Melatonin supplementation enhances mitochondrial dynamics and bioenergetics to support and elevate ATP production
| Melatonin dosage/duration | Study design | Results | Ref. |
|---|---|---|---|
| 20 mg/kg b.w. (IP injection) 24 h before cardiac I/R injury | In vivo cardiac I/R injury C57BL6 mouse model | Melatonin reduced cardiac I/R stress and I/R injury biomarkers, supporting myocardial function via enhancing Opa1 expression | [403] |
| 5 μM 12 h prior to HR treatment | In vitro HR injury treatment using C57BL6 ESCs | Melatonin blocked apoptosis, normalized membrane potential and mitochondrial fusion/fission via Opa1, restoring ATP production to control levels. Opa1 knockout abolished all beneficial effects in cardiomyocytes | [403] |
| 5 μM prior to calcification induction; total 14 days duration | In vitro SD rats aorta VSMCs treated with 10 mM β-GP for 14 days to induce calcification | Melatonin treatment decreased β-GP-induced calcification in VSMCs, normalized ΔΨm dissipation, enhanced expression of Opa1, Mfn1/2, protected mitochondrial structural integrity, reduced fragmentation, and maintained ATP production levels similar to controls by enhancing expression of OXPHOS enzymes | [404] |
| Oral 10 mg/kg b.w., daily for 12 weeks | In vivo ZDF rats, RVL muscles | Long-term melatonin supplementation in ZDF rats enhanced oxidative phenotype, elevating ATP production and increasing antioxidant enzymes by upregulating Drp1, Fis1 and downregulating Opa1, Mfn2, compared to controls | [405] |
| 10 mg/kg b.w. daily in water by oral gavage, starting 7 days post STZ injection, for 3 months | In vivo: male C57BL/6J injected with STZ, 100 mg/kg b.w. to induce type 1 diabetes | Melatonin treatment restored STZ-induced inhibition of Mfn2 to rebalance fusion and fission in diabetic retina | [406] |
| 10 mg/kg or 30 mg/kg, IP injection, 5 min after trauma | In vivo: SD rats subjected to non-lethal MT-induced myocardial injury | 30 mg/kg melatonin reduced myocardial apoptosis by 50% by enhancing protein expression of Opa1, Mfn2 and suppressing mitochondrial fragmentation via downregulating Drp1 in the rats subjected to MT | [407] |
| Pretreatment—100 μM/L melatonin for 2 h | In vitro H9c2 cardiomyoblasts cultured in 20% traumatic plasma for 12 h | Melatonin pretreatment restored ∆Ψm and ATP production to control levels by elevating activity of mitochondrial OXPHOS enzymes complex I, II, III, and IV | [407] |
| 0.01 μM, 0.1 μM, and 1 μM (30 min for ATP) | Murine C2C12 myoblasts | Dose-dependent enhancement of ATP production at 8.6%, 30.8%, and 45.6% (0.01 μM, 0.1 μM, and 1 μM, respectively), 1 μM melatonin elevated the gene expression of OXPHOS enzymes Nd4, Sdha, and Atp5a by 262.7%, 85.9%, and 311.3% respectively | [408] |
| 5 mg (0.5% melatonin) and 50 mg (5% melatonin) | In vitro: SD rat BMMSCs treated with melatonin-loaded interconnected electrospun nanofiber three-dimensional scaffold | Dose-dependent elevation of ATP (29.1%, 59.9%) and membrane potential (130%, 200%) for the respective 0.5% and 5% melatonin scaffolds compared to saline controls. 5% melatonin scaffold-treated BMMSCs increased protein expression of OXPHOS enzymes Atp5, Nd4, and Sdha by 90.5%, 120%, and 80.4%, respectively, compared to controls | [409] |
| 10 mg/kg b.w. diluted in drinking water, for 6 weeks | In vivo: mitochondrial functions in interscapular brown adipose tissue of ZDF rats | Enhanced mitochondrial functionality, increasing ATP production by reducing proton leak and mitochondrial permeability transition pore activity, while enhancing antioxidant superoxide dismutase activity | [410] |
| 10 mg/kg b.w. in drinking water from 1–5 months and 1–10 months of age | In vivo: diaphragmatic mitochondria from female senescent prone (SAMP8) and senescent resistant (SAMR1) mice | Melatonin treatment in drinking water for 9 months extended lifespans of all treated subjects and rescued age-dependent mitochondrial dysfunction in SAMP8 mice, increasing ATP production by > 125% and > 70% compared to SAMP8 and SAMR1 vehicle controls, respectively | [411] |
| 30 mg/kg b.w. in 4 separate doses: IP injections-30 min before CLP, 30 min and 4 h after CLP. Subcutaneous injection, 8 h after CLP | C57/BL/6 mice septic mice induced by CLP with iNOS–/– and iNOS+/+ as wild type controls | Melatonin reversed sepsis-induced damage to mitochondrial OXPHOS proteins and normalized ATP/ADP ratio in iNOS+/+ wild type mice. The increase in ATP production was even higher than melatonin-treated iNOS–/– septic mice | [412] |
| 25–200 µM tested for dose-dependent effects. 100 µM added to reperfusion perfusate | In vitro: male Wistar rat liver cold-storage I/R model | Melatonin improved liver function after cold storage and reperfusion, indicated by significant elevations in bile and bilirubin production in a dose-dependent manner. Treatment with 100 µM melatonin during reperfusion increased ATP production by > 88% compared to untreated controls | [413] |
| 100 µM added to the perfusate solution of KHB and glucose | In situ perfusion: male Wistar rat liver cold-storage I/R model | Reperfusion with melatonin rescued the dramatic 7-fold loss of ATP production in cold-storage livers compared to normal controls. However, ATP levels in melatonin treated livers were still 4–5 times lower in comparison to normal livers not subjected to cold storage | [414] |
| 1 nM to 1 mM | In vitro high-resolution respirometry, fluorometry and spectrophotometry study of mitochondria from normal mouse liver cells | Melatonin increased ATP synthesis by improving respiratory efficiency via reduced ΔΨm and oxygen flux; and enhancing activity of OXPHOS complexes at different doses: complex I (56% at 1 nM), complex II (> 31% from 1 nM to 1 μM), complex III (30% at 1 mM), and complex IV with the most significant increases (609% at 1 mM) | [415] |
| 10 mg/kg b.w. IP injection, 10 min before ruthenium treatment | In vivo male Wistar rats with mitochondrial damage induced by ruthenium red (60 μg/kg b.w., IP injection) | Melatonin IP injection increased activity levels of complex I and IV in the liver and brain of both ruthenium red-treated and untreated subjects. Normal subjects displayed increases in activity of 76% within 30 min and 10% within 60 min for complex I in liver and brain, respectively; these effects were diminished completely at 120 min (brain), with a 75% reduction in activity (liver) at 180 min. Activity increases of 150–166% within 30–90 min and 25% within 30 min for complex IV were observed in the liver and brain, respectively. These increases totally vanished at 120 min (liver) and 180 min (brain) after injection | [416] |
| Oral 10 mg/kg b.w./day × 5 before MI/R; IP injection 10 min before the reperfusion | In vivo MI/R injury study using STZ-induced type 1 diabetic rat model (8-week-old male SD rats); in vitro confirmation experiment using H9c2 cardiomyoblasts | Melatonin reduced MI/R injury by reducing oxidative stress and enhancing mitochondrial biogenesis, while elevating activity levels in complexes II, III, and IV to increase ATP production in an AMPK-PGC-1α-SIRT3 signaling-dependent manner | [421] |
| 100 nM, 1 µM, and 100 µM added in terminal culture medium | In vitro fertilization of oocytes using aged mice. Females aged 10–12 months, males aged 8–12 weeks | Melatonin elevated mRNA expression levels of antioxidant-related genes Sirt1, Sirt3, Gpx4, Sod1, and Sod2, improving oocyte maturation, fertilization and blastocyst formation in aged oocytes compared to controls, with 1 µM achieving the best results, increasing ATP production by 56% compared to controls | [422] |
| 500 nM | In vitro porcine oocytes treated with 600 nM rotenone to impair development via mitochondrial deficiency | Melatonin rescued porcine oocytes from rotenone-induced impairment of early embryo development in a receptor-and SIRT1-dependent manner. By enhancing mitochondrial biogenesis, restoring ΔΨm, and elevating protein expression of OXPHOS enzymes complex I and V melatonin rescued 50% ATP depletion by rotenone treatment to 75% of control levels | [423] |
| 10 mg/kg b.w. IP injection every other day (mice)5 mg/day × 30 days (lung cancer patients) | In vivo: LLC mouse model (male C57 mice); human lung cancer patients | Melatonin enhanced the expression of SIRT3 in humans and mice. In LLC mice, melatonin significantly elevated ATP production by > 3.2-fold, restoring mitochondrial function by elevating membrane potential and increasing the activities of OXPHOS complexes I (1.75-fold) and IV (> 14.5-fold), causing a 5-fold reduction in tumor size at 16 days | [425] |
β-GP: beta-glycerophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; Atp5a: ATP synthase F1 subunit alpha; BMMSCs: bone marrow mesenchymal stem cells; b.w.: body weight; CLP: cecal ligation and puncture; Drp1: dynamin-like-protein-1; ΔΨm: mitochondrial membrane potential; ESCs: embryonic stem cells; Fis1: fission 1; Gpx4: glutathione peroxidase 4; HR: hypoxia-reoxygenation; iNOS: inducible nitric oxide synthase; IP: intraperitoneal; I/R: ischemia/reperfusion; KHB: Krebs-Henseleit bicarbonate; LLC: Lewis lung cancer; Mfn: mitofusin; MI/R: myocardial I/R; MT: mechanical trauma; Nd4: NADH dehydrogenase subunit 4; Opa1: optic atrophy 1; OXPHOS: oxidative phosphorylation; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; RVL: red vastus lateralis; SAMP8: senescent accelerated prone 8; SAMR1: senescence-accelerated mouse resistant 1; SD: Sprague-Dawley; Sdha: succinate dehydrogenase complex flavoprotein subunit A; SIRT3: sirtuin 3; Sod1: superoxide dismutase 1; STZ: streptozotocin; VSMCs: vascular smooth muscle cells; ZDF: Zücker diabetic fatty
