Mitochondria often struggle in insulin resistance not because they are broken, but because there are fewer of them trying to process too much incoming fuel. Exercise and improved metabolic health remain the most effective ways to build healthier mitochondria, while supplements may provide additional—but smaller—benefits.

Summary: In this mini-lecture, Ben explains why mitochondria have become one of the most talked-about topics in health while separating scientific evidence from popular hype. He begins by reviewing how mitochondria convert the energy stored in carbohydrates, fats, and ketones into ATP, the usable energy that powers virtually every function in the body. Along the way, he explains concepts such as glycolysis, the Krebs cycle, the electron transport system, coupling versus uncoupling, and the production of reactive oxygen species.

Ben then examines what happens in insulin resistance and type 2 diabetes. Rather than concluding that mitochondria are "broken," he explains that the evidence points to a different problem: people with insulin resistance generally have fewer mitochondria, more fragmented mitochondrial networks, and an excessive fuel load. As glucose and fatty acids arrive faster than the mitochondria can process them, byproducts such as lactate and acylcarnitines begin to accumulate, signaling a mismatch between fuel supply and mitochondrial capacity.

The lecture also reviews current approaches to measuring mitochondrial health, including fasting lactate, the lactate-to-pyruvate ratio, and newer biomarkers such as GDF15 and FGF21. Dr. Bikman discusses several popular mitochondrial interventions—including methylene blue, urolithin A, CoQ10, red-light therapy, and cold exposure—highlighting where human evidence is promising and where it remains limited.

The central message is that no supplement outperforms the fundamentals. Exercise consistently increases mitochondrial number and function while improving insulin sensitivity, and lowering carbohydrate intake reduces the fuel burden placed on mitochondria. Together, these strategies address the root problem more effectively than relying on supplements alone.

::: spoiler generated summary

Mitochondrial health and fuel capacity

• Mitochondria are central to cellular fuel handling and oxidative stress, so the current attention is partly warranted, but measurement is largely missing; clinical mitochondrial tests were built for rare inherited disease, not ordinary insulin resistance.
• The measurement gap is filled by methylene blue, urolithin A, red and near-infrared light, cold exposure, and other mitochondrial interventions, several of which have human evidence.
• In insulin resistance and type 2 diabetes, too much glucose and fat can arrive for the available mitochondrial capacity. Exercise builds capacity, while lower incoming fuel, insulin, and blood glucose help prevent overload.

How mitochondria process fuel

• Mitochondrion is singular and mitochondria is plural. Every human cell except the red blood cell contains mitochondria, whose main job is converting chemical energy in food or stored fat into usable cellular energy.
• Glycolysis occurs in the cytosol outside mitochondria, splitting one six-carbon glucose into two three-carbon pyruvate molecules and making a little ATP without oxygen.
• Pyruvate enters mitochondria and becomes acetyl-CoA; fats reach acetyl-CoA through beta oxidation, and the ketone beta-hydroxybutyrate can also become acetyl-CoA. These fuels converge and can compete at a common metabolic destination.
• The Krebs or citric acid cycle strips electrons from acetyl-CoA and loads NAD into NADH; NAD-focused products such as NR and NMN target this electron-carrying system.
• NADH delivers electrons to the respiratory or electron transport system in the inner mitochondrial membrane. Oxygen is the final electron acceptor and combines with hydrogen to form metabolic water, so oxygen consumption tracks electron flow.
• Energy released by electron flow is used to make ATP for contraction, nerve impulses, and other cellular work.
• Mitochondrial respiration can be coupled to ATP production or uncoupled toward heat production. Neither is inherently good or bad; brown fat deliberately uncouples mitochondria to make heat.
• Electron transport is imperfect, so some electrons leak and generate reactive oxygen species such as hydrogen peroxide. Low amounts can signal useful adaptations, while excess can damage proteins, membranes, and DNA; hydrogen peroxide relative to oxygen use is informative about oxidative stress.
• Mitochondria continually divide and fuse. The balance of fission and fusion determines mitochondrial morphology and whether the cell has a connected network or many small fragments.

What changes in insulin resistance and type 2 diabetes

• Human thigh-muscle biopsies have respiratory-system activity highest in lean insulin-sensitive people, lower in obese but still insulin-sensitive people, and lowest in type 2 diabetes; electron microscopy in the same work found mitochondria roughly one-third smaller in the obese and diabetic groups. [1]
• A separate analysis found a major loss of subsarcolemmal mitochondria, the population just beneath the muscle-cell membrane and heavily involved in fuel burning, with the diabetic group reduced to about one-seventh of the lean insulin-sensitive level. [2]
• Whole-tissue oxygen consumption can fall simply because tissue contains fewer mitochondria. When respiration is normalized to mitochondrial content, lean, obese, and diabetic groups no longer differ in respiratory capacity per mitochondrion, indicating that reduced capacity can reflect fewer mitochondria and normal individual organelles. [3]
• Network structure matters: connected mitochondria can share contents, distribute fuel, and dilute damage across a larger pool, while isolated fragments lose that buffer.
• MFN2, a protein required for mitochondrial fusion, is reduced in skeletal muscle with obesity and type 2 diabetes, inversely related to BMI, and directly related to insulin sensitivity; this fits the smaller, more fragmented mitochondrial morphology. [4]
• Ceramides accumulate in muscle with obesity and insulin resistance. [5] Ceramide exposure in the lab rapidly forced mitochondrial fission, lowered oxygen consumption, and increased hydrogen peroxide production. [6]
• The resulting problem is not necessarily broken mitochondrial machinery. A supply-capacity mismatch can consist of less mitochondrial mass, greater fragmentation, and more fuel arriving than the network can fully process.

Fuel overflow: lactate, acylcarnitines, and insulin

• When glycolysis makes pyruvate faster than mitochondria can take it in and burn it, excess pyruvate becomes lactate. Resting fasting lactate therefore carries information about mitochondrial capacity outside exercise.
• In a large community case-cohort analysis, fasting lactate rose with fasting glucose and insulin, and the highest lactate quartile had roughly twice the diabetes risk of the lowest even after adjustment for usual risk factors. [7]
• Fat has a parallel overflow signal. When fatty acids enter faster than beta oxidation can finish them, partially processed intermediates leave as acylcarnitines; people with type 2 diabetes have a pattern consistent with incomplete fat oxidation. [8]
• Insulin determines the incoming fuel mix. Hyperinsulinemia drives glucose into cells and suppresses fat oxidation [9], while insulin-resistant fat cells release excess fatty acids into blood.
• Muscle can therefore receive glucose and fatty acids simultaneously while high insulin inhibits beta oxidation. Both fuels compete for limited mitochondrial processing, leaving neither fully burned.

Measuring mitochondrial function

• Clinical mitochondrial testing was designed for rare inherited mitochondrial diseases, not ordinary insulin-resistant people, so it does not provide a validated routine measure of mitochondrial capacity in this population. [10]
• Fasting lactate is simple but imprecise because exercise, prolonged tourniquet use, medications, and impaired blood flow can raise it. [11]
• The lactate-to-pyruvate ratio reflects the NADH-to-NAD redox balance and electron traffic. A respiratory-chain block raises the ratio, while an upstream mitochondrial-entry problem can raise both lactate and pyruvate with a normal ratio; pyruvate instability also makes sample handling critical. [11]
• In children with confirmed mitochondrial disorders compared with other neuromuscular disease and healthy controls, the lactate-to-pyruvate ratio was the weakest discriminator; GDF15 and FGF21 were much stronger, with GDF15 giving the highest discrimination. [12]
• These markers were built around rare congenital disease, and there are not enough data for validated testing in ordinary metabolic dysfunction. An individual's own trajectory is more useful than comparisons across people or laboratories.

Interventions aimed at mitochondria

• Methylene blue can carry electrons past earlier respiratory complexes. In a randomized double-blind placebo-controlled study of 26 healthy adults, one low oral dose increased brain activity in attention and memory regions and produced 7% more correct memory-retrieval responses; metabolic outcomes were not measured. [13]
• Urolithin A activates mitophagy. In a four-month trial of adults aged 65 to 90, it improved muscle endurance at two months and shifted plasma biomarkers favorably, but six-minute walk distance did not differ from placebo. [14]
• A separate four-month trial in middle-aged adults found roughly 12% greater muscle strength and lower plasma acylcarnitines with urolithin A. [15]
• CoQ10 carries electrons from complexes I and II toward complex III. An umbrella review found lower fasting glucose with supplementation, while fasting insulin and HbA1c changes were statistically significant by some analyses but much more modest in real-world magnitude. [16]
• Red and near-infrared light can be absorbed by cytochrome-c oxidase, the final respiratory complex; human work using strong near-infrared stimulation found measurable activation and up-regulation of this complex. [17]
• Cold exposure raises PGC-1alpha, a master regulator of mitochondrial biogenesis. Human muscle biopsies after cold-water immersion showed about a sixfold rise three hours later, and pairing cold exposure with exercise amplified the exercise effect. [18]
• These interventions can improve electron flow, add cofactors, activate mitophagy, or increase capacity, but they do not necessarily reduce the amount of fuel arriving at mitochondria, so fuel overload can remain.

Exercise, substrate control, and ketones

• Exercise is the most reliable stimulus for increasing mitochondrial content in human skeletal muscle. In overweight older adults, calorie-restriction weight loss and exercise both improved insulin sensitivity, but only exercise increased mitochondrial content, electron-transport proteins, and fatty-acid oxidation in muscle biopsies. [19]
• Reducing dietary carbohydrate lowers glycolytic flux and pressure toward lactate accumulation; lowering insulin through carbohydrate restriction restores fat burning so glucose and fat are not both held in the queue at the same time.
• When carbohydrate and insulin fall enough, the liver makes ketones. Beta-hydroxybutyrate is more than a fuel and changes mitochondrial behavior in a tissue-dependent way.
• Beta-hydroxybutyrate increased mitochondrial respiration in fat without increasing ATP, producing uncoupling. Human adipose biopsies in ketosis used about 130% more oxygen than those from people not in ketosis. [20]
• In skeletal muscle, beta-hydroxybutyrate had the opposite coupling effect: it tightened the link between respiration and ATP production and lowered hydrogen peroxide production. [21]

The practical hierarchy

• In insulin resistance and type 2 diabetes, mitochondrial mass can fall while substrate delivery rises; lactate is the glucose-side overflow signal and acylcarnitines are the parallel fat-side signal that capacity is being reached.
• Exercise is best because it increases mitochondrial number and helps control fuel load. Methylene blue, urolithin A, red light, cold exposure, and other additions can help, but they are additions to exercise, not substitutes for it.

References

1. [13:39] Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes — https://doi.org/10.2337/diabetes.51.10.2944
2. [14:29] Deficiency of Subsarcolemmal Mitochondria in Obesity and Type 2 Diabetes — https://doi.org/10.2337/diabetes.54.1.8
3. [15:55] Increased mitochondrial substrate sensitivity in skeletal muscle of patients with type 2 diabetes — https://doi.org/10.1007/s00125-011-2098-4
4. [17:07] Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6 — https://doi.org/10.2337/diabetes.54.9.2685
5. [18:13] Ceramide content is increased in skeletal muscle from obese insulin-resistant humans — https://doi.org/10.2337/diabetes.53.1.25
6. [18:18] Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle — https://doi.org/10.1042/BJ20130807
7. [20:24] Lactate and Risk of Incident Diabetes in a Case-Cohort of the Atherosclerosis Risk in Communities (ARIC) Study — https://doi.org/10.1371/journal.pone.0055113
8. [21:33] Plasma Acylcarnitine Profiles Suggest Incomplete Long-Chain Fatty Acid β-Oxidation and Altered Tricarboxylic Acid Cycle Activity in Type 2 Diabetic African-American Women — https://doi.org/10.3945/jn.108.103754
9. [22:18] Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans — https://doi.org/10.1152/ajpendo.1990.258.6.E923
10. [24:02] Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society — https://doi.org/10.1038/gim.2014.177
11. [24:34] The in-depth evaluation of suspected mitochondrial disease — https://doi.org/10.1016/j.ymgme.2007.11.018
12. [26:23] Circulating FGF21 and GDF15 as Biomarkers for Screening, Diagnosis, and Severity Assessment of Primary Mitochondrial Disorders in Children — https://doi.org/10.3389/fped.2022.851534
13. [28:52] Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain — https://doi.org/10.1148/radiol.2016152893
14. [29:49] Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial — https://doi.org/10.1001/jamanetworkopen.2021.44279
15. [30:18] Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults — https://doi.org/10.1016/j.xcrm.2022.100633
16. [30:55] Effects of Coenzyme Q10 Supplementation on Glycemic Control Biomarkers: An Umbrella Review of Meta-Analyses of Randomised Controlled Trials — https://doi.org/10.1002/edm2.70182
17. [31:59] Interplay between up-regulation of cytochrome-c-oxidase and hemoglobin oxygenation induced by near-infrared laser — https://doi.org/10.1038/srep30540
18. [32:34] Passive and post-exercise cold-water immersion augments PGC-1α and VEGF expression in human skeletal muscle — https://doi.org/10.1007/s00421-016-3480-1
19. [34:53] Calorie Restriction-induced Weight Loss and Exercise Have Differential Effects on Skeletal Muscle Mitochondria Despite Similar Effects on Insulin Sensitivity — https://doi.org/10.1093/gerona/glw328
20. [36:17] Ketones Elicit Distinct Alterations in Adipose Mitochondrial Bioenergetics — https://doi.org/10.3390/ijms21176255
21. [36:57] β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle — https://doi.org/10.3390/ijms19082247 :::