Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

Roque, Willy; Cuevas-Mora, Karina; Romero, Freddy

doi:10.3390/ijms21020643

Cited by 32 publications

(32 citation statements)

References 111 publications

(120 reference statements)

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“…The mitochondrial unfolded protein response (UPR mt ) pathway represents a retrograde mitochondria-to-nucleus signaling pathway induced by mitochondrial proteotoxic stress [185]. This pathway was first identified in the late 1990s, and is an area of considerable scientific research using the worm and mammalian models of human aging-related degenerative diseases and metabolic disorders [186,187]. The molecular mechanisms underlying UPR mt in the progression of NAFLD are not well understood and needs further investigation.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD). The mitochondria are the major sites of β-oxidation, a catabolic process by which fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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“…In addition to mitophagy-dependent mitochondrial quality control, mitochondrion also has its own regulatory mechanisms for mitochondrial quality control, such as the mitochondrial unfolded protein response (UPR mt ) and mitochondrial fusion and fission ( Roque et al, 2020 ).…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

“…The mitochondrial unfolded protein response (UPR mt ) is a stress response pathway that can be activated by multiple stress conditions including mitochondrial DNA defects, decreased mitochondrial membrane potential, accumulated unfolded mitochondrial proteins and ROS detoxification ( Hernando-Rodríguez and Artal-Sanz, 2018 ; Roque et al, 2020 ). At present, the molecular mechanism of UPR mt in Caenorhabditis elegans (C. elegans) is better understood than in mammals.…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

“…Mitochondria are dynamic organelles that continuously undergo fission and fusion to maintain the balance of small fragmented mitochondria and long interconnected mitochondrial network, which is essential for cell growth, division, and distribution of mitochondria during differentiation ( van der Bliek et al, 2013 ; Roque et al, 2020 ). Mitochondrial fission will split a mitochondrion into a healthy mitochondrion with increased mitochondrial membrane potential and a dysfunctional one containing diminished mitochondrial membrane potential, damaged proteins and damaged mtDNA.…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

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Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders

Guo

Huang

et al. 2021

Front. Cell Dev. Biol.

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Metabolic disorders include metabolic syndrome, obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular diseases. Due to unhealthy lifestyles such as high-calorie diet, sedentary and physical inactivity, the prevalence of metabolic disorders poses a huge challenge to global human health, which is the leading cause of global human death. Mitochondrion is the major site of adenosine triphosphate synthesis, fatty acid β−oxidation and ROS production. Accumulating evidence suggests that mitochondrial dysfunction-related oxidative stress and inflammation is involved in the development of metabolic disorders. Mitophagy, a catabolic process, selectively degrades damaged or superfluous mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial function. It is considered to be one of the major mechanisms responsible for mitochondrial quality control. Growing evidence shows that mitophagy can prevent and treat metabolic disorders through suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. In the past decade, in order to expand the range of pharmaceutical options, more and more phytochemicals have been proven to have therapeutic effects on metabolic disorders. Many of these phytochemicals have been proved to activate mitophagy to ameliorate metabolic disorders. Given the ongoing epidemic of metabolic disorders, it is of great significance to explore the contribution and underlying mechanisms of mitophagy in metabolic disorders, and to understand the effects and molecular mechanisms of phytochemicals on the treatment of metabolic disorders. Here, we investigate the mechanism of mitochondrial dysfunction in metabolic disorders and discuss the potential of targeting mitophagy with phytochemicals for the treatment of metabolic disorders, with a view to providing a direction for finding phytochemicals that target mitophagy to prevent or treat metabolic disorders.

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“…Emerging evidence indicates that mitochondrial dysfunction and metabolic reprogramming occur in a wide range of respiratory disorders, including a variety of fibrotic lung conditions (15,29,39). For example, we recently demonstrated that diverse types of profibrotic insults (bleomycin, radiation, silica) induce similar metabolic changes in the alveolar epithelium of the lung (51).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

Roque

Cuevas-Mora²,

Sales³

et al. 2020

Preprint

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The current hypothesis suggests that Idiopathic pulmonary fibrosis (IPF) arises as a result of chronic injury to alveolar epithelial cells and aberrant activation of multiple signaling pathways. Dysfunctional IPF lung epithelium manifests many hallmarks of aging tissues, including cellular senescence, mitochondrial dysfunction, metabolic dysregulation, and loss of proteostasis. Unfortunately, this disease is often fatal within 3-5 years from diagnosis, and there is no effective treatment. One of the major limitations to the development of novel treatments in IPF is that current models of the disease fail to resemble several features seen in elderly IPF patients. In this study, we sought to develop an in vitro epithelial injury model using repeated low levels of bleomycin to mimic the phenotypic and functional characteristics of the IPF lung epithelium. Consistent with the hallmarks of the aging lung epithelium, we found that chronic-injured epithelial cells exhibited features of senescence cells, including an increase in β-galactosidase staining, induction of p53 and p21, mitochondrial dysfunction, excessive ROS production, and proteostasis alteration. Next, combined RNA sequencing, untargeted metabolomics, and lipidomics were performed to investigate the dynamic transcriptional, metabolic, and lipidomic profiling of our in vitro model. We identified that a total of 8,484 genes with different expression variations between the exposed group and the control group. According to our GO enrichment analysis, the down-regulated genes are involved in multiple biosynthetic and metabolic processes. In contrast, the up-regulated genes in our treated cells are responsible for epithelial cell migration and regulation of epithelial proliferation. Furthermore, metabolomics and lipidomics data revealed that overrepresented pathways were amino acid, fatty acid, and glycosphingolipid metabolism. This result suggests that by using our in vitro model, we were able to mimic the transcriptomic and metabolic alterations of those seen in the lung epithelium of IPF patients. We believe this model will be ideally suited for use in uncovering novel insights into the gene expression and molecular pathways of the IPF lung epithelium and performing screening of pharmaceutical compounds.

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Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

Cited by 32 publications

References 111 publications

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

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