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Oxidative phosphorylation is the mitochondrial process by which cells convert oxygen and nutrients into ATP – the molecule that powers virtually every energy-requiring biological process. It accounts for approximately 90% of cellular ATP production, making it the dominant engine of cell function rather than a supporting mechanism. In skin biology, its dual output of energy and reactive oxygen species makes it central to both normal tissue maintenance and age-related decline. In the context of GLP-1 receptor agonist therapy, it is the specific process the Langer et al. (2026) proteomics data shows being upregulated in skeletal muscle – with implications for how fatigue resolves, and why, as treatment continues.

Oxidative phosphorylation is the process by which mitochondria use the controlled transfer of electrons down a series of protein complexes – collectively called the electron transport chain – to generate a proton gradient across the inner mitochondrial membrane, which then drives the synthesis of adenosine triphosphate. It is responsible for approximately 90% of the ATP produced in cells that have access to oxygen, supplying the energy currency required for protein synthesis, membrane transport, DNA repair, cell signalling, and structural maintenance. ^[5]

The Electron Transport Chain

The electron transport chain consists of five multiprotein complexes embedded in the inner mitochondrial membrane. Electrons enter the chain from NADH (produced in glycolysis and the Krebs cycle) at Complex I, or from FADH₂ at Complex II. They then pass through the lipid-soluble carrier ubiquinone to Complex III, via cytochrome c to Complex IV, where they combine with oxygen and protons to form water. Each transfer step pumps protons from the mitochondrial matrix into the intermembrane space, building the electrochemical gradient that drives ATP synthase (Complex V). ^[11]

The efficiency of this chain – how much ATP is produced per unit of oxygen consumed – declines measurably with age, and the consequences extend well beyond reduced energy. The Baltimore Longitudinal Study of Ageing (published in Age and Ageing, 2026, DOI: 10.1093/ageing/afag022; cross-sectional study, n=649, mean age 64.5 years, kPCr measured via ³¹P magnetic resonance spectroscopy of the quadriceps) found that a 40-year-old with low mitochondrial OxPhos capacity showed the same peak oxygen consumption as a 60-year-old of the same sex with high OxPhos capacity – a gap that places poor mitochondrial function at the heart of what distinguishes biological age from chronological age. The association was most pronounced in younger and middle-aged adults, attenuating substantially in those over seventy. ^[9]

The Dual Nature: Energy and Oxidative Stress

OXPHOS has a feature that is rarely explained in accessible health content but is central to understanding skin ageing: the same process that generates ATP also produces the body’s primary source of endogenous reactive oxygen species. Electrons leaking from Complexes I and III reduce molecular oxygen to superoxide radical rather than passing cleanly to the next carrier. This superoxide dismutates to hydrogen peroxide, and in the presence of iron undergoes Fenton chemistry to produce the highly reactive hydroxyl radical. ^[5]

Under normal conditions in young, healthy cells, the rate of electron leakage is low and well-managed by mitochondrial and cellular antioxidant systems. The first line of defence against superoxide leakage is superoxide dismutase 2 (SOD2), the mitochondrial isoform, which converts superoxide to the less reactive hydrogen peroxide. SOD2 expression declines with age in at least some human tissue types – proteomic studies of human cardiac biopsies demonstrate significantly lower SOD2 in older compared with younger donors (Barcena de Arellano et al., 2019), and removal of Sod2 from mouse epidermis reproduces the senescent cell accumulation characteristic of naturally aged skin (Velarde et al., 2012) – meaning the cell’s capacity to neutralise mitochondrial ROS at source falls precisely when the chain is producing more of it. ^{[2] [10]} As the electron transport chain becomes less efficient with age – as the protein complexes accumulate oxidative damage, as mitochondrial DNA acquires deletions, as the chain becomes “leakier” – the dynamics reverse. ROS production increases precisely as ATP output falls. ^[6] The aged cell gets less energy and more oxidative damage simultaneously, and the two compound each other: ROS damage the OXPHOS complexes further, reducing efficiency, generating more ROS. In skin tissue, this plays out as decreased ATP available for fibroblast collagen synthesis, increased oxidative modification of structural proteins, and upregulation of MMPs that dismantle existing matrix. ^[8]

Clinical Pearl The ROS produced by an inefficient mitochondrial chain are not the same as those from UV radiation – they arise internally, continuously, and from the same process that generates cellular energy. Managing external oxidative stress while the mitochondrial chain becomes increasingly leaky addresses only part of the picture.

OXPHOS and the Fibroblast Metabolic Switch

Skin fibroblasts are particularly dependent on mitochondrial function because collagen synthesis is energetically expensive – triple helix assembly, prolyl hydroxylation, and extracellular secretion each require sustained ATP supply. Their metabolic identity is characterised by OXPHOS predominance when functional.

When mitochondrial dysfunction progresses past a threshold, fibroblasts undergo a metabolic shift from OXPHOS to glycolysis. This shift is not simply an energy adaptation – it is the upstream event in the transition to a senescent phenotype. A 2023 study published in Aging Cell (Song et al.) found that suppression of carnitine acetyltransferase – a key enzyme supplying acetyl groups for OXPHOS – in human dermal fibroblasts caused mitochondrial dysfunction, a loss of OXPHOS capacity, and triggered cytosolic release of mitochondrial DNA. That mtDNA release activated the cGAS-STING pathway, which in turn drove NF-κB signalling and the secretion of pro-inflammatory SASP factors – the same inflammatory mediators that characterise senescent skin. ^[7]

The practical implication is that a fibroblast’s metabolic state – OXPHOS-predominant or glycolysis-predominant – predicts its synthetic behaviour. OXPHOS-active fibroblasts produce collagen and maintain extracellular matrix; OXPHOS-depleted fibroblasts secrete the enzymes that degrade it. This directly connects to the mechanisms described in the glycation-related skin changes and fibroblast senescence entities elsewhere in this knowledge base, as both conditions drive fibroblasts toward the glycolytic, pro-inflammatory state. There is also a reinforcing feedback loop worth noting: fibroblasts that have shifted to glycolysis-predominant metabolism generate an elevated flux of glycolytic intermediates, driving increased production of methylglyoxal – the reactive dicarbonyl byproduct of glycolysis that is among the most potent endogenous precursors of advanced glycation end-products. ^[1] The same AGEs that result cross-link collagen and further impair fibroblast function, creating a positive feedback cycle: OXPHOS decline drives the metabolic shift, the metabolic shift accelerates methylglyoxal-driven glycation, and glycation compounds the structural and functional damage. ^[12]

The AMPK Feedback Loop

The cell does not accept OXPHOS decline passively. When output from the electron transport chain falls, the ratio of AMP to ATP in the cell rises – and this ratio is continuously monitored by AMPK (AMP-activated protein kinase), the cell’s master energy sensor. Rising AMP:ATP activates AMPK, which in turn triggers mitochondrial biogenesis through PGC-1α, the transcriptional co-activator that coordinates the production of new mitochondrial proteins. This is the same pathway that exercise activates through ATP depletion, and the same pathway that caloric restriction engages through nutrient-sensing signals. All three routes, exercise, caloric restriction, and GLP-1 receptor activation, share mitochondrial biogenesis via AMPK/PGC-1α as a common downstream outcome, though they reach it through different upstream mechanisms.

For clients on Mounjaro, this convergence has clinical relevance. GLP-1 receptor activation generates the AMPK signal through one pathway; regular movement generates it through a second, independent pathway. Combining the two does not simply add the effects – it engages the same biogenesis machinery through two distinct inputs simultaneously, compounding the upregulation of OXPHOS capacity. This is the mechanistic rationale behind recommending movement as GI symptoms settle during Mounjaro treatment, and it connects directly to the AMPK entity in this knowledge base. (See also: the SIRT1 connection below, where NAD⁺ availability regulates a complementary arm of the same PGC-1α activation network.)

GLP-1 Receptor Activation and the Electron Transport Chain

The most specific evidence linking GLP-1 receptor agonist therapy to OXPHOS comes from the proteomics arm of Langer et al. (2026), published in Cell Reports Medicine. When skeletal muscle protein profiles of semaglutide-treated mice were compared with pair-fed controls eating identical amounts of food, the semaglutide group showed significantly elevated expression of four mitochondrial proteins: NDUFB8 (a subunit of Complex I), UQCRB (Complex III), COX5A (Complex IV), and SIRT5, a mitochondrial deacylase that regulates ETC function and broader mitochondrial metabolism through desuccinylation of multiple target proteins across the electron transport chain. ^[4]

The fact that the comparator group was calorically matched is the critical point. This is not a starvation response or a consequence of eating less. The upregulation of OXPHOS protein expression is driven by GLP-1 receptor activation itself, through mechanisms not yet fully characterised. Taken together, these four proteins represent three of the five electron transport chain complexes – a pattern suggesting the effect is not incidental to one pathway but distributed across the chain.

What this means practically is that GLP-1 receptor agonists may actively improve mitochondrial energy-generation capacity in muscle tissue, rather than simply reducing energy input through appetite suppression. The early fatigue associated with Mounjaro treatment arises from caloric deficit, electrolyte depletion, and GI side effects. The mitochondrial story is the other end of the arc: as treatment continues, evidence suggests the cells responsible for physical activity are being primed to produce and use energy more efficiently. ^[4]

It should be noted that the Langer et al. findings are pre-clinical in the proteomics arm specifically. The human component of the study (n=10, 12 weeks) established maintenance of functional muscle capacity but did not measure OXPHOS protein expression directly. Whether the same mitochondrial upregulation occurs in human skeletal muscle awaits confirmation in larger, purpose-designed studies. This uncertainty is compounded by conflicting findings in the wider literature: a 2025 systematic review examining GLP-1 receptor agonist effects on mitochondrial health found results across studies to be inconsistent, underscoring that the direction of the Langer et al. data, whilst promising, should not be presented as established.

A related arm of this biology involves SIRT1 and the cellular NAD⁺ supply. SIRT1, a sirtuin deacetylase that operates outside the mitochondria but shares the same NAD⁺ dependency as its mitochondrial relatives, activates PGC-1α through deacetylation – the same transcriptional co-activator that drives mitochondrial biogenesis. This link explains why NAD⁺ availability is mechanistically upstream of OXPHOS capacity: as cellular NAD⁺ declines with age, SIRT1 activity falls, PGC-1α activation decreases, and the stimulus for mitochondrial biogenesis weakens, even when the AMPK signal is present. This is the mechanistic basis for the clinical interest in NAD⁺ precursor supplementation (NMN, NR) in the context of mitochondrial ageing: not as a direct energy source, but as substrate for the sirtuin-mediated activation of biogenesis. (See the Sirtuin page in this knowledge base for detail on the full sirtuin family and their individual targets.)

OXPHOS and Photobiomodulation – a Direct Mechanistic Connection

LED photobiomodulation using red (630–660 nm) and near-infrared (810–850 nm) wavelengths is proposed to act directly on the electron transport chain, though the full mechanistic picture remains an active area of research. According to the leading mechanistic hypothesis, the primary proposed chromophore – the molecule absorbing the photon energy – is cytochrome c oxidase (Complex IV). The Hamblin 2018 review ^[3] notes that alternative mechanisms, including light-sensitive ion channel activation, may also contribute. Within the NO photodissociation model: at physiological concentrations, nitric oxide competes with oxygen for the binuclear centre of CCO, acting as a reversible competitive inhibitor of the enzyme. When cells are under metabolic stress, hypoxia, or ageing-related decline, inhibitory NO concentrations increase, reducing OXPHOS throughput. Red and near-infrared photons photodissociate this NO from the CCO binding site, restoring oxygen’s access and increasing electron transfer rate – which increases the proton gradient, which drives more ATP synthesis from Complex V. ^[3]

The mechanism carries an important implication for treatment selection and outcome expectation: photobiomodulation operates by restoring OXPHOS efficiency rather than by directly stimulating any growth factor pathway. Its effects are therefore greatest when OXPHOS is most impaired – in aged, UV-damaged, metabolically stressed, or post-procedure recovering tissue. A young, well-nourished fibroblast operating near peak OXPHOS efficiency will show less dramatic response to LED treatment than an aged or compromised one, because the inhibitory NO bottleneck is smaller to begin with. ^[3]