Cellular Energetics, ATP Production, and Mitochondrial Function
Restoring arterial pressure and oxygen saturation does not guarantee that cellular function has recovered. Oxygen must reach the cell and participate in energy production. The rate of ATP production must then meet cellular demand. A problem at any of these steps can impair organ function.
Cellular energetics explains how cells convert nutrients into usable energy. It also explains why improving circulation may not immediately restore organ function.
3.1 ATP: A Continually Renewed Supply of Usable Energy
Adenosine triphosphate, or ATP, links energy-releasing reactions to the work performed by cells. It supports muscle contraction, membrane transport, protein synthesis, and many other functions. Cells must continually regenerate ATP as they consume it.
Many cellular processes use ATP by converting it to adenosine diphosphate, or ADP, and inorganic phosphate. This reaction involves water and is called hydrolysis. Under cellular conditions, the complete reaction releases free energy. Enzymes couple that reaction to work, such as moving ions against a concentration gradient or producing muscle contraction.
The phrase “energy stored in a phosphate bond” is convenient but incomplete. Breaking a bond itself requires energy. The net energy release depends on the complete reaction and the chemical conditions in the cell.
Cells contain only a limited amount of ATP at any one time. Continued work therefore requires continued ATP production. When muscle work suddenly increases, phosphocreatine transfers a phosphate group to ADP and rapidly regenerates ATP. This helps bridge the short interval before other ATP-producing pathways increase their output. It cannot support sustained work on its own.
The sodium–potassium pump illustrates why ATP supply matters. It uses ATP to move sodium out of the cell and potassium into it. These gradients support electrical activity and help drive the transport of other substances. If ATP supply becomes inadequate, sodium can accumulate inside cells and disturb water balance and cell volume. ATP-dependent calcium handling can also fail. Rising intracellular calcium can activate processes that injure membranes and other cellular structures.
ATP concentration describes how much ATP is present. ATP production rate describes how quickly it is being regenerated. If production falls, a cell may preserve its ATP concentration by reducing its activity and using less ATP. The concentration can therefore remain satisfactory while the cell performs less work and has less capacity to respond to stress.
3.2 Glycolysis: Rapid ATP Production Outside the Mitochondria
Glycolysis converts glucose to pyruvate in the cytosol, the fluid compartment outside the cell’s membrane-bound organelles. The pathway uses ATP in its early steps and produces ATP in later steps. After subtracting the ATP used, the net gain is two ATP molecules for each glucose molecule.
ATP is formed directly by transferring phosphate from metabolic intermediates to ADP. This is called substrate-level phosphorylation. It does not require the mitochondrial electron transport chain.
Glycolysis also transfers electrons to nicotinamide adenine dinucleotide. NAD⁺ is the form available to accept electrons. After accepting them, it becomes NADH. For glycolysis to continue, NADH must give up those electrons and regenerate NAD⁺. Otherwise, the supply of NAD⁺ becomes insufficient and the pathway slows.
Oxygen is not directly consumed by glycolysis. Glycolysis can therefore produce ATP when mitochondrial oxygen use is limited. It also operates when oxygen is readily available.
Cells adjust glycolysis to their workload and hormonal signals. Adrenergic stimulation can increase glucose breakdown and ATP use during critical illness. Glycolytic activity can therefore rise even when oxygen is available. An increase in glycolysis alone does not establish tissue hypoxia.
Mature red blood cells provide an important example. They lack mitochondria and depend on glycolysis for ATP production even while carrying oxygen through the circulation. Other cells can use both glycolysis and mitochondrial pathways, with the balance changing according to their function and circumstances.
The small ATP yield of glycolysis limits what it can sustain when it becomes the main energy source. Cells with high continuous energy requirements are particularly vulnerable when mitochondrial ATP production is substantially impaired.
3.3 Mitochondria: Converting Nutrients and Oxygen Into ATP
Mitochondria use the products of nutrient metabolism to support oxidative phosphorylation. This process supplies much of the ATP required by many organs.
Mitochondria have an outer membrane and an inner membrane. The inner membrane surrounds the matrix, where many fuel-processing reactions occur. Between the two membranes lies the intermembrane space. The inner membrane contains the electron transport chain and ATP synthase. Separating these compartments allows mitochondria to build the ion gradient needed for ATP production.
The citric acid cycle, also called the tricarboxylic acid cycle, processes acetyl-CoA derived from carbohydrates, fatty acids, or some amino acids. During these reactions, electrons from nutrient-derived molecules pass to electron carriers. NAD⁺ becomes NADH, and flavin adenine dinucleotide becomes its reduced form, FADH₂. The carriers then supply electrons to the respiratory chain.
As electrons move through the electron transport chain, some of the released energy pumps hydrogen ions from the matrix into the intermembrane space. The inner membrane restricts their return. Hydrogen ions therefore accumulate on one side, producing a difference in both electrical charge and hydrogen ion concentration. Together, these differences form an electrochemical gradient.
Hydrogen ions can return to the matrix through ATP synthase. Their movement down the gradient drives changes in this enzyme that allow it to form ATP from ADP and phosphate. Electron transport thus builds the gradient, and ATP synthase uses it. Mitchell’s chemiosmotic hypothesis provided the foundational explanation for this process. 1
Oxygen accepts electrons at the end of the respiratory chain and combines with hydrogen ions to form water. Without enough oxygen, electrons cannot continue to pass through the chain at the required rate. The carriers remain reduced instead of being recycled to accept more electrons from fuel metabolism. This also limits the citric acid cycle, although the cycle itself does not directly consume oxygen.
Oxidative phosphorylation produces much more ATP from glucose than glycolysis alone. The amount varies because not all electron transport is converted into ATP synthesis. Some hydrogen ions cross back into the matrix without passing through ATP synthase. This proton leak dissipates part of the gradient. Mitochondria can therefore consume oxygen without producing a fixed amount of ATP for each unit consumed.
3.4 Entry Into Oxidative Metabolism: More Than Oxygen Availability
Pyruvate produced by glycolysis has several possible destinations. It can be converted to lactate. It can also enter mitochondria and be converted to acetyl-CoA by the pyruvate dehydrogenase complex, abbreviated PDH.
PDH provides the route from glycolytic pyruvate to acetyl-CoA and the citric acid cycle. If PDH activity falls, less pyruvate enters this route. Supplying more oxygen does not necessarily restore that enzyme activity. Oxygen availability and the ability to process pyruvate are separate requirements.
PDH needs several cofactors to function. One is derived from thiamine, or vitamin B₁. Severe thiamine deficiency can reduce the conversion of pyruvate to acetyl-CoA. More pyruvate may then be converted to lactate. This explains how thiamine deficiency can raise lactate even when oxygen delivery is adequate.
Nuzzo and colleagues measured PDH in peripheral blood mononuclear cells from patients with sepsis and healthy controls. PDH activity and quantity were lower in the sepsis group. The study supports altered metabolic regulation in human sepsis. However, findings in circulating cells cannot be assumed to quantify metabolism in the heart, liver, or kidneys. The study also did not establish that increasing PDH activity would improve clinical outcomes. 2
ATP production also requires ADP and phosphate, functioning enzymes, and an inner membrane that can maintain the gradient. Cellular work generates ADP by using ATP. That ADP helps stimulate further ATP production. When cells do less work, they produce less ADP and may consume less oxygen even though oxygen supply remains adequate.
The metabolic response to treatment therefore depends on the limiting step. Increasing oxygen delivery can help when oxygen supply is inadequate. It cannot be assumed to correct an enzyme defect, a cofactor deficiency, or damaged mitochondrial machinery.
3.5 Lactate: A Product of Metabolism With Several Explanations
When pyruvate becomes lactate, it accepts electrons from NADH. NADH becomes NAD⁺ again, allowing glycolysis to continue. This route can recycle NAD⁺ rapidly when mitochondrial pathways cannot keep up with glycolytic activity.
Lactate formation does not require oxygen to be absent. It occurs during normal metabolism and can accelerate during illness. Lactate can leave one tissue, enter another, and be converted back to pyruvate for oxidation. The liver and kidneys also use lactate to make glucose. Lactate therefore carries metabolic fuel between tissues as well as helping sustain glycolysis.
Blood lactate rises when lactate enters the circulation faster than it leaves. Production may increase, removal may decrease, or both may occur. Conversely, a falling concentration can result from reduced production as well as increased removal. Calling every fall “lactate clearance” can obscure that distinction.
James and colleagues linked epinephrine-stimulated lactate production to sodium–potassium pump activity in oxygenated rat skeletal muscle. This experimental mechanism does not quantify its contribution in human sepsis or exclude simultaneous tissue hypoxia. 3
Elevated lactate and acidosis often occur together, but they describe different findings. Lactate concentration does not measure every process that changes pH. The pyruvate-to-lactate reaction shown above consumes a hydrogen ion, but this one equation does not describe every reaction that produces or consumes hydrogen ions in the cell. Interpret bicarbonate, carbon dioxide, and other acid–base findings alongside lactate.
In a deteriorating patient, hyperlactatemia should prompt urgent assessment of oxygen delivery and perfusion. Interpretation should also consider adrenergic stimulation, liver dysfunction, seizures, drugs, and possible metabolic deficiencies. The broader discussion of oxygen transport and lactate appears in later chapters.
3.6 Oxygen Limitation, Ischemia, and Reperfusion
Hypoxemia means a low arterial oxygen tension. Tissue hypoxia means that oxygen availability is inadequate for the needs of a tissue. Ischemia means inadequate blood flow. These conditions overlap, but they describe different problems.
Ischemia can impair the delivery of both oxygen and nutrients. It can also limit the removal of metabolic products. A satisfactory arterial oxygen saturation cannot compensate for an extreme reduction in regional blood flow.
When mitochondrial oxygen availability becomes insufficient, electron transport slows and less energy is available to maintain the hydrogen ion gradient. ATP synthase then produces less ATP. Glycolysis may accelerate, but its smaller ATP yield may not meet the tissue’s needs. If ATP use continues to exceed production, membrane pumps fail, intracellular calcium can rise, and cell structures become damaged.
Restore flow and oxygen delivery when they are inadequate. Previously ischemic tissue may nevertheless remain dysfunctional after flow returns. Calcium handling may still be disturbed, and reoxygenation can generate reactive oxygen species. Together with inflammation, these processes can cause additional injury during reperfusion.
Reactive oxygen species are reactive oxygen-containing molecules. They are produced by mitochondria and other cellular systems. At controlled levels, they participate in normal signaling. Excess production, or inadequate antioxidant defenses, can damage proteins, lipids, and DNA.
This distinction prevents an overly simple interpretation of oxygen therapy. The immediate objective is to correct inadequate oxygen availability. Cellular recovery then depends on the severity and duration of injury as well as the restoration of flow. A recovered arterial pressure or saturation should not be mistaken for proof that injured tissue has already recovered.
3.7 Mitochondrial Dysfunction During Sepsis
Sepsis can disturb cellular energetics through several pathways. Regional blood flow may become inadequate. Inflammation can alter enzyme activity. Reactive oxygen and nitrogen species can affect respiratory-chain proteins. Changes in gene expression and mitochondrial turnover can alter the capacity for ATP production.
These processes can coexist. The distinction between impaired oxygen supply and impaired oxygen use is therefore not always a choice between two separate explanations.
Brealey and colleagues examined skeletal muscle biopsies from 28 patients with sepsis and nine surgical controls. Patients who subsequently died had lower muscle ATP concentrations than survivors. Respiratory-chain activity also showed associations with illness severity and biochemical measures. This study linked altered cellular energetics to clinical outcome, but it did not prove that mitochondrial dysfunction caused the deaths. Its muscle findings do not establish the energetic state of every organ. 4
The term cytopathic hypoxia describes impaired cellular oxygen use despite oxygen being available. The proposed problem lies in the cell’s ability to use oxygen for energy production. Routine blood gas and lactate measurements do not identify that intracellular limitation, so they cannot establish this diagnosis.
Central venous oxygen saturation measures how much of the sampled venous hemoglobin remains oxygenated. It can be high because oxygen delivery is high relative to demand. It can also be high when some tissues extract little oxygen or blood bypasses effective exchange. The sample does not represent every organ equally. A normal or high value therefore establishes neither normal cellular oxygen use nor mitochondrial failure.
At the bedside, persistent organ dysfunction after correction of obvious circulatory abnormalities should prompt a broad reassessment. Ongoing infection, regional ischemia, congestion, medication effects, and established tissue injury remain relevant explanations. Mitochondrial dysfunction should not become a label that ends the search for a reversible cause.
3.8 Reduced Activity, Mitochondrial Repair, and Recovery
A stressed cell may reduce protein synthesis, transport, and other activities. Doing less work lowers ATP use. If ATP production has fallen, this reduction can help preserve enough energy for essential processes. The organ may nevertheless function poorly because its cells are performing less of their usual work.
Reduced activity may contribute to organ dysfunction without immediate widespread cell death. However, preserved cell viability does not mean that the organ can perform its usual workload. It also does not establish that every reduction in function is protective.
Recovery requires cells to repair or remove damaged components. Mitochondria can divide through fission or join through fusion. These processes help redistribute contents and separate damaged material. Mitophagy removes damaged mitochondria through selective cellular recycling. Mitochondrial biogenesis produces new mitochondrial components and can help restore ATP-producing capacity. Because mitochondrial proteins depend on genes in both the nucleus and mitochondria, rebuilding requires coordinated activity in both locations.
Carré and colleagues studied muscle biopsies from 16 critically ill patients. Survival was associated with earlier activation of pathways involved in mitochondrial biogenesis. This supports the importance of the recovery response, but the study was small and observational. It did not test a treatment that stimulates biogenesis. 5
The practical implication is that recovery involves rebuilding capacity as well as correcting the initial disturbance. A patient whose shock has resolved may still have limited muscle endurance or organ reserve. Attempts to remove support must therefore consider the workload the recovering system can sustain.
This principle should not be interpreted as a reason to avoid rehabilitation or tolerate untreated dysfunction. It explains why the appropriate workload and support requirements change over time. Cellular recovery cannot be inferred from the calendar alone.
3.9 Translating Metabolic Mechanisms Into Treatment
Understanding a pathway identifies possible treatment targets. It does not establish that manipulating the pathway will benefit patients.
Thiamine provides a useful example. It is required for several metabolic enzymes, including PDH. Treating a genuine deficiency addresses a specific physiological problem. Giving thiamine to an unselected population with septic shock tests a broader and different hypothesis.
In a pilot randomized trial, Donnino and colleagues studied 88 patients with septic shock and elevated lactate. Thiamine did not significantly improve the primary outcome of lactate concentration at 24 hours in the overall study population. A deficient subgroup showed a signal of benefit, but the small subgroup cannot establish a general treatment effect. 6
TRPSS subsequently tested thiamine for renal protection in septic shock. Its primary outcome was the change in serum creatinine over the first 72 hours. That outcome did not differ significantly between groups, so the trial did not establish routine renal protection in the population studied. Patients with a clinical indication for thiamine were excluded. The result therefore does not justify withholding treatment when deficiency is suspected. 7
Providing nutrients supplies the fuels from which cells can produce ATP. If fuel is the limiting requirement, correcting that shortage can help. If an enzyme defect or mitochondrial injury limits ATP production, adding more fuel may not overcome it. Feeding decisions must therefore account for illness phase, tolerance, and metabolic complications. Nutrient delivery alone cannot be assumed to restore mitochondrial function.
The bedside priorities remain to treat the underlying illness, correct inadequate oxygen delivery, identify specific deficiencies or toxic exposures, and provide appropriate organ support. Experimental metabolic explanations should add precision to this work rather than replace it.
3.10 Applying Cellular Energetics at the Bedside
Consider an illustrative patient recovering from septic shock. Mean arterial pressure is stable on a decreasing norepinephrine dose. Capillary refill and mental status have improved. Lactate remains elevated. Urine output is still low, and the patient has received epinephrine during the preceding resuscitation.
The improving circulatory findings suggest progress, but they do not exclude a remaining perfusion problem. Regional ischemia can persist despite acceptable global measurements. Assessment should consider the source of infection, the abdomen and limbs, cardiac function, and the possibility of venous congestion.
Interpret the lactate trend alongside the improving examination. Recent epinephrine exposure may have accelerated glycolysis and lactate production. Hepatic dysfunction may be slowing lactate removal. Residual hypoperfusion can coexist with either process. A single concentration cannot show how much each contributes.
The persistent oliguria also needs an explanation. It may reflect established kidney injury, inadequate perfusion, congestion, or obstruction. Mitochondrial dysfunction is a possible part of the biology of organ injury, but it cannot be diagnosed simply because urine output has not recovered.
If the history reveals prolonged poor intake or another reason to suspect thiamine deficiency, that information changes the metabolic assessment. It identifies a potentially treatable limitation. The decision follows from the clinical context rather than from the assumption that all hyperlactatemia represents the same process.
Further fluid, vasoactive treatment, or metabolic supplementation should have a defined purpose. The response should then be assessed using the relevant physiological and clinical findings. Persistent lactate alone is insufficient to show that additional fluid will improve cellular energy production.
Trace the possible limitation in sequence. First assess whether blood delivers enough oxygen and nutrients. Then consider whether the cells can process those fuels and use oxygen to regenerate ATP. Finally, compare the likely ATP supply with the work the organ must perform. This approach keeps the physiology explicit while directing attention to reversible causes.
References
1. Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature. 1961;191:144–148. doi:10.1038/191144a0.
2. Nuzzo E, Berg KM, Andersen LW, et al. Pyruvate dehydrogenase activity is decreased in the peripheral blood mononuclear cells of patients with sepsis. A prospective observational trial. Annals of the American Thoracic Society. 2015;12(11):1662–1666. doi:10.1513/AnnalsATS.201505-267BC.
3. James JH, Wagner KR, King JK, et al. Stimulation of both aerobic glycolysis and Na+-K+-ATPase activity in skeletal muscle by epinephrine or amylin. Am J Physiol. 1999;277:E176–E186. Original experimental study.
4. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. The Lancet. 2002;360(9328):219–223. doi:10.1016/S0140-6736(02)09459-X.
5. Carré JE, Orban JC, Re L, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. American Journal of Respiratory and Critical Care Medicine. 2010;182(6):745–751. doi:10.1164/rccm.201003-0326OC.
6. Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Critical Care Medicine. 2016;44(2):360–367. doi:10.1097/CCM.0000000000001572.
7. Moskowitz A, Berg KM, Grossestreuer AV, et al. Thiamine for renal protection in septic shock (TRPSS): a randomized, placebo-controlled, clinical trial. American Journal of Respiratory and Critical Care Medicine. 2023;208(5):570–578. doi:10.1164/rccm.202301-0034OC.