The role of mitochondria in aging

Jang, Ji Yong; Blum, Arnon; Liu, Jie; Finkel, Toren

doi:10.1172/jci120842

Cited by 305 publications

(265 citation statements)

References 119 publications

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“…The heart has high energy demand and a high density of mitochondria. Decreased energetic capacity of the cardiac mitochondria is related to aging [32], and the heart is particularly vulnerable to mitochondrial dysfunction caused by damaged structures and increased ROS. Mechanisms contributing to disrupted bioenergetics include decreased nicotinamide adenine dinucleotide (NAD + ) levels [33], reduced efficacy of the respiratory chain, mutated mtDNA, leaking electrons, and dysregulated mitochondrial biogenesis.…”

Section: Mitochondrial Dysfunction In Cardiac Agingmentioning

confidence: 99%

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

Quan

Xin

Tian

et al. 2020

Oxidative Medicine and Cellular Longevity

132

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Mitochondrial DNA (mtDNA) damage is associated with the development of cardiovascular diseases. Cardiac aging plays a central role in cardiovascular diseases. There is accumulating evidence linking cardiac aging to mtDNA damage, including mtDNA mutation and decreased mtDNA copy number. Current wisdom indicates that mtDNA is susceptible to damage by mitochondrial reactive oxygen species (mtROS). This review presents the cellular and molecular mechanisms of cardiac aging, including autophagy, chronic inflammation, mtROS, and mtDNA damage, and the effects of mitochondrial biogenesis and oxidative stress on mtDNA. The importance of nucleoid-associated proteins (Pol γ), nuclear respiratory factors (NRF1 and NRF2), the cGAS-STING pathway, and the mitochondrial biogenesis pathway concerning the development of mtDNA damage during cardiac aging is discussed. Thus, the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.

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Section: Mitochondrial Dysfunction In Cardiac Agingmentioning

confidence: 99%

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

Quan

Xin

Tian

et al. 2020

Oxidative Medicine and Cellular Longevity

132

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“…Recent studies have shown that mitophagy is a critical mechanism for mitochondrial quality control (5). By removing old or damaged mitochondria, mitophagy prevents the accumulation of damaged mitochondria and induces the biogenesis of new mitochondria; thus, mitophagy can improve the overall quality of cellular mitochondria (4,6,7). Mitophagy induces the degradation of whole mitochondria using macroautophagy machinery.…”

mentioning

confidence: 99%

Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo

Kim

Yoon

et al. 2019

FASEB j.

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Mitophagy has been implicated in mitochondrial quality control and in various human diseases. However, the study of in vivo mitophagy remains limited. We previously explored in vivo mitophagy using a transgenic mouse expressing the mitochondria‐targeted fluorescent protein Keima (mt‐Keima). Here, we generated mt‐Keima Drosophila to extend our efforts to study mitophagy in vivo. A series of experiments confirmed that mitophagy can be faithfully and quantitatively measured in mt‐Keima Drosophila. We also showed that alterations in mitophagy upon environmental and genetic perturbation can be measured in mt‐Keima Drosophila. Analysis of different tissues revealed a variation in basal mitophagy levels in Drosophila tissues. In addition, we found a significant increase in mitophagy levels during Drosophila embryogenesis. Importantly, loss‐of‐function genetic analysis demonstrated that the phosphatase and tensin homolog‐induced putative kinase 1 (PINK1)‐Parkin pathway is essential for the induction of mitophagy in vivo in response to hypoxic exposure and rotenone treatment. These studies showed that the mt‐Keima Drosophila system is a useful tool for understanding the role and molecular mechanism of mitophagy in vivo. In addition, we demonstrated the essential role of the PINK1‐Parkin pathway in mitophagy induction in response to mitochondrial dysfunction.—Kim, Y. Y., Um, J.‐H., Yoon, J.‐H., Kim, H., Lee, D.‐Y., Lee, Y. J., Jee, H. J., Kim, Y. M., Jang, J. S., Jang, Y.‐G., Chung, J., Park, H. T., Finkel, T., Koh, H., Yun, J. Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo. FASEB J. 33, 9742–9751 (2019). http://www.fasebj.org

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“…Growing evidence indicates that aging and cellular senescence are tightly interrelated to mitochondrial dysfunction (16,54). Accumulation of dysmorphic/dysfunctional mitochondria has been described in several aged tissues, including AE2 cells of IPF lungs.…”

Section: Discussionmentioning

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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The role of mitochondria in aging

Cited by 305 publications

References 119 publications

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo

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

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