Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

Chen, Pin-I; Cao, Aiqin; Miyagawa, Kazuya; Tojais, Nancy Ferreira; Hennigs, Jan K.; Li, Caiyun G.; Sweeney, Nathaly M.; Inglis, Audrey S.; Wang, Lingli; Li, Dan; Ye, Matthew; Feldman, Brian J.; Rabinovitch, Marlene

doi:10.1172/jci.insight.90427

Cited by 78 publications

(53 citation statements)

References 61 publications

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“…While most data support that diminished OXPHOS drives metabolic dysfunction in PH, contemporary evidence reveals that increased glucose oxidation may mediate PH pathogenesis. Specifically, methamphetamine use, which significantly increases PH risk and is associated with poor prognosis (59), prevented pulmonary endothelial adaptation to additional environmental stressors like hypoxia, thus increasing OXPHOS, mitochondrial ROS, and DNA damage (60). Separately, mitochondrial activity in platelets from PAH patients exhibited increased glycolysis and respiratory reserve capacity dependent on FAO (61).…”

Section: R E V I E W S E R I E S : M I T O C H O N D R I a L D Y S Fmentioning

confidence: 99%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

119

110

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Pulmonary hypertension (PH) is a heterogeneous and fatal disease of the lung vasculature, where metabolic and mitochondrial dysfunction may drive pathogenesis. Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. However, appreciation of metabolic events in PH beyond the Warburg effect is only just emerging. This Review discusses molecular, translational, and clinical concepts centered on the mitochondria and highlights promising, controversial, and challenging areas of investigation. If we can move beyond the "mountains" of obstacles in this field and elucidate these fundamental tenets of pulmonary vascular metabolism, such work has the potential to usher in much-needed diagnostic and therapeutic approaches for the mitochondrial and metabolic management of PH.

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Section: R E V I E W S E R I E S : M I T O C H O N D R I a L D Y S Fmentioning

confidence: 99%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

119

110

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“…Moreover, severe oxidative stress resulting from increasing ROS is known to induce mitochondrial fission that elicits mitochondria’s dynamic response 12 , aggregation 13 and dysfunctions 14 . Mitochondrial fission, one of the mitochondrial dynamic responses, is regulated by the fission protein, dynamin-related protein 1 (Drp1).…”

Section: Introductionmentioning

confidence: 99%

Mito-TEMPO improves development competence by reducing superoxide in preimplantation porcine embryos

Yang

Park

Kim

et al. 2018

Sci Rep

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Mito-TEMPO is a well-known mitochondria-specific superoxide scavenger. However, the effect of Mito-TEMPO on porcine embryo development, to our knowledge, has not been studied yet. In the present study, porcine embryos were classified into two groups (G1 and G2) based on the cytoplasm lipid contents at the zygote stage. The development of blastocysts derived from G2 zygotes was reduced (G2:16.2 ± 7.9% vs G1: 26.5 ± 5.9%; 1.6-fold, p < 0.05) compared to those from G1 zygotes. In G2 embryos, the proportion of TUNEL-positive cells was also higher than that of G1 embryos. Superoxide in G2 embryos was significantly increased compared to that in G1 embryos. Mitochondrial membrane potential and ATP production were lower in G2 embryos than in G1 embryos. Phosphorylation of Drp1 at Ser 616 increased in G1 embryos during the cleavage stages compared to that in the zygote but was not significantly different in G2 embryos. Then, the effects of Mito-TEMPO were investigated in G2 embryos. Blastocyst formation rate (G2: 19.1 ± 5.1% vs G2 + Mito-TEMPO: 28.8 ± 4.0%; 1.5-fold, p < 0.05) and mitochondrial aggregation were recovered after superoxide reduction by Mito-TEMPO treatment. Thus, we showed that Mito-TEMPO improves blastocyst development by superoxide reduction in porcine embryos in vitro.

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“…Despite the causal link between pulmonary arterial hypertension and impairment of BMPR2 signaling 6 , the molecular etiology of pulmonary arterial hypertension remains incompletely understood. For example, in addition to genetic causes, exposure to drugs such as amphetamines, anorexigens, and chemotherapeutic agents can trigger pulmonary arterial hypertension, albeit rarely 8 – 10 .…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenetic protein signaling is required for RAD51-mediated maintenance of genome integrity in vascular endothelial cells

Vattulainen-Collanus

Southwood

et al. 2018

Commun Biol

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The integrity of blood vessels is fundamental to vascular homeostasis. Inactivating mutations in the bone morphogenetic protein (BMP) receptor type II (BMPR2) gene cause hereditary vascular disorders, including pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia, suggesting that BMPR2 and its downstream signaling pathway are pivotal to the maintenance of vascular integrity through an unknown molecular mechanism. Here we report that inactivation of BMPR2 in pulmonary vascular endothelial cells results in a deficit of RAD51, an enzyme essential for DNA repair and replication. Loss of RAD51, which causes DNA damage and cell death, is also detected in animal models and human patients with pulmonary arterial hypertension. Restoration of BMPR2 or activation of the BMP signaling pathway rescues RAD51 and prevents DNA damage. This is an unexpected role of BMP signaling in preventing the accumulation of DNA damage and the concomitant loss of endothelial integrity and vascular remodeling associated with vascular disorders.

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Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

Cited by 78 publications

References 61 publications

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Mito-TEMPO improves development competence by reducing superoxide in preimplantation porcine embryos

Bone morphogenetic protein signaling is required for RAD51-mediated maintenance of genome integrity in vascular endothelial cells

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