Editorial

4 pages, 193 KiB

Open AccessEditorial

Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease

by Yi-Ling Tsang, Chiu-Li Kao, Shu-Chuan Amy Lin and Chia-Jung Li

Biomedicines 2022, 10(11), 2872; https://doi.org/10.3390/biomedicines10112872 - 09 Nov 2022

Cited by 7 | Viewed by 1500

Mitochondria are considered to have a significant influence on aging due to their critical role in the regulation of bioenergetics, oxidative stress, and cell death [...] Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

Research

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16 pages, 3678 KiB

Open AccessArticle

Mitochondrial Ribosome Dysfunction in Human Alveolar Type II Cells in Emphysema

by Loukmane Karim, Chih-Ru Lin, Beata Kosmider, Gerard Criner, Nathaniel Marchetti, Sudhir Bolla, Russell Bowler and Karim Bahmed

Biomedicines 2022, 10(7), 1497; https://doi.org/10.3390/biomedicines10071497 - 24 Jun 2022

Cited by 4 | Viewed by 1837

Abstract

Pulmonary emphysema is characterized by airspace enlargement and the destruction of alveoli. Alveolar type II (ATII) cells are very abundant in mitochondria. OXPHOS complexes are composed of proteins encoded by the mitochondrial and nuclear genomes. Mitochondrial 12S and 16S rRNAs are required to [...] Read more.

Pulmonary emphysema is characterized by airspace enlargement and the destruction of alveoli. Alveolar type II (ATII) cells are very abundant in mitochondria. OXPHOS complexes are composed of proteins encoded by the mitochondrial and nuclear genomes. Mitochondrial 12S and 16S rRNAs are required to assemble the small and large subunits of the mitoribosome, respectively. We aimed to determine the mechanism of mitoribosome dysfunction in ATII cells in emphysema. ATII cells were isolated from control nonsmokers and smokers, and emphysema patients. Mitochondrial transcription and translation were analyzed. We also determined the miRNA expression. Decreases in ND1 and UQCRC2 expression levels were found in ATII cells in emphysema. Moreover, nuclear NDUFS1 and SDHB levels increased, and mitochondrial transcribed ND1 protein expression decreased. These results suggest an impairment of the nuclear and mitochondrial stoichiometry in this disease. We also detected low levels of the mitoribosome structural protein MRPL48 in ATII cells in emphysema. Decreased 16S rRNA expression and increased 12S rRNA levels were observed. Moreover, we analyzed miR4485-3p levels in this disease. Our results suggest a negative feedback loop between miR-4485-3p and 16S rRNA. The obtained results provide molecular mechanisms of mitoribosome dysfunction in ATII cells in emphysema. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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15 pages, 3173 KiB

Open AccessEditor’s ChoiceArticle

Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide

by Maria Elisabetta Clementi, Michela Pizzoferrato, Giada Bianchetti, Anna Brancato, Beatrice Sampaolese, Giuseppe Maulucci and Giuseppe Tringali

Biomedicines 2022, 10(2), 503; https://doi.org/10.3390/biomedicines10020503 - 21 Feb 2022

Cited by 21 | Viewed by 3673

Abstract

Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of [...] Read more.

Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H₂O₂ oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H₂O₂-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Bax/Bcl-2 ratio; (d) maintained the mitochondrial membrane potential (ΔΨ_m) at physiological levels, preserving the functionality of mitochondrial respiratory complexes and counteracting the excessive production of ROS; and (e) reduced mitochondrial cytochrome C-mediated caspase-3 activity. Taken together, our findings show that idebenone protects RPE from oxidative damage by modulating the intrinsic mitochondrial pathway of apoptosis, suggesting its possible role in retinal epitheliopathies associated with mitochondrial dysfunction. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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15 pages, 2355 KiB

Open AccessArticle

Mitochondria-Mediated Apoptosis of HCC Cells Triggered by Knockdown of Glutamate Dehydrogenase 1: Perspective for Its Inhibition through Quercetin and Permethylated Anigopreissin A

by Michela Marsico, Anna Santarsiero, Ilaria Pappalardo, Paolo Convertini, Lucia Chiummiento, Alessandra Sardone, Maria Antonietta Di Noia, Vittoria Infantino and Simona Todisco

Biomedicines 2021, 9(11), 1664; https://doi.org/10.3390/biomedicines9111664 - 11 Nov 2021

Cited by 11 | Viewed by 2648

Abstract

Metabolic reprogramming is a hallmark of cancer cells required to ensure high energy needs and the maintenance of redox balance. A relevant metabolic change of cancer cell bioenergetics is the increase in glutamine metabolism. Hepatocellular carcinoma (HCC), one of the most lethal cancer [...] Read more.

Metabolic reprogramming is a hallmark of cancer cells required to ensure high energy needs and the maintenance of redox balance. A relevant metabolic change of cancer cell bioenergetics is the increase in glutamine metabolism. Hepatocellular carcinoma (HCC), one of the most lethal cancer and which requires the continuous development of new therapeutic strategies, shows an up-regulation of human glutamate dehydrogenase 1 (hGDH1). GDH1 function may be relevant in cancer cells (or HCC) to drive the glutamine catabolism from L-glutamate towards the synthesis of α-ketoglutarate (α-KG), thus supplying key tricarboxylic acid cycle (TCA cycle) metabolites. Here, the effects of hGLUD1 gene silencing (siGLUD1) and GDH1 inhibition were evaluated. Our results demonstrate that siGLUD1 in HepG2 cells induces a significant reduction in cell proliferation (58.8% ± 10.63%), a decrease in BCL2 expression levels, mitochondrial mass (75% ± 5.89%), mitochondrial membrane potential (30% ± 7.06%), and a significant increase in mitochondrial superoxide anion (25% ± 6.55%) compared to control/untreated cells. The inhibition strategy leads us to identify two possible inhibitors of hGDH1: quercetin and Permethylated Anigopreissin A (PAA). These findings suggest that hGDH1 could be a potential candidate target to impair the metabolic reprogramming of HCC cells. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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12 pages, 1845 KiB

Open AccessArticle

Nephroprotective Role of Chrysophanol in Hypoxia/Reoxygenation-Induced Renal Cell Damage via Apoptosis, ER Stress, and Ferroptosis

by Chih-Hung Lin, Han-Fang Tseng, Po-Chun Hsieh, Valeria Chiu, Ting-Yun Lin, Chou-Chin Lan, I-Shiang Tzeng, Huan-Nung Chao, Chia-Chen Hsu and Chan-Yen Kuo

Biomedicines 2021, 9(9), 1283; https://doi.org/10.3390/biomedicines9091283 - 21 Sep 2021

Cited by 17 | Viewed by 2991

Abstract

Acute kidney injury (AKI) is caused by hypoxia-reoxygenation (H/R), which is a kidney injury produced by a variety of causes, resulting in the remaining portion of the kidney function being unable to maintain the balance for performing the tasks of waste excretion metabolism, [...] Read more.

Acute kidney injury (AKI) is caused by hypoxia-reoxygenation (H/R), which is a kidney injury produced by a variety of causes, resulting in the remaining portion of the kidney function being unable to maintain the balance for performing the tasks of waste excretion metabolism, and electrolyte and acid-base balance. Many studies have reported the use of Chinese medicine to slow down the progression and alleviate the complications of chronic renal failure. Chrysophanol is a component of Rheum officinale Baill, a traditional Chinese medicine that has been clinically used to treat renal disease. We aimed to study the nephroprotective effect of chrysophanol on hypoxia/ reoxygenation (H/R)-induced cell damage. The results showed that chrysophanol prevented H/R-induced apoptosis via downregulation of cleaved Caspase-3, p-JNK, and Bax but upregulation of Bcl-2 expression. In contrast, chrysophanol attenuated H/R-induced endoplasmic reticulum (ER) stress via the downregulation of CHOP and p-IRE1α expression. Our data demonstrated that chrysophanol alleviated H/R-induced lipid ROS accumulation and ferroptosis. Therefore, we propose that chrysophanol may have a protective effect against AKI by regulating apoptosis, ER stress, and ferroptosis. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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19 pages, 2747 KiB

Open AccessArticle

Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage

by Carla Iacobini, Martina Vitale, Giuseppe Pugliese and Stefano Menini

Biomedicines 2021, 9(9), 1139; https://doi.org/10.3390/biomedicines9091139 - 02 Sep 2021

Cited by 14 | Viewed by 2783

Abstract

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial [...] Read more.

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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17 pages, 5432 KiB

Open AccessArticle

Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress

by Mei-Chun Chen, Li-Lin Hsu, Sheng-Fan Wang, Yi-Ling Pan, Jeng-Fan Lo, Tien-Shun Yeh, Ling-Ming Tseng and Hsin-Chen Lee

Biomedicines 2021, 9(9), 1101; https://doi.org/10.3390/biomedicines9091101 - 28 Aug 2021

Cited by 5 | Viewed by 2919

Abstract

Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we [...] Read more.

Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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Review

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14 pages, 1163 KiB

Open AccessReview

Mitochondrial Quality Control in the Heart: The Balance between Physiological and Pathological Stress

by Giovanni Fajardo, Michael Coronado, Melia Matthews and Daniel Bernstein

Biomedicines 2022, 10(6), 1375; https://doi.org/10.3390/biomedicines10061375 - 10 Jun 2022

Cited by 4 | Viewed by 3060

Abstract

Alterations in mitochondrial function and morphology are critical adaptations to cardiovascular stress, working in concert in an attempt to restore organelle-level and cellular-level homeostasis. Processes that alter mitochondrial morphology include fission, fusion, mitophagy, and biogenesis, and these interact to maintain mitochondrial quality control. [...] Read more.

Alterations in mitochondrial function and morphology are critical adaptations to cardiovascular stress, working in concert in an attempt to restore organelle-level and cellular-level homeostasis. Processes that alter mitochondrial morphology include fission, fusion, mitophagy, and biogenesis, and these interact to maintain mitochondrial quality control. Not all cardiovascular stress is pathologic (e.g., ischemia, pressure overload, cardiotoxins), despite a wealth of studies to this effect. Physiological stress, such as that induced by aerobic exercise, can induce morphologic adaptations that share many common pathways with pathological stress, but in this case result in improved mitochondrial health. Developing a better understanding of the mechanisms underlying alterations in mitochondrial quality control under diverse cardiovascular stressors will aid in the development of pharmacologic interventions aimed at restoring cellular homeostasis. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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20 pages, 3550 KiB

Open AccessReview

Ferroptosis as a Major Factor and Therapeutic Target for Neuroinflammation in Parkinson’s Disease

by Chih-Jan Ko, Shih-Ling Gao, Tsu-Kung Lin, Pei-Yi Chu and Hung-Yu Lin

Biomedicines 2021, 9(11), 1679; https://doi.org/10.3390/biomedicines9111679 - 12 Nov 2021

Cited by 27 | Viewed by 4230

Abstract

Mounting evidence suggests that ferroptosis is not just a consequence but also a fundamental contributor to the development and progression of Parkinson’s disease (PD). Ferroptosis is characterized as iron-dependent regulated cell death caused by excessive lipid peroxidation, leading to plasma membrane rupture, release [...] Read more.

Mounting evidence suggests that ferroptosis is not just a consequence but also a fundamental contributor to the development and progression of Parkinson’s disease (PD). Ferroptosis is characterized as iron-dependent regulated cell death caused by excessive lipid peroxidation, leading to plasma membrane rupture, release of damage-associated molecular patterns, and neuroinflammation. Due to the crucial role of intracellular iron in mediating the production of reactive oxygen species and the formation of lipid peroxides, ferroptosis is intimately controlled by regulators involved in many aspects of iron metabolism, including iron uptake, storage and export, and by pathways constituting the antioxidant systems. Translational and transcriptional regulation of iron homeostasis and redox status provide an integrated network to determine the sensitivity of ferroptosis. We herein review recent advances related to ferroptosis, ranging from fundamental mechanistic discoveries and cutting-edge preclinical animal studies, to clinical trials in PD and the regulation of neuroinflammation via ferroptosis pathways. Elucidating the roles of ferroptosis in the survival of dopaminergic neurons and microglial activity can enhance our understanding of the pathogenesis of PD and provide opportunities for the development of novel prevention and treatment strategies. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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27 pages, 1430 KiB

Open AccessReview

Sirtuin 3 (SIRT3) Pathways in Age-Related Cardiovascular and Neurodegenerative Diseases

by Ciprian N. Silaghi, Marius Farcaș and Alexandra M. Crăciun

Biomedicines 2021, 9(11), 1574; https://doi.org/10.3390/biomedicines9111574 - 29 Oct 2021

Cited by 13 | Viewed by 3918

Abstract

Age-associated cardiovascular and neurodegenerative diseases lead to high morbidity and mortality around the world. Sirtuins are vital enzymes for metabolic adaptation and provide protective effects against a wide spectrum of pathologies. Among sirtuins, mitochondrial sirtuin 3 (SIRT3) is an essential player in preserving [...] Read more.

Age-associated cardiovascular and neurodegenerative diseases lead to high morbidity and mortality around the world. Sirtuins are vital enzymes for metabolic adaptation and provide protective effects against a wide spectrum of pathologies. Among sirtuins, mitochondrial sirtuin 3 (SIRT3) is an essential player in preserving the habitual metabolic profile. SIRT3 activity declines as a result of aging-induced changes in cellular metabolism, leading to increased susceptibility to endothelial dysfunction, hypertension, heart failure and neurodegenerative diseases. Stimulating SIRT3 activity via lifestyle, pharmacological or genetic interventions could protect against a plethora of pathologies and could improve health and lifespan. Thus, understanding how SIRT3 operates and how its protective effects could be amplified, will aid in treating age-associated diseases and ultimately, in enhancing the quality of life in elders. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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30 pages, 1100 KiB

Open AccessReview

Oxidative Stress, Mitochondrial Dysfunction, and Neuroprotection of Polyphenols with Respect to Resveratrol in Parkinson’s Disease

by Heng-Chung Kung, Kai-Jung Lin, Chia-Te Kung and Tsu-Kung Lin

Biomedicines 2021, 9(8), 918; https://doi.org/10.3390/biomedicines9080918 - 30 Jul 2021

Cited by 56 | Viewed by 4881

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss. The exact pathogenesis of PD is complex and not yet completely understood, but research has established the critical role mitochondrial dysfunction plays in the development of [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss. The exact pathogenesis of PD is complex and not yet completely understood, but research has established the critical role mitochondrial dysfunction plays in the development of PD. As the main producer of cytosolic reactive oxygen species (ROS), mitochondria are particularly susceptible to oxidative stress once an imbalance between ROS generation and the organelle’s antioxidative system occurs. An overabundance of ROS in the mitochondria can lead to mitochondrial dysfunction and further vicious cycles. Once enough damage accumulates, the cell may undergo mitochondria-dependent apoptosis or necrosis, resulting in the neuronal loss of PD. Polyphenols are a group of natural compounds that have been shown to offer protection against various diseases, including PD. Among these, the plant-derived polyphenol, resveratrol, exhibits neuroprotective effects through its antioxidative capabilities and provides mitochondria protection. Resveratrol also modulates crucial genes involved in antioxidative enzymes regulation, mitochondrial dynamics, and cellular survival. Additionally, resveratrol offers neuroprotective effects by upregulating mitophagy through multiple pathways, including SIRT-1 and AMPK/ERK pathways. This compound may provide potential neuroprotective effects, and more clinical research is needed to establish the efficacy of resveratrol in clinical settings. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)

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