Mitochondrial dynamics and mitophagy in lung disorders

Sharma, Archana; Ahmad, Shaniya; Ahmad, Tanveer; Ali, Shakir; Syed, Mansoor Ali

doi:10.1016/j.lfs.2021.119876

Cited by 50 publications

(27 citation statements)

References 219 publications

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“…Disorders of mitochondrial dynamics were noticed in lung epithelial cells and proposed to be the part of pathogenesis of various lung diseases including COPD. 14 , 42 CSE increased mitochondrial fission and reduced mitochondrial fusion in CSE‐induced pulmonary endothelial injury and short OPA1 isoforms increased in COPD subjects. 16 , 43 Of fusion and fission proteins, we found that MFN2 expressed mostly in human airway epithelia, CSE increased MFN2 expression, and adding cholesterol could down‐regulate CSE‐induced over‐expression of MFN2.…”

Section: Discussionmentioning

confidence: 92%

“…Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis and development of lung diseases. 14 Oxidative stress, mitophagy and mitochondrial dynamics including fusion and fission were found to play crucial roles in COPD and serve as therapeutic targets. 15 , 16 Of various metabolic pathways, mitochondria play a key role in lipid metabolism, cholesterol homeostasis and interactions among intracellular organelles, 17 , 18 , 19 although the exact mechanism in COPD remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling

Liu

et al. 2022

Clinical & Translational Med

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Background Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking. Methods Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics‐related proteins were detected by RT‐qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)‐6 and IL‐8 were detected by RT‐qPCR. Results We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia‐driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism‐associated genes in CSE‐induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3‐MFN2 pathway, cholesterol re‐distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down‐regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation. Conclusions Our data provide new insights for understanding molecular mechanisms of cholesterol‐altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling

Liu

et al. 2022

Clinical & Translational Med

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“…The homeostasis and dynamic equilibrium of mitochondria are the preconditions for its functional integrity [ 31 ]. Once the dynamic equilibrium is impaired, cellular metabolic and energy disorder will be triggered, contributing to cell death and various tissue damage [ 32 ]. During sepsis, mitochondrial dysfunction is one of the critical mechanisms resulting in organ injury and failure.…”

Section: Discussionmentioning

confidence: 99%

The Activation of AMPK/NRF2 Pathway in Lung Epithelial Cells Is Involved in the Protective Effects of Kinsenoside on Lipopolysaccharide-Induced Acute Lung Injury

Yang

Zhong

Xiao

et al. 2022

Oxidative Medicine and Cellular Longevity

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The disorder of mitochondrial dynamic equilibrium of lung epithelial cell is one of the critical causes of acute lung injury (ALI). Kinsenoside (Kin) serves as an active small-molecule component derived from traditional medicinal herb displaying multiple pharmacological actions in cancers, hyperglycemia, and liver disease. The objective of this study was to investigate the effects of Kin on lipopolysaccharide- (LPS-) induced ALI and further explore possible molecular mechanisms. Kin was administered orally (100 mg/kg/day) for 7 consecutive days before LPS instillation (5 mg/kg). After 12 hours, pathological injury, inflammatory response, and oxidative stress were detected. The results demonstrated that Kin significantly alleviated lung pathological injury and decreased the infiltration of inflammatory cells and the release of inflammatory mediators in bronchoalveolar lavage fluid (BALF), apart from inhibiting the production of reactive oxygen species (ROS) and lipid peroxidation. Meanwhile, Kin also promoted mitochondrial fusion and restrained mitochondrial fission in mice with ALI. In terms of mechanism, Kin pretreatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and the protein level of nuclear factor erythroid 2-related factor 2 (NRF2). In Ampk-α knockout mice challenged with LPS, Kin lost its pulmonary protective effects, accompanied by lower NRF2 level. In vitro experiments further unveiled that either AMPK inhibition by Compound C or NRF2 knockdown by siRNA abolished the protective roles of Kin in LPS-treated A549 lung epithelial cells. And NRF2 activator TAT-14 could reverse the effects of Ampk-α deficiency. In conclusion, Kin possesses the ability to prevent LPS-induced ALI by modulating mitochondrial dynamic equilibrium in lung epithelial cell in an AMPK/NRF2-dependent manner.

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“…Under pressure, the damaged mitochondria are encapsulated in isolation membranes, membranes seal and fuse with the lysosomes to eliminate damaged mitochondria (17). The functional state of mitochondria depends on the dynamic balance among the biogenesis, fusion, division and autophagy of mitochondria (25). The PTEN-induced putative protein kinase 1 (PINK1)/Parkin pathway is one of the well-known mitophagy pathways.…”

Section: Introductionmentioning

confidence: 99%

Molybdenum and Cadmium Co-induce Mitochondrial Quality Control Disorder via FUNDC1-Mediated Mitophagy in Sheep Kidney

Yang

Zhou³

et al. 2022

Front. Vet. Sci.

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Molybdenum (Mo), fundamental trace mineral for animals and plants, but undue Mo damages animal health. Cadmium (Cd) is a toxic heavy metal that exists in the environment. Nevertheless, the mechanism of Mo and Cd on mitochondrial quality control are still indistinct. The objective of this research was to explore the effects of mitophagy on mitochondrial quality control via the FUNDC1-mediated by Mo and Cd in sheep kidney. Forty-eight 2-month-old sheep were stochastically divided into four groups, as shown below: control group, Mo [45 mg/kg body weight (BW)] group, Cd (1 mg/kg BW) group and Mo (45 mg/kg BW)+Cd (1 mg/kg BW) group, with 50 days feed technique. The results showed that Mo or/and Cd attract an unbalance of trace minerals and vacuoles and granular degeneration of renal tubular epithelial cells, and increase the number of mitophagosomes and vacuole-mitochondria and LC3 puncta and MDA and H2O2 contents, and decrease ATP content in the kidney. Moreover, Mo or/and Cd treatment could upregulate the mRNA levels of FUNDC1, LC3A, LC3B, PGAM5, DRP1, FIS1 and MFF, and the protein levels of FUNDC1, p-FUNDC1, LC3II/LC3I, DRP1, MFF and FIS1, downregulate the mRNA levels of MFN1, MFN2, OPA1, PGC-1α, SIRT1, SIRT3, FOXO1 and FOXO3, and the protein levels of MFN1, MFN2, OPA1 and PGC-1α. Notably, variations of above-mentioned factors in Mo and Cd group were more obvious than in Mo or Cd groups. Taken together, these results displayed that Mo and Cd co-treatment might induce mitochondrial quality control disorder via FUNDC1-mediated mitophagy in sheep kidney.

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Mitochondrial dynamics and mitophagy in lung disorders

Cited by 50 publications

References 219 publications

Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling

Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling

The Activation of AMPK/NRF2 Pathway in Lung Epithelial Cells Is Involved in the Protective Effects of Kinsenoside on Lipopolysaccharide-Induced Acute Lung Injury

Molybdenum and Cadmium Co-induce Mitochondrial Quality Control Disorder via FUNDC1-Mediated Mitophagy in Sheep Kidney

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