Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy

Journal of Complementary Therapies in Health ISSN 2975-9323 |eISSN 2975-9552 Journal of Complementary Therapies in Health 2026:4(1). doi:10.5281/zenodo.17941463 institutoptc.com/journal-complementary-therapies Clinical cases Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. Oren Upekkha Ziv Ram1,2* and Eyal Levi Lidor1. 1 OLA Laser Acupuncture, Mafra, Portugal; 2 OLA Laser Acupuncture Academy, Portugal. * Correspondence: [email protected] Abstract Background: Photobiomodulation (PBM) is a non-thermal light therapy that enhances mitochondrial efficiency by targeting cytochrome-c oxidase, thereby increasing ATP production and reducing oxidative stress. Stem cells rely heavily on these mitochondrial metabolic transitions to determine lineage commitment, migration, and reparative function. This article reviews the bioenergetic rationale for combining PBM with stem-cell therapy and explores the potential of this synergistic approach to treat conditions characterised by autonomic dysregulation, chronic inflammation, and impaired cellular repair. Methods: A narrative critical review was conducted to synthesise literature regarding PBM mechanisms, stem-cell bioenergetics, and marrow-directed phototherapy. Furthermore, a clinical case series evaluated the practical application of PBM-assisted autologous stem-cell therapy in three patients. PBM was applied to the proximal tibial bone marrow to stimulate progenitor mobilisation, as well as to autonomic regulatory sites. Outcomes were assessed using validated measures. Results: Mechanistically, PBM was found to improve mitochondrial oxygen utilisation and support stem-cell viability, paracrine signalling, and systemic mobilisation. Clinically, the combined therapy yielded significant improvements across all cases. The vasomotor case demonstrated reduced hot flash frequency and normalised sleep continuity. The fibromyalgia patient reported a reduction in pain intensity (VAS decreased from 8 to 4) and improved functional capacity. The anxiety case showed a reduction in GAD-7 scores from moderate (15) to mild (6), indicating improved autonomic stability. Conclusion: PBM and stem-cell therapy likely operate in synergy through shared mitochondrial, immune-regulatory, and neuroendocrine pathways. PBM acts as a metabolic primer, creating an optimal microenvironment for stem-cell function and systemic repair. While these early findings are encouraging for treating complex conditions involving autonomic dysfunction, further controlled trials and standardised dosing protocols are necessary to fully validate this therapeutic strategy. Keywords: Photobiomodulation; Stem-cell Therapy; Mitochondrial Bioenergetics; Autonomic Dysregulation; Synergistic Therapy. 1. Introduction PBM refers to the therapeutic use of low-irradiance red and nearinfrared (NIR) light to modulate cellular activity in ways that enhance physiological function without producing thermal tissue damage. The therapeutic potential of light in biology was first proposed in the late 19th century, but modern PBM research emerged following Mester’s work in Citation: Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. Journal of Complementary Therapies in Health. 2026;4(1) 10.5281/zenodo.17941463 Academic Editor: Jorge Rodrigues Received: 8 November 2025 Reviewed: 10 December 2025 Revised: 14 December 2025 Accepted: 15 December 2025 Published: 15 December 2025 Publisher’s Note: IPTC stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: ©2026 by the authors. Submitted for open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Journal of Complementary Therapies in Health 2026: 4(1). 2 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 the 1960s demonstrating accelerated wound healing and hair growth in animals exposed to low-power laser light. Since then, PBM has developed into a clinically and mechanistically validated therapeutic modality with applications in wound healing, neurorehabilitation, pain modulation, and regenerative medicine 1-5. The primary molecular target of PBM is cytochrome-c oxidase in the mitochondrial electron transport chain. This enzyme catalyses the final step of oxidative phosphorylation, transferring electrons to molecular oxygen. Under conditions of cellular stress, hypoxia, inflammation, or oxidative imbalance, nitric oxide may competitively bind to cytochrome-c oxidase, displacing oxygen and reducing ATP production. PBM has been shown to photodissociate nitric oxide from this binding site, restoring oxygen utilisation and electron transfer efficiency. The resulting increase in mitochondrial membrane potential leads to enhanced ATP synthesis, improved oxygen consumption efficiency, and controlled reactive oxygen species (ROS) signalling that acts as a transcriptional regulator rather than as a cytotoxic agent 6-8. These mitochondrial changes initiate a cascade of cellular and systemic effects including modulation of redox balance, stabilisation of calcium signalling, activation of prosurvival transcription factors, increased synthesis of growth factors, and normalisation of inflammatory mediator release. PBM therefore influences not only energy metabolism but also cell phenotype, tissue repair processes, and immune system behaviour 9-11. Stem cells occupy a central role in tissue repair and systemic homeostasis, and their functional behaviour is tightly regulated by mitochondrial metabolic state. Pluripotent and undifferentiated stem cells rely primarily on glycolysis, while lineage commitment and maturation require a shift toward oxidative phosphorylation 12-16. This bioenergetic switch is not merely a reflection of cellular metabolic needs; it is a regulatory checkpoint that determines whether stem cells proliferate, migrate, differentiate, or adopt a trophic signalling role within their microenvironment 17-19. Studies demonstrate that PBM enhances stem-cell viability, proliferation capacity, and resistance to oxidative stress by improving mitochondrial respiratory efficiency, supporting membrane potential stability, and modulating intracellular signalling pathways involved in cell fate determination 20-23. PBM also influences the secretome of mesenchymal stem cells (MSCs), increasing the release of anti-inflammatory cytokines, neurotrophic factors, and angiogenic signals that mediate many therapeutic effects traditionally attributed to cell engraftment 21,24,25. In vivo, PBM may further act on the regenerative niche, modifying the extracellular environment in ways that promote stem-cell retention, homing, and functional performance. Moreover, skeletal regions containing abundant red marrow, such as the proximal tibia, serve as accessible and responsive sites for PBM delivery. Research suggests that PBM applied over the tibial bone marrow can stimulate the mobilisation of endogenous progenitor cells into systemic circulation, reflecting not only local mitochondrial activation but also a coordinated systemic regenerative response 26-28. Taken together, these mechanisms provide a coherent biological rationale for combining PBM with stem-cell–based therapies. PBM may enhance stem-cell treatment outcomes by optimising cellular metabolism, reducing inflammatory interference, and improving both local tissue environments and systemic immune-regulatory conditions. The integration of these approaches represents a promising direction for regenerative medicine, particularly in conditions characterised by mitochondrial dysfunction, chronic inflammation, neuroimmune dysregulation, and reduced adaptive repair capacity 29-33. 2. Mitochondrial Mechanisms of Photobiomodulation The therapeutic effects of PBM originate primarily at the level of the mitochondrion, which serves as a central regulator of cellular respiration, redox balance, calcium handling, and apoptosis. Because these processes influence cell survival, immune activation, and repair capacity, even small improvements in mitochondrial function can have clinically significant systemic consequences 31,34-36. Journal of Complementary Therapies in Health 2026: 4(1). 3 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 2.1. Cytochrome-c Oxidase as the Primary Photoacceptor Cytochrome-c oxidase (Complex IV) is the principal photoacceptor for red and nearinfrared light in the electron transport chain 37,38. Under hypoxic or inflammatory conditions, nitric oxide (NO) can bind to cytochrome-c oxidase and block oxygen utilisation, leading to impaired ATP production². PBM photodissociates NO from this binding site, restoring electron flow, mitochondrial membrane potential, and ATP synthesis 39-41. 2.2. Regulation of Redox Signaling and Controlled ROS Production While excessive ROS can cause oxidative damage, low-level ROS is a physiologic signalling molecule involved in adaptive cellular communication. PBM increases mitochondrial ROS only within controlled ranges, generating a redox-signalling response rather than oxidative stress 2,42-44³. This signalling activates transcriptional regulatory pathways including: • Nrf2 – Upregulation of endogenous antioxidant defences 45. • NF-κB – Modulated and not suppressed inflammatory signalling 46. • CREB – Enhancement of neuronal plasticity and cellular repair 47. This controlled redox modulation contributes to reduced inflammatory cytokine expression and enhanced tissue recovery 48. 2.3. Modulation of Calcium Homeostasis Mitochondria regulate intracellular calcium in coordination with the endoplasmic reticulum. PBM stabilises the mitochondrial membrane potential (ΔΨm), increasing mitochondrial calcium buffering capacity and improving intracellular calcium rhythm regulation 49-53. These effects protect neurons from excitotoxicity, stabilise synaptic signalling, reduce inflammatory cytokine secretion, and promote balanced cellular metabolism. This is directly relevant in nociplastic pain, sleep dysregulation, and autonomic imbalance, where calcium-signalling abnormalities are central to symptom persistence. 2.4. ATP-Driven Support for Repair, Immunity, and Neuroendocrine Regulation ATP availability determines whether cells maintain function or engage in repair. When ATP is scarce, cells adopt a conservation mode. By restoring mitochondrial ATP production, PBM shifts cells toward pro-repair and pro-regeneration metabolic states. This results in improved protein synthesis and extracellular matrix remodelling, enhanced angiogenesis and microcirculation, restoration of immune tolerance patterns, and stabilisation of hypothalamic autonomic regulation centres 54,55 Thus, PBM acts not only locally but also systemically through mitochondrial–neuroendocrine coupling. 2.5. Implications for Stem-Cell Biology Stem cells exhibit metabolic plasticity in which mitochondrial state determines fate (Table 1). Table 1. Mitochondrial State and corresponding Stem-Cell Behaviour 56-61. Mitochondrial State Stem-Cell Behaviour Low oxidative phosphorylation; glycolysis dominant Self-renewal / pluripotency Higher oxidative phosphorylation, stable ΔΨm Directed differentiation and reparative signalling Journal of Complementary Therapies in Health 2026: 4(1). 4 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 Therefore, PBM may support stem-cell function by: • Increasing mitochondrial ATP output 62; • Reducing oxidative stress susceptibility 63,64; • Enhancing survival and migration to injury sites 65,66; • Increasing release of trophic anti-inflammatory and angiogenic factors 67,68. This suggests the reasons for the positive clinical synergy observed when PBM is combined with stem-cell therapy. 3. Rationale for Photobiomodulation Targeting the Tibial Bone Marrow The proximal tibia contains a high concentration of active red bone marrow, which houses both mesenchymal stem cells (MSCs) and hematopoietic stem/progenitor cells (HSPCs). Unlike deeper marrow reservoirs such as the pelvis or vertebral bodies, the tibial metaphysis has relatively thin cortical bone, low adipose interference, and close proximity to the skin surface. This anatomical configuration allows red and near-infrared wavelengths to penetrate adequately into the marrow cavity when delivered with appropriate irradiance and contact coupling 69,70. Bone marrow is not a static storage site for progenitor cells; it is a dynamic immunometabolic organ responsible for cellular regeneration, immune coordination, and inflammatory adaptation. The marrow microenvironment includes a network of stromal cells, endothelial niches, sympathetic innervation, and metabolic gradients that collectively determine stem-cell activation, quiescence, and release into systemic circulation 7173. 3.1. Evidence for PBM-Induced Stem-Cell Mobilisation Preclinical studies have demonstrated that PBM directed to bone marrow activates intrinsic regenerative pathways 74, accelerated tissue repair following cardiac and neural injury 75-77, and enhanced survival and differentiation of MSCs in vivo 78,79. More recent clinical data provide translational support. A human pilot trial reported that PBM applied to the proximal tibia produced a measurable increase in circulating CD34+ progenitor cells, with peak mobilisation occurring 2–4 days post-treatment, indicating a coordinated biological release rather than transient photostimulation 80. 3.2. Systemic Immunoregulatory Effects of Marrow-Directed PBM Bone marrow stimulation influences not only cell quantity but also immune phenotype and inflammatory signalling. PBM to marrow regions has been associated with: • Mobilisation of regenerative mononuclear cell populations 81-83; • Shift toward M2 (pro-repair) macrophage phenotype expression 84; • Reduction of pro-inflammatory cytokines including TNF-α and IL-6 2; • Improvement of vagal–sympathetic balance and neuroimmune responsiveness 85,86. This systemic signalling likely arises from coordinated interplay between mitochondrial metabolic restoration, endothelial nitric oxide regulation, anti-inflammatory paracrine factor release by MSCs, and autonomic regulation of marrow immune activity 87-90. 3.3. Why the Tibial Site is Clinically Advantageous The tibial marrow site offers several practical advantages in therapeutic settings (Table 2). Journal of Complementary Therapies in Health 2026: 4(1). 5 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 Table 2. Clinical considerations for the benefits of using the tibial site. Clinical Consideration Justification Biological accessibility Thin cortical bone enables therapeutic light penetration with predictable dose delivery. High progenitor density Contains both MSC and HSPC populations relevant to systemic regeneration. Consistent anatomy Provides reproducible and standardised patient positioning. Comfort & safety Minimally invasive, does not require imaging or invasive access. Systemic therapeutic reach Allows body-wide modulation through marrow-derived cell signalling. PBM applied to the proximal tibia penetrates cortical bone and reaches the red marrow, where it enhances mitochondrial function in mesenchymal and hematopoietic stem cells. Improved metabolic signaling promotes CD34+ progenitor mobilisation, M2 macrophage polarisation, and regenerative cytokine modulation, enabling systemic therapeutic effects from a localised treatment site 91,92 (Figure 1). Figure 1. Tibial Bone Marrow PBM Mechanism 4. Clinical Synergy of Photobiomodulation and Stem-Cell Therapy The therapeutic interaction between PBM and stem cell therapy arises from their complementary effects on mitochondrial metabolism, immune regulation, tissue repair, and neuroendocrine balance. PBM does not replace the function of transplanted or mobilised stem cells. Rather, it creates a metabolic and microenvironmental context in which endogenous or administered stem cells can survive, signal, and integrate more effectively 65,78,93-95. Stem cells require adequate mitochondrial function to transition between quiescence, proliferation, and differentiation. Mitochondrial bioenergetics therefore determine the reparative capacity of stem-cell populations. PBM enhances electron transport chain efficiency at cytochrome-c oxidase, restores ATP production, and regulates nitric-oxide availability, which improves mitochondrial performance in both stem cells and the host tissue milieu 36,96-98. Journal of Complementary Therapies in Health 2026: 4(1). 6 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 At the immunological level, PBM induces a regulatory shift characterised by reduced proinflammatory cytokines (IL-1β, IL-6, TNF-α) and increased anti-inflammatory mediators (IL-10, TGF-β). This environment supports mesenchymal stem-cell driven modulation of macrophage phenotype and promotes regenerative M2 polarisation. The combined result is reduction of inflammatory burden and support of tissue remodelling in chronic and nociplastic conditions 97,99-103. PBM also promotes angiogenesis through upregulation of VEGF and stabilisation of endothelial cell metabolism. Enhanced microvascular perfusion improves the trophic signalling efficiency of stem cells, particularly in tissues with autonomic dysregulation, metabolic exhaustion, or chronic inflammation 82. Finally, PBM influences neuroendocrine centres including the hypothalamus, locus coeruleus, and brainstem autonomic nuclei. By improving cellular energy availability and modulating inflammatory signalling that reaches the central nervous system, PBM contributes to stabilisation of sleep cycles, vasomotor tone, pain perception, and affective regulation 104-107. This integrated framework explains the multimodal improvements observed in sleep stability, vasomotor symptom reduction, nociplastic pain reduction, and reduced anxiety in the clinical cases presented. 4.1. Autonomic Nervous System Modulation and Sleep Physiology Chronic pain, anxiety, and vasomotor instability share a characteristic pattern of sympathetic dominance with insufficient parasympathetic recovery. This dysregulated autonomic tone is reinforced by inflammatory cytokine signalling and disrupted hypothalamic feedback loops. PBM improves mitochondrial efficiency in limbic, hypothalamic, and brainstem autonomic circuits, increasing inhibitory neurotransmission and vagal parasympathetic tone. These effects contribute to reduced hyperarousal, improved sleep consolidation, and stabilisation of thermoregulatory control 108-113. Stem-cell derived immunomodulatory and neurotrophic factors introduce longerterm stabilisation of autonomic activity by decreasing microglial-driven cytokine release and promoting a shift toward regenerative M2 macrophage states. This reduces the neuroimmune drivers of sympathetic overactivation often implicated in nociplastic pain, vasomotor symptoms, and anxiety-related physiological patterns. Sleep architecture depends on adequate mitochondrial ATP availability. Deep nonREM sleep requires synchronised low-energy neuronal states. When ATP is insufficient, cortical networks maintain light, fragmented, or hypervigilant sleep. PBM enhances oxidative phosphorylation and restores mitochondrial coupling, supporting metabolic transitions required for deep, continuous sleep cycles 114-116. 5. Clinical Case Series 5.1. Methods Three clinical cases were documented to illustrate the functional interaction between PBM and autologous stem-cell therapy in endocrine, nociplastic pain, and anxiety-related presentations. Low-burden, validated scales were used to standardise symptom tracking and reduce subjective interpretation bias: • Hot Flash Score (HFS) and Pittsburgh Sleep Quality Index (PSQI) for vasomotor and sleep symptoms; • Visual Analogue Scale (VAS) and Revised Fibromyalgia Impact Questionnaire • (FIQ-R) for nociplastic pain and functional status; • Generalised Anxiety Disorder 7-item scale (GAD-7) for anxiety severity. Treatments included autologous stem-cell therapy and PBM directed to the proximal tibial bone marrow, consistent with strategies shown to mobilise mesenchymal and hematopoietic progenitors into systemic circulation 117. PBM was also applied to symptom- Journal of Complementary Therapies in Health 2026: 4(1). 7 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 relevant regulatory regions (e.g., cervical sympathetic chain, thoracic paraspinals, abdomen, auricular autonomic points) depending on presentation. Treatment intervals were once weekly. Photobiomodulation Parameters PBM was delivered in contact mode to the proximal tibia to target active red marrow. Approximately 1000 J was delivered per tibial site per session. This approach is consistent with marrow-directed PBM protocols designed to influence stem-cell mobilisation and systemic immunoregulatory signaling²³. Additional PBM was applied to autonomic and regional pain-modulating sites as clinically indicated. Frequency Modulation Protocol Frequency-modulated PBM followed clinical neuromodulation practices derived from Nogier and Bahr. Two primary modulation frequencies were used: • 2442 Hz, applied to support stem-cell metabolic activation and trophic signalling; • 4625 Hz, applied to support autonomic stabilisation and self-regulatory recovery processes. These frequencies are not presented as disease-specific codes but as structured bioenergetics modulation domains influencing cellular redox tone and neuroimmune balance. Rationale for Frequency Selection Mesenchymal stem cells depend on controlled redox signalling and mitochondrial respiration to transition between quiescence, proliferation, and differentiation¹⁶. PBM delivered at frequencies in the 2–3 kHz range has been associated with increased mitochondrial coupling, enhanced oxidative phosphorylation efficiency, and increased release of paracrine repair mediators such as SDF-1, VEGF, and IL-10 118-120. This mechanistic profile aligns with the regenerative orientation attributed to 2442 Hz. Autonomic dysregulation plays a central role in vasomotor instability, nociplastic pain, and anxiety disorders 121,122. PBM frequencies in the 4–5 kHz domain have been associated with enhanced vagal tone, reduced sympathetic drive, and modulation of hypothalamic-limbic circuits linked to sleep and affective stability. This corresponds to the clinical use of 4625 Hz to promote systemic regulatory recalibration 123-125. These frequency selections are reported to support transparency and reproducibility. The parameters remain exploratory and require controlled clinical trials. 5.2. Case 1: Vasomotor Instability and Sleep Disruption A 50-year-old woman presented with new-onset hot flashes, night-time thermal dysregulation, and fragmented sleep. Baseline assessment demonstrated elevated Hot Flash Score and PSQI, consistent with impaired sleep quality and hypothalamic autonomic instability. Following the first session of PBM-directed stem-cell therapy, the patient reported her first uninterrupted night of sleep in several weeks. By the fifth session, the Hot Flash Score demonstrated a marked reduction in both frequency and intensity of vasomotor episodes, and PSQI scores indicated clinically meaningful improvement in sleep continuity and depth. These clinical changes align with mechanistic models in which PBM enhances mitochondrial coupling and redox stability within hypothalamic thermoregulatory centres, reducing erratic autonomic discharge. Stem cell derived paracrine signalling likely further reduced neuroinflammatory tone and contributed to stabilisation of hypothalamicpitui- Journal of Complementary Therapies in Health 2026: 4(1). 8 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 tary feedback dynamics. Notably, improvement in sleep quality preceded vasomotor normalisation, consistent with evidence that restoration of non-REM metabolic quieting is a prerequisite for neuroendocrine homeostasis. 5.3. Case 2: Fibromyalgia and Nociplastic Pain A patient with chronic widespread musculoskeletal pain, fatigue, and sensory hypersensitivity consistent with fibromyalgia underwent PBM-supported autologous stem cell therapy. At baseline, VAS pain score was approximately 8/10 with reduced functional capacity reflected in FIQ-R scores. After three treatments, VAS pain decreased to approximately 4/10, and FIQ-R functional domains improved, indicating enhanced activity tolerance and decreased nociceptive amplification. This pattern aligns with PBM-mediated microglial downregulation, reduced cytokine-driven central sensitisation, and restoration of mitochondrial efficiency in dorsal horn and limbic circuits. Stem cell derived immunoregulatory factors further supported sustained reduction in inflammatory signalling and facilitated repair of neuromuscular microenvironments. 5.4. Case 3: Anxiety and Autonomic Dysregulation A patient with generalised anxiety and episodic autonomic reactivity was evaluated using GAD-7, with a baseline score of ~15, consistent with moderate anxiety severity. After five treatments, GAD-7 decreased to ~6, within the mild range, accompanied by the patient’s report of improved emotional regulation, reduced somatic tension, and a subjective sense of restored internal coherence. Observed changes are consistent with PBM-mediated enhancement of limbic inhibitory neurotransmission and improved vagal tone, combined with stem-cell driven attenuation of neuroinflammatory signalling, resulting in recalibration of autonomic balance. 5.5. Interpretation Across all three cases, the observed improvements appear to reflect shared mitochondrial–neuroimmune regulatory mechanisms rather than isolated symptomatic effects. PBM functioned as a metabolic primer, enhancing mitochondrial oxidative phosphorylation, restoring ATP availability, and modulating nitric-oxide and redox-mediated cellular signalling. These changes support normalisation of hypothalamic and limbic autonomic centres, reduction of sympathetic hyperactivation, and stabilisation of sleep regulation and thermoregulatory control. Stem-cell therapy contributed a longer-duration immunological and reparative influence by releasing paracrine mediators that reduce microglial-driven cytokine signalling, promote M2 macrophage polarisation, and support neural–endocrine tissue resilience. The resulting environment favours recovery of neurovascular tone, nociceptive modulation, and restoration of homeostatic autonomic patterns associated with emotional and pain regulation. The consistency of improvement across conditions as diverse as vasomotor dysregulation, nociplastic pain, and anxiety suggests involvement of a common physiological convergence point: improved mitochondrial energy status, reduced neuroinflammation, and rebalancing of autonomic nervous system dynamics. This integrated pattern aligns with contemporary models in which endocrine instability, chronic pain, and anxiety share overlapping bioenergetic and neuroimmune dysregulation pathways rather than being independent disease entities. The clinical trends observed here therefore support the rationale for combined PBM and stem-cell approaches aimed at restoring systemic regulatory stability, rather than targeting isolated symptoms. Journal of Complementary Therapies in Health 2026: 4(1). 9 of 16 Ram O. U. Z., Lidor E. L. Mitochondrial Bioenergetics and Systemic Regeneration: A Narrative Review and Clinical Case Series of Photobiomodulation-Assisted Stem-Cell Therapy. doi:10.5281/zenodo.17941463 6. Limitations The clinical observations presented in this case series are uncontrolled and exploratory, and therefore cannot establish causality. Improvements may reflect the combined influence of PBM, stem-cell therapy, placebo responsiveness, natural symptom fluctuation, or concurrent lifestyle factors. Controlled studies with randomisation, comparator groups, and blinded outcome assessment are required to determine the magnitude and specificity of the therapeutic effects. PBM delivered to bone marrow presents dosimetric challenges. Variations in tibial cortical bone thickness, marrow vascularity, and individual tissue optical properties may influence the penetration and bioavailability of near-infrared light. Standardised dosing models for marrow-targeted PBM are not yet established, and the 1000 J per tibial site protocol used here should be interpreted as a clinically derived approach, not a validated standard. Similarly, stem-cell preparations are heterogeneous. Differences in cell source, concentration, preparation technique, viability, and paracrine secretome composition may influence outcomes and limit reproducibility across clinical settings. The cases described here used autologous preparations, which reduce immunological risk but do not control for biological variability. Outcome measures relied on self-reported and functional scales (HFS, PSQI, VAS, FIQ-R, GAD-7). While these instruments are validated, they may still be influenced by expectancy, context, and regression to the mean. Future studies should incorporate objective physiological biomarkers, such as heart rate variability for autonomic balance, cytokine and inflammatory panel assays, and mitochondrial functional indices. The sample size was small and spanned heterogeneous diagnostic categories. While this diversity supports exploration of shared regulatory mechanisms, it limits conclusions regarding condition-specific responsiveness, optimal dosing frequency, and treatment sequencing. These limitations underscore the need for prospective, protocol-standardised, multicentre trials evaluating the combined application of PBM and stem cell therapy, including clear mechanistic endpoints and long-term follow-up. 7. Conclusion The synergistic integration of PBM and stem cell therapy appears to restore systemic homeostasis by optimising shared mitochondrial and neuroimmune pathways. By addressing the bioenergetic roots of autonomic dysregulation, this combined strategy offers a promising, mechanism-based approach for treating complex, multi-system disorders. Author statement: Conceptualisation: O.U.Z.R.; Methodology: O.U.Z.R., and E.L.L.; Investigation: O.U.Z.R.; Visualisation: E.L.L.; Writing – Original Draft: O.U.Z.R.; Writing – Review and Editing: O.U.Z.R., and E.L.L. All authors have read and agreed to the published version of the manuscript. Acknowledgements: We extend our sincere thanks to the practitioners and patients who contributed their clinical observations, insights and feedback throughout this work. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of Interest: Oren Ram is an authorised distributor of RG Laser devices in Portugal and Spain and provides professional training in laser therapy. Eyal Levi Lidor declares no conflicts of interest. Institutional Review Board Statement: Not applicable. Journal of Complementary Therapies in Health 2026: 4(1). 16 of 16 Ram O. U. Z., Lidor E. L. 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