Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome

Kato, Hiromichi; Han, Xu; Yamaza, Haruyoshi; Masuda, Keiji; Hirofuji, Yuta; Satō, Hiroshi; Pham, Thanh; Taguchi, Tomoaki; Nonaka, Kenichi

doi:10.1016/j.bbrc.2017.09.045

Cited by 17 publications

(17 citation statements)

References 22 publications

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“…After informed parental consent was obtained, deciduous teeth were collected from a normal participant and a patient with DS at 6 and 14 years of age, respectively. The isolation procedure was completed as previously described [15]. Briefly, the pulp tissue was subjected to an enzymatic dissociation in 3 mg/mL collagenase I (Washington, NJ, USA) and 4 mg/mL dispase II (Wako, Osaka, Japan) for 1 h, and then maintained at 37 °C in a humidified 5% CO 2 incubator in the Alpha modification of Eagle’s Minimal Essential Medium (α-MEM; Sigma-Aldrich, MO, USA) containing 15% fetal bovine serum (Sigma-Aldrich), 100 μM L-ascorbic acid 2-phosphate (Wako), 2 mM L-glutamine (Life Technologies, NY, USA), 250 μg/mL Fungizone (Life Technologies), 100 U/mL penicillin (Life Technologies), and 100 μg/mL streptomycin (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

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Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome

et al. 2018

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BackgroundDown syndrome (DS) is a common developmental disorder resulting from the presence of an additional copy of chromosome 21. Abnormalities in dopamine signaling are suggested to be involved in cognitive dysfunction, one of the symptoms of DS, but the pathophysiological mechanism has not been fully elucidated at the cellular level. Stem cells from human exfoliated deciduous teeth (SHED) can be prepared from the dental pulp of primary teeth. Importantly, SHED can be collected noninvasively, have multipotency, and differentiate into dopaminergic neurons (DN). Therefore, we examined dopamine signaling in DS at the cellular level by isolating SHED from a patient with DS, differentiating the cells into DN, and examining development and function of DN.MethodsHere, SHED were prepared from a normal participant (Ctrl-SHED) and a patient with DS (DS-SHED). Initial experiments were performed to confirm the morphological, chromosomal, and stem cell characteristics of both SHED populations. Next, Ctrl-SHED and DS-SHED were differentiated into DN and morphological analysis of DN was examined by immunostaining. Functional analysis of DN was performed by measuring extracellular dopamine levels under basal and glutamate-stimulated conditions. In addition, expression of molecules involved in dopamine homeostasis was examined by quantitative real-time polymerase chain reaction and immunostaining. Statistical analysis was performed using two-tailed Student’s t-tests.ResultsCompared with Ctrl-SHED, DS-SHED showed decreased expression of nestin, a neural stem-cell marker. Further, DS-SHED differentiated into DN (DS-DN) exhibiting decreased neurite outgrowth and branching compared with Ctrl-DN. In addition, DS-DN dopamine secretion was lower than Ctrl-DN dopamine secretion. Moreover, aberrant expression of molecules involved in dopaminergic homeostasis was observed in DS-DN.ConclusionsOur results suggest that there was developmental abnormality and DN malfunction in the DS-SHED donor in this study. In the future, to clarify the detailed mechanism of dopamine-signal abnormality due to DN developmental and functional abnormalities in DS, it is necessary to increase the number of patients for analysis. Non-invasively harvested SHED may be very useful in the analysis of DS pathology.Electronic supplementary materialThe online version of this article (10.1186/s12883-018-1140-2) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

“…Stem cells from human exfoliated deciduous teeth (SHED) can be acquired noninvasively and used for research [13–15]. Thus, using SHED, consent to participate in research may be obtained more readily from the parents of young patients.…”

Section: Introductionmentioning

confidence: 99%

Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome

et al. 2018

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“…Kato et al. reported that decreased mitochondrial function caused impaired osteoblast differentiation. Weili et al suggested that Scolopin‐2‐NH2 interacted with mitochondria and could play an important role in the apoptosis process.…”

Section: Discussionmentioning

confidence: 99%

Sodium hydrosulfide mitigates dexamethasone‐induced osteoblast dysfunction by interfering with mitochondrial function

Zhu

et al. 2019

Biotech and App Biochem

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Osteoporosis is one of the clinical complications of long‐term treatment with glucocorticoids (GCs), characterized by systemic damage of bone mass and osteoblast dysfunction. Hydrogen sulfide was found to be involved in GCs‐induced osteoblast dysfunction. Osteoblastic MC3T3‐E1 cell and mitochondrial function were determined by cell viability, M‐CSF level, and ALP activity and superoxide production, membrane potential, and ATP level, respectively. The purpose of this research was to explore the impact of NaHS on osteoblastic MC3T3‐E1 cell function as well as on Sirt1 and PGC1α expression in dexamethasone (DEX)‐treated osteoblast cells. DEX‐treated MC3T3‐E1 cells exhibited decreased cell viability and ALP activity, as well as increased M‐CSF level; all these changes were dramatically attenuated by NaHS. DEX‐treated cells also displayed mitochondrial dysfunction, namely decreased mitochondrial membrane potential and ATP generation and increased superoxide generation, which were partly reversed by NaHS. We confirmed decreased Sirt1 and PGC1α protein expression in DEX‐treated MC3T3‐E1 cells by Western blot, which was also partly reversed by NaHS. Silencing of Sirt1 abrogated the protective effect of NaHS against DEX‐induced cell damage and mitochondrial dysfunction. NaHS alleviates DEX‐induced osteoblastic MC3T3‐E1 cell injury by improving mitochondrial function.

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“…Deciduous teeth were collected from a healthy control and a child with LS at 4 and 6 years of age, respectively. SHED were isolated from dental pulp tissues as described previously [10] , and grown in a SHED culture medium consisting of Minimum Essential Medium Eagle Alpha Modification (Sigma-Aldrich, MO, USA) with 15% fetal bovine serum (Sigma-Aldrich), 100 µM L-ascorbic 2-phosphate (Wako Pure Chemical Industries, Osaka, Japan), 2 mM L -glutamine (Life Technologies, NY, USA), 100 U/mL penicillin (Life Technologies), 100 µg/mL streptomycin (Life Technologies) and 25 µg/mL Fungizone (Life Technologies) at 37 °C in 5% CO 2 . SHED were used at passage 4–6.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, SHED may be used as a disease-specific or patient-specific cellular model to elucidate the pathology and identify therapeutic targets of diseases. A recent study demonstrated the impaired osteogenesis in SHED derived from a child with LS, harboring the G13513A mutation in the mtDNA region encoding the ND5 subunit of respiratory chain (RC) complex I [10] .…”

Section: Introductionmentioning

confidence: 99%

Osteoblastic differentiation improved by bezafibrate-induced mitochondrial biogenesis in deciduous tooth-derived pulp stem cells from a child with Leigh syndrome

Han

Nonaka

Kato

et al. 2019

Biochemistry and Biophysics Reports

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Leigh syndrome is a highly heterogeneous condition caused by pathological mutations in either nuclear or mitochondrial DNA regions encoding molecules involved in mitochondrial oxidative phosphorylation, in which many organs including the brain can be affected. Among these organs, a high incidence of poor bone health has been recognized in primary mitochondrial diseases including Leigh syndrome. However, the direct association between mitochondrial dysfunction and poor bone health has not been fully elucidated. Mitochondrial biosynthesis is a potential therapeutic target for this syndrome, as it can ameliorate the impairment of oxidative phosphorylation without altering these gene mutations. A recent study has shown the impaired osteogenesis in the dental pulp stem cells derived from the deciduous teeth of a child with Leigh syndrome, harboring the heteroplasmic mutation G13513A in the mitochondrial DNA region encoding the ND5 subunit of the respiratory chain complex I. The present study aimed to investigate whether mitochondrial biogenesis could be a therapeutic target for improving osteogenesis, using the same stem cells in a patient-specific cellular model. For this purpose, bezafibrate was used because it has been reported to induce mitochondrial biogenesis as well as to improve bone metabolism and osteoporosis. Bezafibrate clearly improved the differentiation of patient-derived stem cells into osteoblasts and the mineralization of differentiated osteoblasts. The mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1α, ATP production, and mitochondrial Ca2+ levels were all significantly increased by bezafibrate in the patient-derived cells. In addition, the increased amount and morphological shift from the fragmentary to network shape associated with DRP1 downregulation were also observed in the bezafibrate-treated patient-derived cells. These results suggest that mitochondrial biogenesis may be a potential therapeutic target for improving osteogenesis in patients with Leigh syndrome, and bezafibrate may be one of the candidate treatment agents.

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Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome

Cited by 17 publications

References 22 publications

Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome

Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome

Sodium hydrosulfide mitigates dexamethasone‐induced osteoblast dysfunction by interfering with mitochondrial function

Osteoblastic differentiation improved by bezafibrate-induced mitochondrial biogenesis in deciduous tooth-derived pulp stem cells from a child with Leigh syndrome

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