Mitochondrial Bioenergetic Approach to Restore Veteran Vitality: A Feasibility Pilot

Omowunmi Osinubi, MD, MSc, MBA, FRCA, ABIHM, IFM-CP; Steven Greer, MS, EP-C; Pauline McManus, BSN, RN, COHN-S; Carrie J. Carlson, DO, FAAFP, IFMCP, ABOIM; Elijah Sacra, FMCHC CPT, E-RYT 200; Clarissa A. Kussin, FMCHC, CNHP, E-RYT 500; Helena Chandler, PhD; Kari Haws, PhD

Omowunmi Osinubi, MD, MSc, MBA, FRCA, ABIHM, IFM-CP, War-Related Illness and Injury Study Center – VA New Jersey Health Care System (WRIISC-VANJ), East Orange, New Jersey, USA; Rutgers School of Public Health, Rutgers Biomedical and Health Sciences, Piscataway, New Jersey, USA. Steven Greer, MS, EP-C; Pauline McManus, BSN, RN, COHN-S; Helena Chandler, PhD; Kari Haws, PhD; War-Related Illness and Injury Study Center – VA New Jersey Health Care System (WRIISC-VANJ), East Orange, New Jersey, USA. Carrie J. Carlson, DO, FAAFP, IFMCP, ABOIM; Avera Medical Group, Sioux Falls, South Dakota, USA. Elijah Sacra, FMCHC CPT, E-RYT 200; Clarissa A. Kussin, FMCHC, CNHP, E-RYT 500; Wellness Solutions Group, LLC, Durham, North Carolina, USA.

Corresponding author: Omowunmi Osinubi, MD

E-mail: omowunmi.osinubi@va.gov

Keywords: Gulf War Illness, Functional Medicine, Mitochondrial Health, Bioenergetics, Veterans, Whole Health, Systems-Based Care, Virtual Intervention

Introduction

Gulf War Illness (GWI), also termed chronic multisystem illness (CMI), affects 25–35% of Veterans from the 1990–1991 Gulf War and later deployments, presenting with persistent fatigue, cognitive issues, musculoskeletal pain, neurological symptoms, and gastrointestinal disturbances.^1,2 These symptoms significantly impair longterm quality of life. Although the underlying causes remain unclear, research suggests contributions from mitochondrial dysfunction, inflammation, and oxidative stress.³ Traditional treatments are limited, highlighting the need for whole person approaches that address upstream biological dysfunction.

Functional medicine emphasizes personalized, systemsbased strategies and is aligned with VA Whole Health.⁴ Because mitochondrial impairment may drive bioenergetic deficits seen in GWI,^3,5,6 the ME-FELLOW-CMI program (Mitochondrial Enhancement – Functional Medicine and Lifestyle Optimization for Whole Health in CMI) was developed to target mitochondrial resilience through lifestyle interventions, nutraceuticals, and integrative therapies.

Methods

Seventeen Veterans participated in a six-month tele-health delivered ME-FELLOW-CMI program integrated into VA clinical operations.

Mitochondrial Function Assessment

A non-invasive buccal swab test evaluated respiratory chain activity for Complex I (RC-I), Complex IV (RC-IV), Complexes II+III (RC-II+III), and citrate synthase (CS). Buccal enzyme activity demonstrates >80% concordance with muscle assays for RC-I and RC-IV.⁷

Mitochondrial Enhancement Program — Clinical Intervention

The intervention included four components:

• Infra-red sauna therapy (IST): mild hyperthermia to support circulation and detoxification.^8,9
• Photobiomodulation therapy (PBMT): red/near infra-red light to stimulate mitochondrial activity.^10,11
• Lifestyle integration: coaching on movement, pacing, stress reduction, and nutrient-dense diets.^4,12,13
• Nutritional support: glutathione, coenzyme Q10, riboflavin, acetyl-L-carnitine, R-lipoic acid, and anti-inflammatory nutraceuticals.¹⁴

Care plans were individualized based on symptom patterns and patient goals.

Outcome Measures

Assessments included Defense and Veterans Pain Rating Scale (DVPRS), Medical Symptoms Questionnaire (MSQ), Pittsburgh Sleep Quality Index (PSQI), Patient Health Questionnaire-8 (PHQ-8, for depression), Generalized Anxiety Disorder (GAD-7, for anxiety), and Functional Movement Screen (FMS). Buccal mitochondrial testing was performed at baseline and completion.

Statistical Methods

Paired t tests evaluated baseline-to-program completion changes; Wilcoxon signed-rank tests were used when difference scores were non-normal. For domains with multiple outcomes (DVPRS, MSQ, PHQ-8, GAD-7, PSQI), Benjamini–Hochberg FDR correction (q=0.05) was applied to paired t test pvalues. Outcomes are reported with means, standard deviations (SDs) and 95% confidence intervals (CIs). Analyses were performed using SAS software (SAS/STAT 15.3).¹⁵

Results

All 17 Veterans completed the program. Clinical outcomes included 17 paired cases, whereas mitochondrial analyses included 16; one Veteran missed follow‑up testing due to unrelated life circumstances.

Clinical Outcomes

Pain interference (DVPRS) scores significantly decreased across all domains (Figure 1): activity (−29.1%), sleep (−31.4%), mood (−41.5%), and stress (−46.2%); with mean reductions of 1.6 to 2.5 points, and 95% CIs from −2.6 to −0.5 depending on domain (P = .009 to .001; FDR-adjusted P = .002 to .009).

Figure 1. Impact of ME-FELLOW-CMI Intervention on Pain Experience (N=17)

Pain Interference Over Time: Pain interference decreased significantly across all four domains. The largest reductions occurred in Mood and Stress (Δ ≈ −2.2 to −2.5; t and Wilcoxon P < .001; FDR q < 0.001). Activity and Sleep also improved significantly (paired t P = .004 to .009; FDR q ≤ 0.013). Scores shifted from moderately severe to mild, indicating clinically meaningful reductions in pain-related impact on daily functioning, sleep, emotional wellbeing, and stress by program completion.

Global physical symptom burden (MSQ Total) decreased 25.4%, with change or Δ = −25.8 points (95% CI: −42.0 to −9.6; P = .004; FDR = 0.004). The most notable improvements were in musculoskeletal/joint discomfort, energy/activity levels, and digestive symptoms (Figure 2).

Figure 2. Impact of ME-FELLOW-CMI Intervention on Medical Symptoms Burden N=17

Change in Physical Symptom Burden: Total multiple symptom questionnaire (MSQ) scores decreased by approximately 25% (Δ ≈ −26 points), representing a statistically significant reduction by paired t and Wilcoxon tests (P ≤ .015; FDR q = 0.004). The most pronounced improvements were in musculoskeletal, digestive, and energy/activity domains, reflecting broad functional gains and reduced systemic symptom load.

Mood and sleep also improved, with depression scores (PHQ-8) reduced by 27.0%; Δ = –3.1 (CI =  –4.9 to –1.2) and anxiety scores (GAD-7) decreased by 24.8%; Δ = –2.6 (CI  = –4.6 to –0.6). Sleep quality (PSQI) improved by 19.0%; Δ = –2.3 (CI = –4.3 to –0.4). P values (.003 to .022) remained significant after FDR correction (adjusted P = .009 to .022). (Figure 3)

Figure 3. Impact of ME-FELLOW-CMI Intervention on Mood and Sleep (N= 17)

Improvements in Mood and Sleep: Depression (PHQ-8) and anxiety (GAD-7) showed significant improvements, with reductions of 27% (Δ = −3.1) and 24.8% (Δ = −2.6), respectively (paired t p = 0.003–0.012; Wilcoxon P = .006–.024; all FDR q ≤ 0.018). Sleep quality (PSQI) also improved (Δ = −2.3; paired t P = .022; Wilcoxon P = .022; FDR q = 0.022). Overall, these changes reflect meaningful decreases in mood symptoms from moderate to mild levels; and nearly a 20% improvement in sleep quality, indicating partial recovery of restorative sleep function.

Functional movement (FMS) scores increased by 29.4%, with Δ = +3.7 points (95% CI: +1.6 to +5.8; paired t P = .002; Wilcoxon P < .001) and largest improvements in trunk stability (Figure 4).

Figure 4. Impact of ME-FELLOW-CMI Intervention on Functional Movement (N = 17)

Gains in Functional Movement: The Functional Movement Screen (FMS) assesses mobility, stability, and asymmetries across seven painprovoking movement patterns scored from 0–3, with total scores ranging 0–21; higher scores indicate painfree, efficient movement. Group FMS scores significantly increased by ≈30% from baseline to completion (Δ = +3.7; 95% CI +1.6 to +5.8; paired t P = .002; Wilcoxon P < .001). The largest improvement occurred in trunk stability, which increased by ~70%, reflecting enhanced core control and reduced movement-related discomfort. Overall, these gains indicate meaningful improvements in mobility, balance, and functional movement capacity.

Mitochondrial Function

Among 16 paired assays, Complex II (RC-II/CS) exhibited the clearest improvement, increasing ~27% (+0.037) with a moderate effect size (dz ≈ 0.43). However, mean changes were not statistically significant (paired t
P ≈ .108; Wilcoxon P ≈ .130). RC-I/CS differences were non-normal (Shapiro–Wilk P = .011); Wilcoxon testing showed no significant change. RC-IV/CS, RC-II+III/CS, and CS also showed non-significant changes. (Table 1)

Table 1. Mitochondrial Buccal Cell Bioenergetic Biomarkers at Baseline and Program Follow-up (Paired N = 16)

 ^aActivity value as nanomoles/min/mg buccal protein

^bPresented as ratio of the corresponding RC activity to CS activity

^cRC-I/CS difference scores were non-normal (Shapiro–Wilk P = .011), and Wilcoxon testing showed no significant median change (P ≈ .159).

 Mitochondrial Bioenergetic Metrics: This table summarizes changes in respiratory chain complex activity normalized to citrate synthase among 16 Veterans with paired buccal MitoSwab assays. Complex II (RC-II/CS) demonstrated the strongest improvement, increasing by 27% (Δ = +0.037; Cohen’s dz ≈ 0.43), although this did not reach statistical significance (paired t P ≈ .108; Wilcoxon P ≈ .130). Other mitochondrial metrics, RC-IV/CS, RC-II+III/CS, CS, and total buccal protein showed nonsignificant paired changes, indicating generally stable enzymatic activity across these components. Based on the observed effect size for RC-II/CS, a future study would require approximately 43 participants for 80% statistical power and 58 participants for 90% power to detect this magnitude of change at α = 0.05. Larger sample sizes would be needed to detect changes in the other complexes given their smaller observed effects.

Clinical Importance of Electron Transport Chain (ETC) Respiratory Complexes in Gulf War Illness: Complex I (RC-I/CS): The primary entry point for electrons from NADH; dysfunction reduces ATP synthesis and increases oxidative stress, correlating with symptom severity in GWI.^18,19 Complex II (RC-II/CS): Links the TCA cycle to the ETC via FADH₂; impairments disrupt midchain electron flow. Prolonged phosphocreatine recovery in GWI suggests compromised Complex II function.⁶ Complex III (RC-II+III/CS): Transfers electrons from coenzyme Q to cytochrome c; dysfunction disrupts proton gradient maintenance and ATP synthesis. Complex IV (RC-IV/CS): Catalyzes the final electron transfer to oxygen; reduced activity has been associated with fatigue and cognitive impairments in GWI.^6,18

 Note: The buccal mitochondrial assay is a laboratory-developed test (LDT), not FDAapproved, and is used here as a functional biomarker rather than a diagnostic test.

Responder analysis accounting for assay precision thresholds ( ≥10% increase for RC-I, RC-II, and RC-II+III; ≥15% increase for RC-IV reflecting higher variability in cytochrome c oxidase; and ≥10% decrease for CS toward normalization)^16,17 revealed RC-II responders in 12/16 (75%), with a Wilson 95% CI 50.5–89.8%, the only marker demonstrating a true majority response (Table 2). Other complexes had lower responder rates (25–37.5%) and did not achieve statistical significance.

Table 2. Participant Responder Rates by Predefined Thresholds for Mitochondrial Metrics (N = 16)

Participant Responder Rates: This table presents the proportion of participants who demonstrated clinically meaningful improvements in mitochondrial function using predefined thresholds that exceed normal assay variability. These thresholds help distinguish true biochemical change from background noise and assay fluctuation.

Using a benchmark of ≥50% responders to indicate a true majority, Complex II (RC‑II/CS) showed the strongest response: 75% of participants met the ≥10% improvement threshold, with a Wilson 95% CI of 50.5–89.8%, confirming a majority response in this feasibility cohort. In contrast, Complex IV (RC‑IV/CS) and Complex II+III (RC‑II+III/CS) each had 37.5% responders; because their confidence intervals include 50%, these proportions do not represent a statistically reliable majority.

Complex I (RC‑I/CS) and citrate synthase (CS) both showed 25% responder rates, with Wilson intervals (10.2–49.5%) that fall below 50%, indicating significantly fewer than half of participants met their respective improvement thresholds. A decrease in CS toward normal occurred in 25% of participants, which is considered favorable since elevated CS may represent compensatory mitochondrial proliferation rather than efficient function.

Overall, the responder pattern demonstrates heterogeneous mitochondrial improvement, with Complex II showing the most frequent and clinically meaningful change. This suggests that mid‑chain electron transport, particularly the Complex II pathway, may be uniquely responsive to the intervention and may represent a promising therapeutic target in Gulf War Illness.

Power estimates indicated that ~43 participants would be required for 80% power and ~58 for 90% power to detect the observed Complex II effect size at α = 0.05. Larger samples are needed for smaller mitochondrial changes.

Discussion

This feasibility pilot shows that a telehealth mitochondrial-enhancement program can yield statistically significant improvements in pain, mood, sleep, multisystem symptoms, and functional movement. Confidence intervals for all major clinical outcomes excluded zero, and results remained significant after FDR correction, strengthening confidence that improvements reflect true clinical change rather than random variation. Photobiomodulation, infrared sauna therapy, personalized nutrition, and lifestyle integration may collectively support mitochondrial resilience and bioenergetics.^{5,6,8-14,18-20}

Mitochondrial findings suggest a targeted, rather than global, biochemical effect, with Complex II demonstrating the strongest trend and the only majority responder rate. Although group mean changes did not reach significance in this small sample, the effect size and responder profile indicate potential biological relevance. Power estimates suggest that a trial with 40–60 participants could verify these findings and help identify phenotypes or biological predictors of response.

Overall, the pattern of clinical improvements, combined with early bioenergetic signals, supports the potential role of lifestyle based mitochondrial enhancement in GWI/CMI care. The fully virtual model proved feasible and scalable within VA Whole Health frameworks.

Limitations

Generalizability is limited by the small sample size, lack of a randomized control group, self reporting, and limited follow-up duration.

Conclusion

The ME‑FELLOW‑CMI program is feasible and yields statistically significant, clinically meaningful improvements in physical, emotional, and functional health in GWI Veterans. Larger controlled trials with objective biomarkers and longer follow‑up are needed for validation, and economic analyses are required to guide broader VA implementation.

Declarations:

Ethics Statement

Informed consent was obtained from the subjects.

Funding

Funding for the clinical process improvement and the health coaching program was provided by the Department of Veteran Affairs Health Outcomes of Military Exposures (HOME)/War Related Illness and Injury Study Center VA New Jersey Healthcare System (WRIISC–VANJ).

Conflict of Interest

None.

Individual Author Contribution Statement

OO and KH drafted the original manuscript. OO, ES, SG, and CAK designed the clinical program. SG coordinated and provided clinical support for program implementation, as well as data management. OO, ES, CJC, and CAK provided clinical services, coaching content, and dissemination. OO, SG, PM, CJC, and KH collected and reviewed the data and edited the manuscript.  HC assisted with allocating funds for the project.  All authors read and approved the final manuscript.

Acknowledgements

The authors gratefully acknowledge the expertise of Sandhya Bandi and Frank Molina in clinical data management and analytical support

Publication Declaration

This manuscript has not been published elsewhere and is not in the process of being published elsewhere.

Disclaimer

The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Institutional Clearance

Institutional clearance approved for the clinical process improvement feasibility project.

References

1. Steele L, Quaden R, Ahmed ST, et al; Department of Veterans Affairs Cooperative Studies Program #2006 and the VA Million Veteran Program. Association of deployment characteristics and exposures with persistent ill health among 1990-1991 Gulf War veterans in the VA Million Veteran Program. Environ Health. 2024;23(1):92. doi:10.1186/s12940-024-01118-7
2. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Mil Med. 2017;182(3):1507-1508. doi:10.7205/MILMED-D-16-00381
3. Mantilla F, Patel N, Cheema AK, Parmar MS. Gulf War Illness: Neurological Impacts, Pathophysiological Insights, and Therapeutic Prospects. Mol Neurobiol. 2026;63(1):411. doi:10.1007/s12035-026-05708-z
4. Haws K, Mak S, Greer S, et al. A Virtual Functional Medicine-Based Interdisciplinary and Integrative Intervention for Gulf War Illness. Mil Med. 2024;189(suppl 3):99-105. doi:10.1093/milmed/usae054
5. Chen Y, Meyer JN, Hill HZ, et al. Correction: role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. PLoS One. 2017;12(10):e0186711. doi:10.1371/journal.pone.0186711
6. Golomb BA, Han JH, Fung A, Berg BK, Miller BJ, Hamilton G. Bioenergetic impairment in Gulf War illness assessed via 31P-MRS. Sci Rep. 2024;14(1):7418. doi:10.1038/s41598-024-57725-4
7. Spinazzi M, Casarin A, Pertegato V, Salviati L, Angelini C. Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc. 2012;7(6):1235-1246. doi:10.1038/nprot.2012.058
8. Laukkanen JA, Laukkanen T, Kunutsor SK. Cardiovascular and Other Health Benefits of Sauna Bathing: A Review of the Evidence. Mayo Clin Proc. 2018;93(8):1111-1121. doi:10.1016/j.mayocp.2018.04.008
9. Cho KH, Jung SH, Choi MS, Jung YJ, Lee CG, Choi NC. Effect of water filtration infrared-A (wIRA) sauna on inorganic ions excreted through sweat from the human body. Environ Sci Pollut Res Int. 2023;30(7):18260-18267. doi:10.1007/s11356-022-23437-3
10. Waisberg E, Ong J, Masalkhi M, Lee AG. Near infrared/ red light therapy a potential countermeasure for mitochondrial dysfunction in spaceflight associated neuro-ocular syndrome (SANS). Eye (Lond). 2024;38(13):2499-2501. doi:10.1038/s41433-024-03091-4
11. Hamblin MR. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys. 2017;4(3):337-361. doi:10.3934/biophy.2017.3.337
12. Hood DA, Memme JM, Oliveira AN, Triolo M. Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging. Annu Rev Physiol. 2019;81(1):19-41. doi:10.1146/annurev-physiol-020518-114310
13. Little JP, Safdar A, Wilkin GP, Tarnopolsky MA, Gibala MJ. A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms. J Physiol. 2010;588(Pt 6):1011-1022. doi:10.1113/jphysiol.2009.181743
14. Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol. 2010;5(1):297-348. doi:10.1146/annurev.pathol.4.110807.092314
15. SAS Institute Inc. SAS/STAT® 15.3 User’s Guide.SAS Institute Inc; 2023.
16. Goldenthal MJ, Kuruvilla T, Damle S, et al. Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: comparison with studies in muscle biopsy. Mol Genet Metab. 2012;105(3):457-462. doi:10.1016/j.ymgme.2011.11.193
17. Complex IV Human Enzyme Activity Microplate Assay Kit (ab109909). Accessed April 13, 2026. https://www.abcam.com/en-us/products/assay-kits/complex-iv-human-enzyme-activity-microplate-assay-kit-ab109909
18. Koslik HJ, Hamilton G, Golomb BA. Mitochondrial dysfunction in Gulf War Illness revealed by 31P-MRS: a case-control study. PLoS One. 2014;9(3):e92887. doi:10.1371/journal.pone.0092887
19. Golomb BA, Sanchez Baez R, Schilling JM, et al. Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity. Sci Rep. 2023;13(1):10739. doi:10.1038/s41598-023-35896-w
20. Meyer JN, Pan WK, Ryde IT, et al. Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness. PLoS One. 2023;18(11):e0287412. doi:10.1371/journal.pone.0287412