Daily Value
Daily Value brings science out of the lab and into daily life. Hosted by Dr. William Wallace, each short, research-driven episode explores how nutrients, supplements, and metabolism influence how we think, move, and age. It’s evidence-based, concise, and designed to make you smarter about what fuels you.
Daily Value
Creatine’s Role in Mitochondria is Bigger Than You Thought
Creatine’s story has been far too small for its biology. Most people still see it as a supplement for strength or cognitive performance, but its most important work happens inside the mitochondria.
In this episode, we explore a side of creatine few people talk about: how it may function as mitochondrial medicine. We’ll break down 3 distinct ways creatine acts in and supports the mitochondria; roles that could reshape how we think about energy, resilience, and cellular health. And beyond that, how creatine may be one of the few molecules that can both diagnose and treat mitochondrial dysfunction.
00:00 Understanding Mitochondrial Dysfunction
00:43 Introduction to Creatine's Role
01:16 Mitochondrial Dysfunction Explained
01:56 Creatine as a Theranostic Agent
02:57 Mechanisms of Creatine in Mitochondria
04:09 Therapeutic Roles of Creatine
05:22 Redox Control and Antioxidant Properties
06:27 Conclusion: The Unique Power of Creatine
PMID: 40948982
Mitochondrial dysfunction is bland for nearly every condition we can name fatigue, neurodegeneration, metabolic disease, even aging itself. Yet, despite how often the term is used, it remains vague and hard to measure. Few molecules sit at the intersection of diagnosis and therapy, compounds that can both reveal dysfunction and help correct it. But one does. Inside the mitochondria, it doesn't just buffer energy, it signals when that system is failing. It can stabilize, restore, and maybe even reveal disease before symptoms appear. Most still see it as a performance supplement, whether for brain or muscle, but in reality, it may be one of the first true theronostic agents in mitochondrial medicine. I'm your host, William Wallace, and this is Daily Value. For as much as we've been inundated with research and marketing around creatine lately, its story has been far too small for its biology. Everyone knows it as the gold standard supplement for strength, and it's gaining recognition for its impact on cognitive performance. But its most important function happens at a level that almost no one is talking about. Inside the mitochondria, mitochondria produce more than 90% of the body's ATP. When that system falters, fatigue, inflammation, and degeneration set in. Yet what we call mitochondrial dysfunction is an umbrella term that doesn't tell us where or why things go wrong. It could mean one of three things. One, a failure in energy transfer, two, a loss of membrane stability, or three, an imbalance and oxidative control, each capable of disrupting the entire system. And that's where creatine enters the picture. Inside the mitochondria, it doesn't just serve as an energy reserve, it acts as a stabilizing molecule, a redox buffer, and potentially a measurable indicator of mitochondrial health. Recent literature has reframed creatine as a mitochondrial targeted therognostic, meaning it functions both as a therapy and as a diagnostic tool for disorders of cellular energy. On the diagnostic side, it's been suggested that creatine levels in plasma, saliva, urine, and tissue reflect a bioenergetic status of the mitochondria. Low systemic creatine often parallels low mitochondrial reserve, and researchers are now exploring whether creatine depletion and loading protocols could serve as functional tests of mitochondrial capacity, essentially a stress test for cellular energy systems. In mitochondrial and cephalomyopathies and other oxidative phosphorylation disorders, creatine concentrations measured by magnetic resonant spectroscopy closely track with disease severity and with how well patients respond to therapy. If things continue to play out this way, that makes it one of the few molecules that can both report on mitochondrial dysfunction and also be used to treat it. Therapeutically creatine acts through several defined mechanisms inside the mitochondria. The first way is through its stabilizing of the mitochondrial membrane. Inside the mitochondria, the enzyme mitochondrial creatine kinase, this is the enzyme that attaches a phosphate to free creatine to form phosphocreatine, binds to a lipid called cardiolipin. Cardiolipin is a structural lipid of the inner mitochondrial membrane where ATP is produced and accounts for 20% of all lipids in that membrane. Cardiolipin anchors complexes 3 through 5 of the electron transport chain in place. It helps keep them stable. The mitochondrial creatin kinase, cardiolipin complex is needed to remain intact to preserve the electrochemical potential of the mitochondria itself. When creatine is present, mitochondrial creatine kinase can continue transferring phosphate groups efficiently, and the membrane remains intact even under stress. Without creatine, that coupling fails. ATP production drops, the membrane depolarizes, and the mitochondria become more prone to apoptosis. In simple terms, creatine helps the power plant hold its shape under stress, which leads us to the second therapeutic role of creatine for mitochondria, and that is preventing catastrophic failure through mitochondrial permeability transition pore, or MPTP as it's shortened to. Under conditions of calcium overload or high oxidative stress, this pore opens and out of it leaks something called cytochrome C. This is an electron courier of the electron transport chain. When cytochrome C escapes this transition pore, the mitochondria lose their charge. That's a signal that triggers programmed cell death. Creatine helps keep the mitochondrial permeability transition pore closed by doing what we talked about a minute ago, preserving the mitochondrial membrane potential and maintaining adequate phosphocreatine levels around the pore complex. Studies show that creatine supplemented cells resist calcium-induced swelling and membrane rupture. That means that under stress, when this pore is likely to open and leak out energy, creatine helps keep it closed. This protective effect is significant. It means creatine doesn't just make cells more efficient, it keeps them alive during energy crisis, delaying or preventing the point where mitochondrial collapse becomes irreversible. The next mechanism is redox control. Creatine helps reduce the buildup of reactive oxygen species, the damaging byproducts of energy metabolism. It does this in two ways. First, indirectly by stabilizing ATP levels so the electron transport chain runs smoothly and doesn't leak electrons that form superoxide radicals. And second, by conserving a compound called NADPH, the molecule used to regenerate the body's primary antioxidant, or one of them, glutathione. The last mechanism is through creatine's ability to act as a direct and an indirect antioxidant in mitochondria. NADPH is a compound that is needed to recycle glutathione in our bodies. When the mitochondria are stressed, NADPH is often consumed just to maintain ATP. When creatine is present to relieve that burden by handling the energy buffering itself, NADPH is then available for glutathione recycling. Thus, creatine acts as an indirect antioxidant because its presence allows the true and powerful antioxidants to be made. Taken together, creatine's actions inside the mitochondria, stabilizing membranes, reducing oxidative stress, and keeping the permeability transition port closed, restore the most fundamental property of the cell, energetic stability. Supplementation has been shown to restore bioenergetic buffering, improving how efficiently cells generate and distribute ATP under stress. It also enhances mitochondrial resilience in both muscle and brain, helping neurons, myocytes, and other high-energy tissues recover from oxidative and metabolic strain. On the diagnostic side, measurable creatine levels in plasma saliva or tissues may soon serve as a biomarker of mitochondrial health, reflecting how much energetic reserve remains. That dual capacity to both reveal dysfunction and correct it is what makes creatine unique among many nutrients. Creatine doesn't just support performance in your muscles and your brain, it protects the engines of life themselves. Thank you for joining me today on Daily Value. Until next time. Stay healthy.
