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Mitochondrial Function in Human Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 33163

Special Issue Editor

Dr. Yumay Chen

E-Mail Website
Guest Editor
Department of Medicine, Division of Endocrinology, University of California, Irvine, CA 92697, USA
Interests: cell cycle checkpoint control; DNA damage and repair pathway; Nek1 protein kinase; polycystic kidney disease; AKT and mitochondrial function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria play critical metabolic roles in fatty acid oxidation, the Krebs cycle, and oxidative phosphorylation. All of these metabolic processes result in reactive oxygen species (ROS) production. ROS is toxic to cells because it causes oxidative damage to mitochondrial lipids, DNA, and proteins. Damaged mitochondria also release high levels of Ca2+ and cytochrome C to induce apoptosis.  To control the quality and quantity of mitochondria, selective autophagy, known as mitophagy, plays an important role by eliminating damaged mitochondria. Besides causing ROS damage in mitochondria, alterations in mitochondrial function through mutations in either the mitochondrial or nuclear genome have also been found to be associated with various diseases, such as cancer, aging, metabolic disorders, etc. The first known involvement of mitochondria in cancer came from Warburg’s landmark observation that tumors produce excess lactate in the presence of oxygen, now known as the “Warburg effect”, which is a form of aerobic glycolysis. Activation of cellular signaling transduction pathways, such as the PI3’K/PTEN/Akt pathway, also plays an important role in shifting metabolism from oxidative to glycolytic phosphorylation. Now, more evidence suggests that AKT kinase activity in mitochondria is crucial for cellular defense to extrinsic insults such as ischemia reperfusion. This special issue elucidates various aspects of mitochondrial function in cancer, kidney disease, apoptosis, and autophagy, and further discusses the therapeutic potential of targeting mitochondria.

Dr. Yumay Chen
Guest Editor

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Keywords

  • mitochondial genesis and disease
  • mitochondrial function and aging
  • mitochondrial dysfunction and cancer
  • mitochondrial function and apoptosis
  • mitophage
  • autophage
  • mitochondrial AKT

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Published Papers (15 papers)

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Research

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14 pages, 3995 KiB  
Article
Pennogenin 3-O-β-Chacotrioside Attenuates Hypertrophied Lipid Accumulation by Enhancing Mitochondrial Oxidative Capacity
by Seungmin Yu, Hee Min Lee, Jangho Lee, Jin-Taek Hwang, Hyo-Kyoung Choi and Yu Geon Lee
Int. J. Mol. Sci. 2024, 25(5), 2970; https://doi.org/10.3390/ijms25052970 - 4 Mar 2024
Viewed by 643
Abstract
Excessive lipid accumulation in adipocytes is a primary contributor to the development of metabolic disorders, including obesity. The consumption of bioactive compounds derived from natural sources has been recognized as being safe and effective in preventing and alleviating obesity. Therefore, we aimed to [...] Read more.
Excessive lipid accumulation in adipocytes is a primary contributor to the development of metabolic disorders, including obesity. The consumption of bioactive compounds derived from natural sources has been recognized as being safe and effective in preventing and alleviating obesity. Therefore, we aimed to explore the antilipidemic effects of pennogenin 3-O-β-chacotrioside (P3C), a steroid glycoside, on hypertrophied 3T3-L1 adipocytes. Oil Red O and Nile red staining demonstrated a P3C-induced reduction in lipid droplet accumulation. Additionally, the increased expression of adipogenic and lipogenic factors, including PPARγ and C/EBPα, during the differentiation process was significantly decreased by P3C treatment at both the protein and mRNA levels. Furthermore, P3C treatment upregulated the expression of fatty acid oxidation-related genes such as PGC1α and CPT1a. Moreover, mitochondrial respiration and ATP generation increased following P3C treatment, as determined using the Seahorse XF analyzer. P3C treatment also increased the protein expression of mitochondrial oxidative phosphorylation in hypertrophied adipocytes. Our findings suggest that P3C could serve as a natural lipid-lowering agent, reducing lipogenesis and enhancing mitochondrial oxidative capacity. Therefore, P3C may be a promising candidate as a therapeutic agent for obesity-related diseases. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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19 pages, 7924 KiB  
Article
High-Throughput Measure of Mitochondrial Superoxide Levels as a Marker of Coronary Artery Disease to Accelerate Drug Translation in Patient-Derived Endothelial Cells Using Opera Phenix® Technology
by Weiqian E. Lee, Marie Besnier, Elijah Genetzakis, Owen Tang, Katharine A. Kott, Stephen T. Vernon, Michael P. Gray, Stuart M. Grieve, Michael Kassiou and Gemma A. Figtree
Int. J. Mol. Sci. 2024, 25(1), 22; https://doi.org/10.3390/ijms25010022 - 19 Dec 2023
Viewed by 1555
Abstract
Improved human-relevant preclinical models of coronary artery disease (CAD) are needed to improve translational research and drug discovery. Mitochondrial dysfunction and associated oxidative stress contribute to endothelial dysfunction and are a significant factor in the development and progression of CAD. Endothelial colony-forming cells [...] Read more.
Improved human-relevant preclinical models of coronary artery disease (CAD) are needed to improve translational research and drug discovery. Mitochondrial dysfunction and associated oxidative stress contribute to endothelial dysfunction and are a significant factor in the development and progression of CAD. Endothelial colony-forming cells (ECFCs) can be derived from peripheral blood mononuclear cells (PBMCs) and offer a unique potentially personalised means for investigating new potential therapies targeting important components of vascular function. We describe the application of the high-throughput and confocal Opera Phenix® High-Content Screening System to examine mitochondrial superoxide (mROS) levels, mitochondrial membrane potential, and mitochondrial area in both established cell lines and patient-derived ECFCs simultaneously. Unlike traditional plate readers, the Opera Phenix® is an imaging system that integrates automated confocal microscopy, precise fluorescent detection, and multi-parameter algorithms to visualize and precisely quantify targeted biological processes at a cellular level. In this study, we measured mROS production in human umbilical vein endothelial cells (HUVECs) and patient-derived ECFCs using the mROS production probe, MitoSOXTM Red. HUVECs exposed to oxidized low-density lipoprotein (oxLDL) increased mROS levels by 47.7% (p < 0.0001). A pooled group of patient-derived ECFCs from participants with CAD (n = 14) exhibited 30.9% higher mROS levels compared to patients with no CAD when stimulated with oxLDL (n = 14; p < 0.05). When tested against a small group of candidate compounds, this signal was attenuated by PKT-100 (36.22% reduction, p = 0.03), a novel P2X7 receptor antagonist. This suggests the P2X7 receptor as a valid target against excess mROS levels. As such, these findings highlight the potential of the MitoSOX-Opera Phenix technique to be used for drug discovery efforts in CAD. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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19 pages, 15458 KiB  
Article
Improving Mitochondrial Function in Skeletal Muscle Contributes to the Amelioration of Insulin Resistance by Nicotinamide Riboside
by Qiuyan Li, Xuye Jiang, Yujia Zhou, Yingying Gu, Yijie Ding, Jing Luo, Nengzhi Pang, Yan Sun, Lei Pei, Jie Pan, Mengqi Gao, Sixi Ma, Ying Xiao, De Hu, Feilong Wu and Lili Yang
Int. J. Mol. Sci. 2023, 24(12), 10015; https://doi.org/10.3390/ijms241210015 - 12 Jun 2023
Cited by 1 | Viewed by 2559
Abstract
High-fat diet (HFD)-induced insulin resistance (IR) in skeletal muscle is often accompanied by mitochondrial dysfunction and oxidative stress. Boosting nicotinamide adenine dinucleotide (NAD) using nicotinamide riboside (NR) can effectively decrease oxidative stress and increase mitochondrial function. However, whether NR can ameliorate IR in [...] Read more.
High-fat diet (HFD)-induced insulin resistance (IR) in skeletal muscle is often accompanied by mitochondrial dysfunction and oxidative stress. Boosting nicotinamide adenine dinucleotide (NAD) using nicotinamide riboside (NR) can effectively decrease oxidative stress and increase mitochondrial function. However, whether NR can ameliorate IR in skeletal muscle is still inconclusive. We fed male C57BL/6J mice with an HFD (60% fat) ± 400 mg/kg·bw NR for 24 weeks. C2C12 myotube cells were treated with 0.25 mM palmitic acid (PA) ± 0.5 mM NR for 24 h. Indicators for IR and mitochondrial dysfunction were analyzed. NR treatment alleviated IR in HFD-fed mice with regard to improved glucose tolerance and a remarkable decrease in the levels of fasting blood glucose, fasting insulin and HOMA-IR index. NR-treated HFD-fed mice also showed improved metabolic status regarding a significant reduction in body weight and lipid contents in serum and the liver. NR activated AMPK in the skeletal muscle of HFD-fed mice and PA-treated C2C12 myotube cells and upregulated the expression of mitochondria-related transcriptional factors and coactivators, thereby improving mitochondrial function and alleviating oxidative stress. Upon inhibiting AMPK using Compound C, NR lost its ability in enhancing mitochondrial function and protection against IR induced by PA. In summary, improving mitochondrial function through the activation of AMPK pathway in skeletal muscle may play an important role in the amelioration of IR using NR. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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12 pages, 2042 KiB  
Article
Development of a Mitochondrial Targeting Lipid Nanoparticle Encapsulating Berberine
by Ikuma Hori, Hideyoshi Harashima and Yuma Yamada
Int. J. Mol. Sci. 2023, 24(2), 903; https://doi.org/10.3390/ijms24020903 - 4 Jan 2023
Cited by 4 | Viewed by 2248
Abstract
Delivering drugs to mitochondria, the main source of energy in neurons, can be a useful therapeutic strategy for the treatment of neurodegenerative diseases. Berberine (BBR), an isoquinoline alkaloid, acts on mitochondria and is involved in mechanisms associated with the normalization and regulation of [...] Read more.
Delivering drugs to mitochondria, the main source of energy in neurons, can be a useful therapeutic strategy for the treatment of neurodegenerative diseases. Berberine (BBR), an isoquinoline alkaloid, acts on mitochondria and is involved in mechanisms associated with the normalization and regulation of intracellular metabolism. Therefore, BBR has attracted considerable interest as a possible therapeutic drug for neurodegenerative diseases. While BBR has been reported to act on mitochondria, there are few reports on the efficient delivery of BBR into mitochondria. This paper reports on the mitochondrial delivery of BBR using a lipid nanoparticle (LNP), a “MITO-Porter” that targets mitochondria, and its pharmacological action in Neuro2a cells, a model neuroblastoma. A MITO-Porter containing encapsulated BBR (MITO-Porter (BBR)) was prepared. Treatment with MITO-Porter (BBR) increased the amount of BBR that accumulated in mitochondria compared with a treatment with naked BBR. Treatment with MITO-Porter (BBR) resulted in increased ATP production in Neuro2a cells, which are important for maintaining life phenomena, compared with treatment with naked BBR. Treatment with MITO-Porter (BBR) also increased the level of expression of mitochondrial ubiquitin ligase (MITOL), which is involved in mitochondrial quality control. Our findings indicate that increasing the accumulation of BBR into mitochondria is important for inducing enhanced pharmacological actions. The use of this system has the potential for being important in terms of the regulation of the metabolic mechanism of mitochondria in nerve cells. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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11 pages, 2584 KiB  
Article
Mitochondrial DNA as a Candidate Marker of Multiple Organ Failure after Cardiac Surgery
by Evgeny Grigoriev, Anastasia V. Ponasenko, Anna V. Sinitskaya, Artem A. Ivkin and Roman A. Kornelyuk
Int. J. Mol. Sci. 2022, 23(23), 14748; https://doi.org/10.3390/ijms232314748 - 25 Nov 2022
Cited by 3 | Viewed by 1378
Abstract
Assess the level of mitochondrial DNA depending on the presence of multiple organ failure in patients after heart surgery. The study included 60 patients who underwent surgical treatment of valvular heart disease using cardiopulmonary bypass. Uncomplicated patients were included in the 1st group [...] Read more.
Assess the level of mitochondrial DNA depending on the presence of multiple organ failure in patients after heart surgery. The study included 60 patients who underwent surgical treatment of valvular heart disease using cardiopulmonary bypass. Uncomplicated patients were included in the 1st group (n = 30), patients with complications and multiple organ failure (MOF) were included in the 2nd group (n = 30). Serum mtDNA levels were determined by quantitative real-time polymerase chain reaction with fluorescent dyes. Mitochondrial DNA gene expression did not differ between group before surgery. Immediately after the intervention, cytochrome B gene expression was higher in the group with MOF, and it remained high during entire follow-up period. A similar trend was observed in cytochrome oxidase gene expression. Increased NADH levels of gene expressions during the first postoperative day were noted in both groups, the expression showed tendency to increase on the third postoperative day. mtDNA gene expression in the “MOF present” group remained at a higher level compared with the group without complications. A positive correlation was reveled between the severity of MOF according to SOFA score and the level of mtDNA (r = 0.45; p = 0.028) for the end-point “First day”. The ROC analysis showed that mtDNA circulating in plasma (AUC = 0.605) can be a predictor of MOF development. The level of mtDNA significantly increases in case of MOF, irrespective of its cause. (2) The expression of mtDNA genes correlates with the level of MOF severity on the SOFA score. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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21 pages, 3004 KiB  
Article
Brain Effects of SC-Nanophytosomes on a Rotenone-Induced Rat Model of Parkinson’s Disease—A Proof of Concept for a Mitochondria-Targeted Therapy
by Daniela Mendes, Francisco Peixoto, Maria Manuel Oliveira, Paula Branquinho Andrade and Romeu António Videira
Int. J. Mol. Sci. 2022, 23(20), 12699; https://doi.org/10.3390/ijms232012699 - 21 Oct 2022
Cited by 1 | Viewed by 2395
Abstract
Mitochondria are an attractive target to fight neurodegenerative diseases due to their important functions for cells and the particularly close relationship between the functional connectivity among brain regions and mitochondrial performance. This work presents a mitochondria-targeted therapy designed to modulate the functionality of [...] Read more.
Mitochondria are an attractive target to fight neurodegenerative diseases due to their important functions for cells and the particularly close relationship between the functional connectivity among brain regions and mitochondrial performance. This work presents a mitochondria-targeted therapy designed to modulate the functionality of the mitochondrial respiratory chain and lipidome, parameters that are affected in neurodegeneration, including in Parkinson’s disease (PD). This therapy is supported by SC-Nanophytosomes constructed with membrane polar lipids, from Codium tomentosum, and elderberry anthocyanin-enriched extract, from Sambucus nigra L. SC-Nanophytosomes are nanosized vesicles with a high negative surface charge that preserve their properties, including anthocyanins in the flavylium cation form, under conditions that mimic the gastrointestinal tract pH changes. SC-Nanophytosomes, 3 µM in phospholipid, and 2.5 mg/L of EAE-extract, delivered by drinking water to a rotenone-induced PD rat model, showed significant positive outcomes on disabling motor symptoms associated with the disease. Ex vivo assays were performed with two brain portions, one comprising the basal ganglia and cerebellum (BG-Cereb) and the other with the cerebral cortex (C-Cortex) regions. Results showed that rotenone-induced neurodegeneration increases the α-synuclein levels in the BG-Cereb portion and compromises mitochondrial respiratory chain functionality in both brain portions, well-evidenced by a 50% decrease in the respiratory control rate and up to 40% in complex I activity. Rotenone-induced PD phenotype is also associated with changes in superoxide dismutase and catalase activities that are dependent on the brain portion. Treatment with SC-Nanophytosomes reverted the α-synuclein levels and antioxidant enzymes activity to the values detected in control animals. Moreover, it mitigated mitochondrial dysfunction, with positive outcomes on the respiratory control rate, the activity of individual respiratory complexes, and the fatty acid profile of the membrane phospholipids. Therefore, SC-Nanophytosomes are a promising tool to support mitochondria-targeted therapy for neurodegenerative diseases. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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Review

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14 pages, 1742 KiB  
Review
Mitochondrial Dysfunction and Metabolic Reprogramming in Obesity and Asthma
by Paige Hartsoe, Fernando Holguin and Hong Wei Chu
Int. J. Mol. Sci. 2024, 25(5), 2944; https://doi.org/10.3390/ijms25052944 - 3 Mar 2024
Viewed by 1121
Abstract
Mitochondrial dysfunction and metabolic reprogramming have been extensively studied in many disorders ranging from cardiovascular to neurodegenerative disease. Obesity has previously been associated with mitochondrial fragmentation, dysregulated glycolysis, and oxidative phosphorylation, as well as increased reactive oxygen species production. Current treatments focus on [...] Read more.
Mitochondrial dysfunction and metabolic reprogramming have been extensively studied in many disorders ranging from cardiovascular to neurodegenerative disease. Obesity has previously been associated with mitochondrial fragmentation, dysregulated glycolysis, and oxidative phosphorylation, as well as increased reactive oxygen species production. Current treatments focus on reducing cellular stress to restore homeostasis through the use of antioxidants or alterations of mitochondrial dynamics. This review focuses on the role of mitochondrial dysfunction in obesity particularly for those suffering from asthma and examines mitochondrial transfer from mesenchymal stem cells to restore function as a potential therapy. Mitochondrial targeted therapy to restore healthy metabolism may provide a unique approach to alleviate dysregulation in individuals with this unique endotype. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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18 pages, 1709 KiB  
Review
Mitochondrial Signaling, the Mechanisms of AKI-to-CKD Transition and Potential Treatment Targets
by Li-Yun Chang, Yu-Lin Chao, Chien-Chih Chiu, Phang-Lang Chen and Hugo Y.-H. Lin
Int. J. Mol. Sci. 2024, 25(3), 1518; https://doi.org/10.3390/ijms25031518 - 26 Jan 2024
Viewed by 1184
Abstract
Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and [...] Read more.
Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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33 pages, 1824 KiB  
Review
Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology
by Kyle M. Siemers, Abigail K. Klein and Michelle L. Baack
Int. J. Mol. Sci. 2023, 24(17), 13123; https://doi.org/10.3390/ijms241713123 - 23 Aug 2023
Cited by 6 | Viewed by 3540
Abstract
Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease, all comorbidities that are [...] Read more.
Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease, all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under the transcriptional regulation of both the nuclear and mitochondrial genome to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, as well as the dynamics that regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted, the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function, causing disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs, including the ovary (oocytes and granulosa cells), uterus, placenta, and circulation, causing reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in the transgenerational transmission of PCOS and metabolic disorders. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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17 pages, 1557 KiB  
Review
ATAD3A: A Key Regulator of Mitochondria-Associated Diseases
by Liting Chen, Yuchang Li, Alexander Zambidis and Vassilios Papadopoulos
Int. J. Mol. Sci. 2023, 24(15), 12511; https://doi.org/10.3390/ijms241512511 - 7 Aug 2023
Cited by 2 | Viewed by 2414
Abstract
Mitochondrial membrane protein ATAD3A is a member of the AAA-domain-containing ATPases superfamily. It is important for the maintenance of mitochondrial DNA, structure, and function. In recent years, an increasing number of ATAD3A mutations have been identified in patients with neurological symptoms. Many of [...] Read more.
Mitochondrial membrane protein ATAD3A is a member of the AAA-domain-containing ATPases superfamily. It is important for the maintenance of mitochondrial DNA, structure, and function. In recent years, an increasing number of ATAD3A mutations have been identified in patients with neurological symptoms. Many of these mutations disrupt mitochondrial structure, function, and dynamics and are lethal to patients at a young age. Here, we summarize the current understanding of the relationship between ATAD3A and mitochondria, including the interaction of ATAD3A with mitochondrial DNA and mitochondrial/ER proteins, the regulation of ATAD3A in cholesterol mitochondrial trafficking, and the effect of known ATAD3A mutations on mitochondrial function. In the current review, we revealed that the oligomerization and interaction of ATAD3A with other mitochondrial/ER proteins are vital for its various functions. Despite affecting different domains of the protein, nearly all documented mutations observed in ATAD3A exhibit either loss-of-function or dominant-negative effects, potentially leading to disruption in the dimerization of ATAD3A; autophagy; mitophagy; alteration in mitochondrial number, size, and cristae morphology; and diminished activity of mitochondrial respiratory chain complexes I, IV, and V. These findings imply that ATAD3A plays a critical role in mitochondrial dynamics, which can be readily perturbed by ATAD3A mutation variants. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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18 pages, 732 KiB  
Review
The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore
by Hagai Rottenberg
Int. J. Mol. Sci. 2023, 24(15), 12295; https://doi.org/10.3390/ijms241512295 - 1 Aug 2023
Cited by 5 | Viewed by 2234
Abstract
It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm [...] Read more.
It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm in C. elegans increased lifespan. Here, I critically review studies that reported reduction in ∆Ψm in aged animals, including worms, and conclude that many of these observations are best interpreted as evidence that the fraction of depolarized mitochondria is increased in aged cells because of the enhanced activation of the mitochondrial permeability transition pore, mPTP. Activation of the voltage-gated mPTP depolarizes the mitochondria, inhibits oxidative phosphorylation, releases large amounts of calcium and mROS, and depletes cellular NAD+, thus accelerating degenerative diseases and aging. Since the inhibition of mPTP was shown to restore ∆Ψm and to retard aging, the reported lifespan extension by artificially generated ∆Ψm in C. elegans is best explained by inhibition of the voltage-gated mPTP. Similarly, the reported activation of the mitochondrial unfolded protein response by reduction in ∆Ψm and the reported preservation of ∆Ψm in dietary restriction treatment in C. elegans are best explained as resulting from activation or inhibition of the voltage-gated mPTP, respectively. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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13 pages, 2223 KiB  
Review
SUV3 Helicase and Mitochondrial Homeostasis
by Phang-Lang Chen
Int. J. Mol. Sci. 2023, 24(11), 9233; https://doi.org/10.3390/ijms24119233 - 25 May 2023
Viewed by 1767
Abstract
SUV3 is a nuclear-encoded helicase that is highly conserved and localizes to the mitochondrial matrix. In yeast, loss of SUV3 function leads to the accumulation of group 1 intron transcripts, ultimately resulting in the loss of mitochondrial DNA, causing a petite phenotype. However, [...] Read more.
SUV3 is a nuclear-encoded helicase that is highly conserved and localizes to the mitochondrial matrix. In yeast, loss of SUV3 function leads to the accumulation of group 1 intron transcripts, ultimately resulting in the loss of mitochondrial DNA, causing a petite phenotype. However, the mechanism leading to the loss of mitochondrial DNA remains unknown. SUV3 is essential for survival in higher eukaryotes, and its knockout in mice results in early embryonic lethality. Heterozygous mice exhibit a range of phenotypes, including premature aging and an increased cancer incidence. Furthermore, cells derived from SUV3 heterozygotes or knockdown cultural cells show a reduction in mtDNA. Transient downregulation of SUV3 leads to the formation of R-loops and the accumulation of double-stranded RNA in mitochondria. This review aims to provide an overview of the current knowledge regarding the SUV3-containing complex and discuss its potential mechanism for tumor suppression activity. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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18 pages, 1367 KiB  
Review
The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases
by Adeena Shafique, Martina Brughera, Marta Lualdi and Tiziana Alberio
Int. J. Mol. Sci. 2023, 24(7), 6268; https://doi.org/10.3390/ijms24076268 - 27 Mar 2023
Viewed by 2249
Abstract
Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in [...] Read more.
Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause–effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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28 pages, 1735 KiB  
Review
Mitochondrial Control in Inflammatory Gastrointestinal Diseases
by Guo-Yan Sui, Feng Wang, Jin Lee and Yoon Seok Roh
Int. J. Mol. Sci. 2022, 23(23), 14890; https://doi.org/10.3390/ijms232314890 - 28 Nov 2022
Cited by 2 | Viewed by 3698
Abstract
Mitochondria play a central role in the pathophysiology of inflammatory bowel disease (IBD) and colorectal cancer (CRC). The maintenance of mitochondrial function is necessary for a stable immune system. Mitochondrial dysfunction in the gastrointestinal system leads to the excessive activation of multiple inflammatory [...] Read more.
Mitochondria play a central role in the pathophysiology of inflammatory bowel disease (IBD) and colorectal cancer (CRC). The maintenance of mitochondrial function is necessary for a stable immune system. Mitochondrial dysfunction in the gastrointestinal system leads to the excessive activation of multiple inflammatory signaling pathways, leading to IBD and increased severity of CRC. In this review, we focus on the mitochondria and inflammatory signaling pathways and its related gastrointestinal diseases. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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9 pages, 5081 KiB  
Review
Mitochondrial Role in Oncogenesis and Potential Chemotherapeutic Strategy of Mitochondrial Infusion in Breast Cancer
by Prisha S. Patel, Christopher Castelow, Disha S. Patel, Syamal K. Bhattacharya, Cem Kuscu, Canan Kuscu, Liza Makowski, James D. Eason and Amandeep Bajwa
Int. J. Mol. Sci. 2022, 23(21), 12993; https://doi.org/10.3390/ijms232112993 - 27 Oct 2022
Cited by 7 | Viewed by 2048
Abstract
Triple negative breast cancer (TNBC) is one of the most aggressive cancers diagnosed amongst women with a high rate of treatment failure and a poor prognosis. Mitochondria have been found to be key players in oncogenesis and tumor progression by mechanisms such as [...] Read more.
Triple negative breast cancer (TNBC) is one of the most aggressive cancers diagnosed amongst women with a high rate of treatment failure and a poor prognosis. Mitochondria have been found to be key players in oncogenesis and tumor progression by mechanisms such as altered metabolism, reactive oxygen species (ROS) production and evasion of apoptosis. Therefore, mitochondrial infusion is an area of interest for cancer treatment. Studies in vitro and in vivo demonstrate mitochondrial-mediated reduction in glycolysis, enhancement of oxidative phosphorylation (OXPHOS), reduction in proliferation, and an enhancement of apoptosis as effective anti-tumor therapies. This review focuses on mitochondrial dysregulation and infusion in malignancies, such as TNBC. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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