Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Marshall, Jeffrey D.; Bazán, Isabel; Zhang, Yi; Fares, Wassim H.; Lee, Patty J

doi:10.1152/ajplung.00331.2017

Cited by 77 publications

(58 citation statements)

References 188 publications

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“…Yan and colleagues demonstrated that SRY on the Y chromosome binds to and positively regulates the BMPR2 promoter to reduce the prevalence of PAH in males [31]. Moreover, studies have demonstrated mitochondria also play an important role in PAH [32]. Does female mitochondria also be differ from male mitochondria?…”

Section: Discussionmentioning

confidence: 99%

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Zhu

Zhang

et al. 2020

Respir Res

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Objective: To investigate the differences in the proportions of BMPR2 mutations in familial hereditary pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH) between males and females and the relationship between BMPR2 mutation and PAH severity. Methods: A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and EMBASE databases for clinical trials containing information on the relationship between PAH prognosis and BMPR2 mutations through March 2019. After obtaining the data, a meta-analysis was performed using Review Manager Version 5.3 and Stata. Results: A meta-analysis was performed on 17 clinical trials (2198 total patients: 644 male, 1554 female). The results showed that among patients with HPAH and IPAH, the BMPR2 mutation rate is higher in male than in female patients [male group (224/644, 34.78%), female group (457/1554, 29.41%), OR = 1.30, 95% CI: 1.06~1.60, P = 0.01, I 2 = 10%]. Furthermore, haemodynamic and functional parameters were more severe in IPAH and HPAH patients with BMPR2 mutations than in those without, and those with BMPR2 mutation were diagnosed at a younger age. The risk of death or transplantation was higher in PAH patients with BMPR2 mutations than in those without (OR = 2.51, 95% CI: 1.29~3.57, P = 0.003, I 2 = 24%). Furthermore, the difference was significant only in male patients (OR = 5.58, 95% CI: 2.16~14.39, P = 0.0004, I 2 = 0%) and not in female patients (OR = 1.41, 95% CI: 0.75~2.67, P = 0.29, I 2 = 0%). Conclusion: Among patients with HPAH and IPAH, men are more likely to have BMPR2 mutations, which may predict more severe PAH indications and prognosis.

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Section: Discussionmentioning

confidence: 99%

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Zhu

Zhang

et al. 2020

Respir Res

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“…The delay in eliminating damaged mtDNA may also be explained by a defect in mitochondrial quality control (e.g., mitophagy) 66 . It has been reported that in the pathobiology of lung diseases, impaired mitochondria contribute to reduced mitochondrial mass and ATP production 67 . ROS can also induce mtDNA damage and mitochondrial dysfunction, leading to cell death 68 .…”

Section: Discussionmentioning

confidence: 99%

The effect of cysteine oxidation on DJ-1 cytoprotective function in human alveolar type II cells

et al. 2019

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DJ-1 is a multifunctional protein with cytoprotective functions. It is localized in the cytoplasm, nucleus, and mitochondria. The conserved cysteine residue at position 106 (Cys106) within DJ-1 serves as a sensor of redox state and can be oxidized to both the sulfinate (-SO 2 − ) and sulfonate (-SO 3 − ) forms. DJ-1 with Cys106-SO 2 − has cytoprotective activity but high levels of reactive oxygen species can induce its overoxidation to Cys106-SO 3 − . We found increased oxidative stress in alveolar type II (ATII) cells isolated from emphysema patients as determined by 4-HNE expression. DJ-1 with Cys106-SO 3 − was detected in these cells by mass spectrometry analysis. Moreover, ubiquitination of Cys106-SO 3 − DJ-1 was identified, which suggests that this oxidized isoform is targeted for proteasomal destruction. Furthermore, we performed controlled oxidation using H 2 O 2 in A549 cells with DJ-1 knockout generated using CRISPR-Cas9 strategy. Lack of DJ-1 sensitized cells to apoptosis induced by H 2 O 2 as detected using Annexin V and propidium iodide by flow cytometry analysis. This treatment also decreased both mitochondrial DNA amount and mitochondrial ND1 (NADH dehydrogenase 1, subunit 1) gene expression, as well as increased mitochondrial DNA damage. Consistent with the decreased cytoprotective function of overoxidized DJ-1, recombinant Cys106-SO 3 − DJ-1 exhibited a loss of its thermal unfolding transition, mild diminution of secondary structure in CD spectroscopy, and an increase in picosecond–nanosecond timescale dynamics as determined using NMR. Altogether, our data indicate that very high oxidative stress in ATII cells in emphysema patients induces DJ-1 overoxidation to the Cys106-SO 3 − form, leading to increased protein flexibility and loss of its cytoprotective function, which may contribute to this disease pathogenesis.

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“…In addition to defects in this mitochondrial quality control system, general organelle dysfunction has been reported to be involved during HT [70,152,153]. At the level of the microvasculature of HT patients, capillary rarefaction is an important clinical sign to be evaluated.…”

Section: Hypertensionmentioning

confidence: 99%

Mitophagy in Cardiovascular Diseases

Morciano

Patergnani

Bonora

et al. 2020

JCM

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Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes.

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Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Cited by 77 publications

References 188 publications

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

The effect of cysteine oxidation on DJ-1 cytoprotective function in human alveolar type II cells

Mitophagy in Cardiovascular Diseases

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