Effects of 5-aminolevulinic acid and sodium ferrous citrate on fibroblasts from individuals with mitochondrial diseases

Shimura, Masaru; Nozawa, Naoko; Ogawa-Tominaga, Minako; Fushimi, Takuya; Tajika, Makiko; Ichimoto, Keiko; Matsunaga, Ayako; Tsuruoka, Tomoko; Kishita, Yoshihito; Ishii, Takuya; Takahashi, Kiwamu; Tanaka, Tohru; Nakajima, Motowo; Okazaki, Yasushi; Ohtake, Akira; Murayama, Kei

doi:10.1038/s41598-019-46772-x

Cited by 23 publications

(24 citation statements)

References 35 publications

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“…Recently, it has been reported that 5-aminolevulinic acid and sodium ferrous citrate improved mitochondrial functions in skin fibroblasts from patients with mitochondrial diseases, which may become a new treatment option for mitochondrial diseases. 25 In our case, as the symptoms gradually worsened and there were no other specific treatment, we initiated 5-aminolevulinic acid as a treatment, which decreased frequency of seizures. Long-term follow-up is necessary to evaluate the efficacy of 5-aminolevulinic acid.…”

Section: Discussionmentioning

confidence: 74%

A case report of Leigh syndrome diagnosed by endomyocardial biopsy

Maruo

Ueda

Murayama

et al. 2021

European Heart Journal - Case Reports

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Background Leigh syndrome is a neurodegenerative disorder caused by mitochondrial dysfunction with both phenotypic and genetic heterogeneity. Mitochondrial impairments are usually demonstrated by skeletal muscle biopsy. We report a case of Leigh syndrome diagnosed by endomyocardial biopsy (EMB), not by skeletal muscle biopsy. Case summary At aged 7 months, the patient had delayed motor development. He developed metabolic acidosis triggered by an infection with elevated lactate and pyruvate values in serum and cerebrospinal fluid when he was 1 year old. T2-weighted imaging on magnetic resonance imaging of the brain revealed bilateral hyperintensity in midbrain and dorsal pons. Biopsied skeletal muscle did not show evidence of mitochondrial disease. Left ventricular hypertrophy, bilateral putamen hyperintensity in T2-weighted imaging and a lactate peak in the right basal ganglia in single voxel spectroscopy, and a convulsive seizure appeared at the age of 12, 15, and 16, respectively. When he was 17 years old, biopsied myocardium showed cytoplasmic vacuolization and a marked proliferation of mitochondria within myofibrils pathologically. Respiratory chain enzyme activity of the biopsied myocardium showed decreased activity of complex I. Genetic testing revealed an m.14453 A>G mutation on the MT-ND6 gene. He was finally diagnosed with Leigh syndrome. Administration of oral 5-aminolevulinic acid reduced the frequency of seizures. Discussion EMB led to the diagnosis of Leigh syndrome. Efforts to find and conduct the biopsy of affected organs are important to diagnose mitochondrial disease. EMB is a useful diagnostic method when there is a difficulty in diagnosing mitochondrial disease by skeletal muscle biopsy.

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Section: Discussionmentioning

confidence: 74%

A case report of Leigh syndrome diagnosed by endomyocardial biopsy

Maruo

Ueda

Murayama

et al. 2021

European Heart Journal - Case Reports

Self Cite

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“…In present study, addition of 5-ALA significantly increased the sperm mitochondrial membrane depolarization ( Figure 1A–B ) maybe because the sperm utilizes 5-ALA to synthesise heme. It was supported by Shimura et al [ 29 ] who observed that 5-ALA upregulated oxidative phosphorylation proteins with increased oxidative phosphorylation gene expression in human skin fibroblasts. The result also agreed with the observation that 5-ALA was necessary to produce heme proteins [ 26 , 30 – 32 ].…”

Section: Discussionmentioning

confidence: 75%

5-Aminolevulinic acid improves chicken sperm motility

et al. 2021

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Objective: This study investigated the effects of 5-aminolevulinic acid (5-ALA) on the motility parameters, mitochondrial membrane depolarization, and ATP levels in chicken sperm.Methods: The pooled semen from Barred Plymouth Rock males was used. In the first experiment, the semen was diluted 4-times with phosphate-buffered saline (PBS (-)) containing various concentrations (0, 0.01, 0.05, and 0.1 mM) of 5-ALA, and then the sperm motility parameters after incubation were evaluated by computer-assisted sperm analysis (CASA). In the second experiment, the semen was diluted 4-times with PBS (-) containing 0.05 mM 5-ALA, and then sperm mitochondrial membrane depolarization and ATP levels after 1.5 h of incubation were analyzed with the MitoPT® JC-1 Assay and ATP Assay kits, respectively. In the third experiment, the semen was removed from the seminal plasma and resuspended with the mediums of PBS (-), PBS (-) supplemented with CaCl2 and MgCl2 (PBS (+)) + 5-ALA, PBS (+) + caffeine, and PBS (+) + caffeine + 5-ALA. Then, the sperm motility parameters after incubation were evaluated by CASA. In the last experiment, the semen was treated with the mediums of PBS (-), PBS (-) + 5-ALA, 5.7% glucose, 5.7% glucose + 5-ALA after removing the seminal plasma, and then the sperm motility parameters were evaluated by CASA.Results: The addition of 0.05 mM 5-ALA significantly increased the chicken sperm motility, progressive motility, linearity, average path velocity, curvilinear velocity, straight-line velocity, and the wobble. The sperm mitochondrial membrane depolarization was also increased by the 5-ALA treatment. The 5-ALA treatment decreased the sperm ATP levels. Both the caffeine treatment and glucose treatment decreased the sperm motility during incubation period.Conclusion: 5-ALA might increase sperm mitochondrial membrane depolarization to utilize the ATP for enhancing sperm movement.

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“…[ 6 ] In addition, Shimura et al recently reported that 5-ALA/SFC increased the oxygen consumption rate and ATP level via an oxidative phosphorylation protein's expression induced by upregulations of heme, heme oxygenase-1, and the mtDNA copy number in skin fibroblasts from individuals with mitochondrial disease. [ 17 ]…”

Section: Discussionmentioning

confidence: 99%

A single-arm, open-label, intervention study to investigate the improvement of glucose tolerance after administration of the 5-aminolevulinic acid (5-ALA) in the patients with mitochondrial diabetes mellitus

et al. 2021

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Background: Mitochondrial diabetes mellitus (MDM) is characterized by maternal inheritance, progressive neurosensory deafness, insulin secretory disorder, and progressive microvascular complications. Mitochondria are critical organelles that provide energy in the form of adenosine triphosphate (ATP). An impairment of ATP production in pancreatic β cells is regarded as the main cause of the insulin secretory disorder in patients with MDM, and these patients require insulin replacement therapy early after the diagnosis. The amino acid 5-aminolevulinic acid (5-ALA), a precursor of heme metabolites, is a non-proteinogenic δ amino acid synthesized in mitochondria. An addition of ferrous iron to 5-ALA enhances heme biosynthesis and increases ATP production through an upregulation of the respiratory complex. Several studies have reported that the administration of 5-ALA and ferrous iron to existing treatment improved the glycemic control in both patients with prediabetes and those with type 2 diabetes mellitus. The additional administration of 5-ALA and ferrous iron to MDM patients on insulin therapy may improve their insulin secretory capacity and glycemic control by improving their mitochondrial function. The findings of this study are expected to provide new treatment options for MDM and improve the patients’ glycemic control and prognosis. Methods/design: This study is a single-arm, open-label pilot intervention study using clinical endpoints to investigate the effects of treatment with 5-ALA plus sodium ferrous citrate (SFC) to patients with MDM on their glucose tolerance. A total of 5 patients with MDM will be administered 5-ALA/SFC (200 mg/d) for 24 weeks. We will perform a 75-g oral glucose tolerance test before and at 24 weeks after the start of this 5-ALA/SFC treatment to evaluate glucose-dependent insulin responses. Discussion: To the best of our knowledge, this study will be the first assessment of the effects of 5-ALA/SFC in patients with MDM. This study will obtain an evidence regarding the effectiveness and safety of 5-ALA/SFC for patients with MDM. Trial registration: This study was registered with the University Hospital Medical Information Network (UMIN000040581) on July 1, 2020 and with the Japan Registry of Clinical Trials (jRCTs071200025) on August 3, 2020.

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Effects of 5-aminolevulinic acid and sodium ferrous citrate on fibroblasts from individuals with mitochondrial diseases

Cited by 23 publications

References 35 publications

A case report of Leigh syndrome diagnosed by endomyocardial biopsy

A case report of Leigh syndrome diagnosed by endomyocardial biopsy

5-Aminolevulinic acid improves chicken sperm motility

A single-arm, open-label, intervention study to investigate the improvement of glucose tolerance after administration of the 5-aminolevulinic acid (5-ALA) in the patients with mitochondrial diabetes mellitus

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