other compounds to attain stability. Thus the attacked molecule loses its electron and becomes a free radical itself, beginning a chain reaction cascade which damages cells. For example, free radical attacks on lipids can disrupt cell membranes, on proteins can cause misfolding, and on DNA can lead to mutations. If not neutralised, the chain reaction continues and accumulates harm.
A specific and important category of free radicals is reactive oxygen species (ROS). These are oxygen-containing molecules that play crucial roles in both normal cellular processes and disease development. At low levels, ROS can play useful roles in cell signaling and immune defense. However, when they accumulate in excess, they contribute to oxidative stress, which damages cellular components. Oxidative stress refers to an imbalance between ROS and antioxidants in the body, leading to potential cellular damage and various health issues.
The free radicals induced oxidative stress has been reported to be involved in several diseased conditions such as diabetes mellitus, neurodegenerative disorders (Amyotrophic Lateral Sclerosis-ALS, Parkinson’s disease-PD, Alzheimer’s disease-AD and Multiple sclerosis-MS), cardiovascular diseases (atherosclerosis and hypertension), respiratory diseases (asthma), cataract development, rheumatoid arthritis and in various cancers (colorectal, prostate, breast, lung, bladder cancers).
Free radicals are produced both endogenously (inside the body) and through exogenous (external) sources. Within the body, they form as byproducts of normal processes such as mitochondrial energy production, where small amounts of electrons “leak” from the electron transport chain. Immune cells also deliberately produce ROS to kill pathogens, and certain enzymes (such as xanthine oxidase or nitric oxide synthase) generate them during normal metabolism. Inflammation itself is another major internal source. Externally, free radicals can be triggered by ultraviolet (UV) radiation, pollution, cigarette smoke, alcohol, heavy metals, toxins, and ionising radiation such as X-rays.
TL;DR: free radicals are unstable molecules that cause a domino effect of damage by taking electrons from other molecules, turning them into radicals themselves. Reactive oxygen species (ROS) are the most relevant biologically, being produced both naturally inside our cells and from environmental exposures. The body keeps this in check with antioxidants, which can safely donate electrons and break the damaging chain reactions.
Sources: (Oxidative Stress: Causes, Symptoms & Treatment, What is oxidative stress? Effects on the body and how to reduce, https://pmc.ncbi.nlm.nih.gov/articles/PMC4310837/