Infrared Light and Mitochondria: Mechanisms, Disease Applications, and Clinical Outlook

Key points

• Core mechanism — Photobiomodulation (PBM): Infrared light in the 600–1350 nm range is primarily absorbed by mitochondrial cytochrome c oxidase (CCO). This activates the electron transport chain, increases ATP synthesis, modulates reactive oxygen species (ROS) as signaling molecules, and promotes nitric oxide (NO) release, leading to improved cellular energy metabolism, balanced oxidative stress, and better tissue oxygenation. Net outcomes include anti-inflammatory, antioxidant, and regenerative effects.
• Wavelength-dependent control of mitochondrial dynamics:
• Near-infrared (~850 nm): Upregulates fusion proteins MFN1/2, promotes mitochondrial fusion, enhances OXPHOS and fatty acid oxidation, and drives macrophage polarization toward an anti-inflammatory M2 phenotype. In mouse wound models, 850 nm at 50 J/cm² for 12 days achieved >95% healing.
• Red light (~625 nm): Upregulates the fission protein DRP1, promotes mitochondrial fission, enhances glycolysis, and skews macrophages toward a pro-inflammatory M1 phenotype, delaying resolution (same dose yielded <55% healing).
• Far-infrared: Stabilizes mitochondrial dynamics by upregulating OPA1, restores membrane potential, reduces oxidative stress, and provides neuroprotection in rat ischemic stroke (MCAO) models and oxygen-glucose-deprived neurons.
• Nervous system applications:
• Acquired brain injury (stroke, TBI): Near-infrared PBM (NIR-PBM) enhances mitochondrial function, reduces oxidative stress and neuroinflammation, and promotes synaptic repair. Clinical studies report improved cognition and reduced PTSD symptoms in TBI patients. Far-infrared reduces infarct volume and cerebral edema in ischemic stroke.
• Neurodegenerative disease: Transcranial PBM protects dopaminergic neurons in Parkinson's models, possibly via improved mitochondrial function and reduced α-synuclein aggregation.
• Cardiovascular rehabilitation: Transsternal irradiation with 810 nm near-infrared reduced infarct size by over 60% in preclinical models, raised ATP and IL-10 levels, and lowered MDA, IL-6, and TNF-α. Novel devices such as transsternal applicators and programmable transcranial helmets are under development.
• Wound healing and skin repair: Near-infrared promotes M2 macrophage polarization, angiogenesis, fibroblast proliferation, and collagen deposition, achieving >95% wound closure in murine models.
• Innovative oncology strategies:
• Mitochondria as drug carriers: A Peking University team engineered mitochondria with CRISPR/siRNA targeting PINK1 to suppress mitophagy, triggering a compensatory boost in tunneling nanotubes (TNTs), OXPHOS, and mitochondrial motility. Loaded with photosensitizer IR780, these "self-driven" mitochondria achieved deep tumor penetration, with potential applications in glioblastoma.
• Precision photothermal therapy (PTT): TPP-modified gold nanorods concentrated in mitochondria enabled the first live-cell capture of a two-stage outer-membrane rearrangement (transient fusion followed by fission). Tuning the thermal dose routed cell death through apoptosis, necroptosis, or pyroptosis, achieving precise "pan-optosis" control.
• Translational milestones and future directions:
• Historical milestones: 1960s — Hungarian researchers observed red-light hair growth; 2000s — NASA demonstrated red-light wound healing; 2020s — CCO confirmed as the key photoreceptor and mitochondrial dynamics mechanisms elucidated; 2025 — FDA approved a red-light device for dry age-related macular degeneration, and oral red-light therapy entered guidelines for preventing cancer-therapy-induced oral mucositis.
• Remaining challenges:

1. Biphasic dose response requires individualized optimization of wavelength, dose, power, duration, and frequency. 2. Most evidence is preclinical or from small clinical trials; large randomized controlled trials (RCTs) are urgently needed, especially in cardiovascular and neurological indications. 3. Photobiomodulation persists even when mitochondrial inhibitors are applied, suggesting CCO-independent mechanisms such as biophoton emission and intercellular mitochondrial communication warrant deeper study. 4. Device engineering is largely empirical; standardization of equipment and clinical guidelines is essential. 5. Combination strategies — PTT with photodynamic therapy (PDT), or light therapy with immune checkpoint inhibitors — may yield synergistic effects.

Conclusion

Infrared–mitochondria research has progressed from phenomenological observation to mechanistic dissection. Central to this progress is PBM's ability to precisely modulate mitochondrial function and, consequently, cellular metabolism, immune polarization, and fate decisions. The discovery of wavelength-dependent regulation of mitochondrial dynamics (red light promoting fission, near-infrared promoting fusion) and the novel concept of engineering mitochondria as drug carriers and delivery networks lay a solid foundation for non-invasive, precise, and efficient physical therapies. Although dose optimization, device standardization, and large-scale validation remain, the field opens a promising new frontier for neuroprotection, cardiovascular rehabilitation, and treatment of refractory tumors.