Table 3.

Clinical studies, molecular targets, and possible implications in LC.

No	References	Study Design	Targets/Trial Protocol/Main Parameters Measured	Brief Results	Conclusions
1.	[109] Grossini, E. et al., 2021. https://doi.org/10.3389/fphys.2021.707587	60 subjects mostly women (mean age 84 years), 12 years older than men, admitted to a LTC facility. All without cognitive impairment.	Plasma markers of lipidic peroxidation: thiobarbituric acid reactive substances (TBARS) release, 8-hydroxy 2 deoxyguanosine (8 OH-2dG), 8-isoprostanes, superoxide dismutase (SOD) activity, glutathione (GSH), and 25(OH) vitamin D. Thymosin β4 (human TMS β4). Cell viability, mitochondrial membrane potential, and ROS on HUVEC.	TBARS, 8 OH-2dG, and 8-isoprostanes exhibited an “oxidative” plasma status. The antioxidant system was well preserved. Vitamin D and GSH were within the physiological range. SOD activity was about 51%. HUVEC treatment with plasma has reduced cell viability by about 60% and increased ROS by about 80% compared to untreated HUVEC.	Assessment of mitochondrial function in the elderly hospitalized in LTC facilities is essential for estimating susceptibility to COVID-19 and identifying patients at high “risk” for the development of infections.
2.	[110] Levy, D. et al., 2022; https://doi.org/10.3390/nu14040912	139 patients who survived after COVID-19 and admitted to the ICU.	Sarcopenia and weight evolution at 3 (M3) and 6(M6) months after ICU discharge.	At M3: Sarcopenia (n = 22), weight decrease > 5% (n = 13). At M6: Persistent sarcopenia: n = 6. Recovering from sarcopenia: n = 16.	The persistence of sarcopenia was associated with female sex, older age, and more severe baseline sarcopenia. In a holistic approach, sarcopenia is reversible through individualized nutritional programs and personalized physical rehabilitation.
3.	[111] Ghanem, J. et al., 2022; https://doi.org/10.3390/nu14153027	37 patients hospitalized for a severe SARS-CoV-2 infection.	Long-term evaluation of autonomy, malnutrition, and LC symptoms.	An important decrease in autonomy is associated with malnutrition after ICU hospitalization. Beneficial effects of personalized rehabilitation.	6 months after discharge: 20% are still without full autonomy; 70% are still with chronic fatigue. Need for personalized and persistent follow-up.
4.	[112] Guntur, V.P. et al., 2022; https://doi.org/10.3390/metabo12111026	Plasma samples from 75 patients divided into 3 groups: G1: LC. G2: fully recovered. G3: healthy controls.	Mass spectrometry-based untargeted metabolomics.	Higher levels of fatty acid metabolites; lower levels of mono-, di-, and tri-carboxylates; and depletion of tryptophan in plasma samples of patients with LC (G1).	The need for therapeutic intervention to restore mitochondrial fat-burning capacity in LC.
5.	[113] Díaz-Resendiz, K. et al., 2022; https://doi.org/10.1002/JLB.3MA0322-279RRR	Human plasma study with 4 groups: HC, C-19, R1, and R2.	ΔΨm measured in human leucocytes for all 4 groups.	ΔΨm was decreased in all three groups compared to healthy controls, even 11 months post-infection; a sex-associated response.	The loss of ΔΨm could indicate a susceptibility to developing LC.
6.	[114] Díaz-Resendiz, K.J.G. et al., 2022; https://doi.org/10.3390/md20020099	76 subjects, divided into different groups, were administered Fucoidan. Phase 1: HC (n = 24) C-19 (n = 31) R1 (n = 21). Phase 2: HC (n = 19) R2 (n = 19).	Ex-vivo fucoidan treatment in HPBMCs. ∆Ψm measurements.	COVID-19 induces an elevated inflammatory/ oxidative state, mitochondrial dysfunction, and ∆Ψm loss.	Fucoidan may constitute a potential treatment to prevent LC, with mitochondria as a therapeutic target to restore homeostasis and ∆Ψm.
7.	[115] Pozzi, A., 2022. https://doi.org/10.3389/fphys.2021.805005	RNA samples extracted from PBMC in patients recovering from COVID-19.	Expression of canonical and non-canonical genes encoded on the mitochondrial genome.	Only some non-canonical mitochondrial genes are disrupted by COVID-19, being limited to mt-sRNAs, without altering the overall mitochondrial transcription.	Further studies on the role of mt-sRNAs in LC are required.
8.	[116] Lage, S.L. et al., 2022; https://doi.org/10.3389/fimmu.2021.799558	47 COVID-19 patients, enrolled from March 2020 to August 2020, divided into mild (n = 31) and moderate-severe (n = 16) groups.	Plasma biomarkers. Inflammasome and mitochondrial status. Lipid peroxidation. Intracellular GSH levels. Mitochondrial superoxide. Circulating monocyte subsets.	↑↑CD14high CD16− classical monocytes compared to HCs. ↑Inflammasome activation. ↑Oxidative stress/NLRP3 signaling pathway. Target therapy to mitigate early hyperinflammation and LC outcome.	Sustained deregulated oxidative stress and inflammasome activation in monocytes after short-term recovery support one of the current hypotheses that LC is driven by persistent pathological inflammation and suggest the pathways involved as potential targets for the management of LC.
9.	[117] Peluso, M.J. et al., 2022; https://doi.org/10.1002/ana.26350	Human plasma study with 4 groups, relative to controls. G1: post-COVID, without LC, G2: LC without NP, G3: LC with NP, and G4: LC with severe NP.	Measurements of SARS-CoV-2 proteins and MPs in NDEVs and ADEVs.	S1 and N proteins were increased in all LC subgroups compared to controls; N concentrations were higher in LC with NP.	Development of new biomarkers and a faster effective technology to identify MPs or SARS-CoV-2′s protein abnormalities in NDEVs or ADEVs during acute infection to accurately predict the risk of developing LC.
10.	[118] Goetzl, E.J. et al., 2023; https://doi.org/10.1016/j.amjmed.2023.03.026	4 study groups: G1= no infection, G2= acute infection, G3 = LC, and G4= post-acute COVID without LC.	Measurements of plasma TEVs proteins in all 4 groups.	For SARS-CoV-2 S1 (RBD) and N: - confirmation of the intracellular presence of the virus. - detection of a specific strain of SARS-CoV-2. For functional MP altered by SARS-CoV-2 in G3 (or LC): ↓MOTS-c, VDAC-1, and humanin. ↑SARM-1 in G2 that progressed to LC.	Management with anti-viral drugs. Abnormal levels of humanin, MOTS-c, and SARM-1 in LC predict neuropsychiatric symptoms.
11.	[119] Siekacz, K. et al., 2023; https://doi.org/10.3390/jcm12134253	80 patients post-COVID-19 divided into two groups: 1. (P(+), n = 40) with persistent interstitial lung lesions on CT. 2. (P(−), n = 40) without lung lesions on CT.	Mitochondrial biomarkers by (ELISA).	P(+) compared to P(−): ↑PTEN-induced kinase 1 (PINK1). ↑Dynamin-1-like protein (DNM1L). ↑Mitofusin-2 (MFN2). ↑Chemokine ligand 18 (PARC, CCL18). ↑IL-6 and ↑ tumor necrosis factor-alpha (TNF-α). ↓Interferon alpha (IFN-α). In P(+) patients: correlations between: - advanced glycation end product (sRAGE) and TNF-α - between DNM1L and IFN-α.	SARS-CoV-2 could trigger mitochondrial dysfunction and chronic inflammation by deregulating PINK1, DNM1L, and MFN2. ↑↑ CLL18, TNF-α, and IL-6 could support long-term pulmonary complications in LC. TNF-α = a potential predictor.
12.	[120] Gvozdjáková, A. et al., 2023; https://doi.org/10.1007/s11356-022-22949-2	2 groups: G1 = 14 LC patients compared to 15 healthy subjects (G2= CG), before and after MR.	Functional capacity of the lungs. Questionnaire for clinical symptoms before and after MR. Blood count and biochemical parameters. CoQ10 and TBARS. Mitochondrial bioenergetics in platelets. Citrate synthase as a mitochondrial marker.	Important adjustment of clinical symptoms, lung function, and regeneration of platelet mitochondrial metabolism after MR.	High-altitude SPA rehabilitation accelerates post-COVID recovery by improving mitochondrial bioenergetics.