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Special Issue "Targeting Mitochondria in Aging and Disease"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 August 2020).

Special Issue Editors

Dr. Alessandra Stacchiotti
Website1 Website2
Guest Editor
Division of Anatomy and Physiopathology, Department Experimental and Clinical Sciences, Università degli Studi di Brescia, Brescia, Italy
Interests: traslational preclinical models of diseases; metabolic diseases; oxidative damage; endoplasmic reticulum stress; mitochondria; autophagy; mitophagy; role of antioxidants; ageing; sirtuins
Special Issues and Collections in MDPI journals
Dr. Maria Monsalve
Website
Guest Editor
Instituto de Investigaciones Biomédicas Alberto Sols (IIBm), CSIC-UAM, Madrid, Spain
Interests: mitochondria; metabolic diseases; oxidative stress; cardiovascular diseases; retinopathy; NAFLD; cancer; biomarkers; type 2 diabetes

Special Issue Information

Dear Colleagues,

Emerging evidence indicates that mitochondria, the essential energy powerhouse in cells, can be pharmacologically targeted. Aging dramatically impacts mitochondrial efficacy and plasticity, and to sustain mitochondrial biogenesis is the main objective of anti-aging medicine. Mitochondrial dysfunction at an ultrastructural level can be evidenced by the observation of abnormal cristae at the cellular level, characterized by altered size, number, and sub-cellular localization, as well as by reduced turnover and dynamics. These changes are associated with the disrupted function of the electron transport chain, showing lower electronic capacity, reduced membrane potential, increased production of superoxide, and reduced capacity to couple electronic flux to ATP synthesis. Neurons, skeletal and cardiac myocytes, and hepatocytes are among the most affected cell types due to their reliance on mitochondrial ATP output. Noted bioenergetic alterations—characteristics of aging— are also shared by cancer cells and have been suggested to have an impact on the control of cell death pathways, autophagy, and proteostasis. Recently, mitophagy has become a focus of attention in aging, metabolic diseases, and cancer. This is a selective mitochondrial clearing mechanism dependent on lysosomes, which has been shown to be defective or functionally altered, leading to the accumulation of dysfunctional mitochondria in the cell. Thus, targeting the mitochondria and restoring proper mitochondrial homeostasis are fundamental to treating disorders in which mitochondrial dysfunction has been shown to be a key driver of the disease. Novel developments have boosted our capacity to analyze mitochondria by evaluating cellular and circulating mtDNA—free and associated with regulatory factors. Therefore, the evaluation of epigenetic cues and mitochondrial medicine are challenging topics for future diagnostic and therapeutic developments. We believe that now is the time to support the exchange of ideas and the latest results on mitochondrial biology and medicine and have therefore decided to propose this Special Issue for interested clinical, academic, or industrial researchers all over the world. Original articles, comprehensive reviews, or perspective articles are welcome.

Topics of interest include, but are not limited to, the following:

  • Mitochondria in aging;
  • Mitochondria in exercise;
  • Mitochondria in cancer,
  • Mitochondria in neurodegeneration;
  • Mitochondria in metabolic diseases;
  • Mitochondrial mtDNA regulation;
  • Mitochondrial oxidative pathways;
  • Hypoxia regulation;
  • Antioxidants and nutraceutical drugs.

Dr. Alessandra Stacchiotti
Dr. Maria Monsalve
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mitophagy
  • new generation antioxidants
  • exercise
  • aging
  • metabolic diseases
  • neurodegenerative diseases
  • mitochondrial plasticity
  • targeting mitochondria
  • epigenetics
  • mtDNA
  • cancer

Published Papers (15 papers)

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Research

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Open AccessArticle
Insulin Modulates the Bioenergetic and Thermogenic Capacity of Rat Brown Adipocytes In Vivo by Modulating Mitochondrial Mosaicism
Int. J. Mol. Sci. 2020, 21(23), 9204; https://doi.org/10.3390/ijms21239204 - 03 Dec 2020
Abstract
The effects of insulin on the bioenergetic and thermogenic capacity of brown adipocyte mitochondria were investigated by focusing on key mitochondrial proteins. Two-month-old male Wistar rats were treated acutely or chronically with a low or high dose of insulin. Acute low insulin dose [...] Read more.
The effects of insulin on the bioenergetic and thermogenic capacity of brown adipocyte mitochondria were investigated by focusing on key mitochondrial proteins. Two-month-old male Wistar rats were treated acutely or chronically with a low or high dose of insulin. Acute low insulin dose increased expression of all electron transport chain complexes and complex IV activity, whereas high dose increased complex II expression. Chronic low insulin dose decreased complex I and cyt c expression while increasing complex II and IV expression and complex IV activity. Chronic high insulin dose decreased complex II, III, cyt c, and increased complex IV expression. Uncoupling protein (UCP) 1 expression was decreased after acute high insulin but increased following chronic insulin treatment. ATP synthase expression was increased after acute and decreased after chronic insulin treatment. Only a high dose of insulin increased ATP synthase activity in acute and decreased it in chronic treatment. ATPase inhibitory factor protein expression was increased in all treated groups. Confocal microscopy showed that key mitochondrial proteins colocalize differently in different mitochondria within a single brown adipocyte, indicating mitochondrial mosaicism. These results suggest that insulin modulates the bioenergetic and thermogenic capacity of rat brown adipocytes in vivo by modulating mitochondrial mosaicism. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
Thermogenic Activation Downregulates High Mitophagy Rate in Human Masked and Mature Beige Adipocytes
Int. J. Mol. Sci. 2020, 21(18), 6640; https://doi.org/10.3390/ijms21186640 - 10 Sep 2020
Abstract
Thermogenic brown and beige adipocytes oxidize metabolic substrates producing heat, mainly by the mitochondrial uncoupling protein UCP1, and can thus counteract obesity. Masked beige adipocytes possess white adipocyte-like morphology, but can be made thermogenic by adrenergic stimuli. We investigated the regulation of mitophagy [...] Read more.
Thermogenic brown and beige adipocytes oxidize metabolic substrates producing heat, mainly by the mitochondrial uncoupling protein UCP1, and can thus counteract obesity. Masked beige adipocytes possess white adipocyte-like morphology, but can be made thermogenic by adrenergic stimuli. We investigated the regulation of mitophagy upon thermogenic activation of human masked and mature beige adipocytes. Human primary abdominal subcutaneous adipose-derived stromal cells (hASCs) and Simpson–Golabi–Behmel syndrome (SGBS) preadipocytes were differentiated to white and beige adipocytes, then their cAMP-induced thermogenic potential was assessed by detecting increased expressions of UCP1, mitochondrial DNA content and respiratory chain complex subunits. cAMP increased the thermogenic potential of white adipocytes similarly to beige ones, indicating the presence of a masked beige population. In unstimulated conditions, a high autophagic flux and mitophagy rates (demonstrated by LC3 punctae and TOM20 co-immunostaining) were observed in white adipocytes, while these were lower in beige adipocytes. Silencing and gene expression experiments showed that the ongoing mitophagy was Parkin-independent. cAMP treatment led to the downregulation of mitophagy through PKA in both types of adipocytes, resulting in more fragmented mitochondria and increased UCP1 levels. Our data indicates that mitophagy is repressed upon encountering a short-term adrenergic stimulus, as a fast regulatory mechanism to provide high mitochondrial content for thermogenesis. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression
Int. J. Mol. Sci. 2020, 21(16), 5939; https://doi.org/10.3390/ijms21165939 - 18 Aug 2020
Abstract
Carbonic anhydrase IX (CA9), a pH-regulating transmembrane protein, is highly expressed in solid tumors, and particularly in clear cell renal cell carcinoma (ccRCC). The catalytic mechanisms of CA9 are well defined, but its roles in mediating cell migration/invasion and survival in ccRCC remain [...] Read more.
Carbonic anhydrase IX (CA9), a pH-regulating transmembrane protein, is highly expressed in solid tumors, and particularly in clear cell renal cell carcinoma (ccRCC). The catalytic mechanisms of CA9 are well defined, but its roles in mediating cell migration/invasion and survival in ccRCC remain to be determined. Here, we confirmed that the mRNA expression of CA9 in ccRCC was significantly higher than that in para-carcinoma tissues from analysis of the datasets in The Cancer Genome Atlas. CA9 knockdown upregulated oxidative phosphorylation-associated proteins and increased mitochondrial biogenesis, resulting in the reversal of the Warburg phenotype and the inhibition of cell growth. Our study revealed that CA9 knockdown upregulated mitochondrial arginase 2 (ARG2), leading to the accumulation of putrescine, which suppressed ccRCC proliferation. Surfaceomics analysis revealed that CA9 knockdown downregulated proteins associated with extracellular matrix (ECM)—receptor interaction and cell adhesion, resulting in decreased cell migration. CA9 silencing also downregulated amino acid transporters, leading to reduced cellular amino acids. Collectively, our data show that CA9 knockdown suppresses proliferation via metabolic reprogramming and reduced cell migration, reaffirming that CA9 is a potential therapeutic target for ccRCC treatment. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
The Cbs Locus Affects the Expression of Senescence Markers and mtDNA Copy Number, but not Telomere Dynamics in Mice
Int. J. Mol. Sci. 2020, 21(7), 2520; https://doi.org/10.3390/ijms21072520 - 05 Apr 2020
Cited by 1
Abstract
Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we examined a possible involvement of senescence, mitochondrial [...] Read more.
Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we examined a possible involvement of senescence, mitochondrial DNA, and telomeres in the reduced life span of Cbs−/− mice. We found that senescence-related p21, Pai-1, Mcp1, and Il-6 mRNAs were significantly upregulated (2–10-fold) in liver, while p21 was upregulated in the brain of Cbs−/− mice (n = 20) compared with control Cbs+/− siblings (n = 20) in a sex- and age-dependent manner. Telomere length in blood (n = 80), liver (n = 40), and brain (n = 40) was not affected by the Cbs−/− genotype, but varied with sex and/or age. Levels of mitochondrial DNA tended to be reduced in livers, but not brains and blood, of Cbs−/− females (n = 20–40). The Cbs−/− genotype significantly reduced Tert mRNA expression in brain, but not liver, in a sex- and age-dependent manner. Multiple regression analysis showed that the senescence-related liver (but not brain) mRNAs and liver (but not brain or blood) mitochondrial DNA were associated with the Cbs genotype. In contrast, telomere length in blood, brain, and liver was not associated with the Cbs genotype or hyperhomocysteinemia, but was associated with sex (in brain and liver) and age (in brain and blood). Taken together, these findings suggest that the changes in senescence marker expression and mtDNA levels, but not telomere shortening, could account for the reduced life span of Cbs−/− mice. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
Pioglitazone and Deoxyribonucleoside Combination Treatment Increases Mitochondrial Respiratory Capacity in m.3243A>G MELAS Cybrid Cells
Int. J. Mol. Sci. 2020, 21(6), 2139; https://doi.org/10.3390/ijms21062139 - 20 Mar 2020
Abstract
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ [...] Read more.
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
Hibernator-Derived Cells Show Superior Protection and Survival in Hypothermia Compared to Non-Hibernator Cells
Int. J. Mol. Sci. 2020, 21(5), 1864; https://doi.org/10.3390/ijms21051864 - 09 Mar 2020
Cited by 2
Abstract
Mitochondrial failure is recognized to play an important role in a variety of diseases. We previously showed hibernating species to have cell-autonomous protective mechanisms to resist cellular stress and sustain mitochondrial function. Here, we set out to detail these mitochondrial features of hibernators. [...] Read more.
Mitochondrial failure is recognized to play an important role in a variety of diseases. We previously showed hibernating species to have cell-autonomous protective mechanisms to resist cellular stress and sustain mitochondrial function. Here, we set out to detail these mitochondrial features of hibernators. We compared two hibernator-derived cell lines (HaK and DDT1MF2) with two non-hibernating cell lines (HEK293 and NRK) during hypothermia (4 °C) and rewarming (37 °C). Although all cell lines showed a strong decrease in oxygen consumption upon cooling, hibernator cells maintained functional mitochondria during hypothermia, without mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential decline or decreased adenosine triphosphate (ATP) levels, which were all observed in both non-hibernator cell lines. In addition, hibernator cells survived hypothermia in the absence of extracellular energy sources, suggesting their use of an endogenous substrate to maintain ATP levels. Moreover, hibernator-derived cells did not accumulate reactive oxygen species (ROS) damage and showed normal cell viability even after 48 h of cold-exposure. In contrast, non-hibernator cells accumulated ROS and showed extensive cell death through ferroptosis. Understanding the mechanisms that hibernators use to sustain mitochondrial activity and counteract damage in hypothermic circumstances may help to define novel preservation techniques with relevance to a variety of fields, such as organ transplantation and cardiac arrest. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
The Influence of Statins on the Aerobic Metabolism of Endothelial Cells
Int. J. Mol. Sci. 2020, 21(4), 1485; https://doi.org/10.3390/ijms21041485 - 21 Feb 2020
Cited by 4
Abstract
Endothelial mitochondrial dysfunction is considered to be the main cause of cardiovascular disease. The aim of this research was to elucidate the effects of cholesterol-lowering statins on the aerobic metabolism of endothelial cells at the cellular and mitochondrial levels. In human umbilical vein [...] Read more.
Endothelial mitochondrial dysfunction is considered to be the main cause of cardiovascular disease. The aim of this research was to elucidate the effects of cholesterol-lowering statins on the aerobic metabolism of endothelial cells at the cellular and mitochondrial levels. In human umbilical vein endothelial cells (EA.hy926), six days of exposure to 100 nM atorvastatin (ATOR) induced a general decrease in mitochondrial respiration. No changes in mitochondrial biogenesis, cell viability, or ATP levels were observed, whereas a decrease in Coenzyme Q10 (Q10) content was accompanied by an increase in intracellular reactive oxygen species (ROS) production, although mitochondrial ROS production remained unchanged. The changes caused by 100 nM pravastatin were smaller than those caused by ATOR. The ATOR-induced changes at the respiratory chain level promoted increased mitochondrial ROS production. In addition to the reduced level of mitochondrial Q10, the activity of Complex III was decreased, and the amount of Complex III in a supercomplex with Complex IV was diminished. These changes may cause the observed decrease in mitochondrial membrane potential and an increase in Q10 reduction level as a consequence, leading to elevated mitochondrial ROS formation. The above observations highlight the role of endothelial mitochondria in response to potential metabolic adaptations related to the chronic exposure of endothelial cells to statins. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
Adaptation of Mitochondrial Substrate Flux in a Mouse Model of Nonalcoholic Fatty Liver Disease
Int. J. Mol. Sci. 2020, 21(3), 1101; https://doi.org/10.3390/ijms21031101 - 07 Feb 2020
Abstract
Maladaptation of mitochondrial oxidative flux seems to be a considerable feature of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to induce NAFLD in mice fed a Western-style diet (WD) and to evaluate liver mitochondrial functions. Experiments were performed on [...] Read more.
Maladaptation of mitochondrial oxidative flux seems to be a considerable feature of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to induce NAFLD in mice fed a Western-style diet (WD) and to evaluate liver mitochondrial functions. Experiments were performed on male C57BL/6J mice fed with a control diet or a WD for 24 weeks. Histological changes in liver and adipose tissue as well as hepatic expression of fibrotic and inflammatory genes and proteins were evaluated. The mitochondrial respiration was assessed by high-resolution respirometry. Oxidative stress was evaluated by measuring lipoperoxidation, glutathione, and reactive oxygen species level. Feeding mice a WD induced adipose tissue inflammation and massive liver steatosis accompanied by mild inflammation and fibrosis. We found decreased succinate-activated mitochondrial respiration and decreased succinate dehydrogenase (SDH) activity in the mice fed a WD. The oxidative flux with other substrates was not affected. We observed increased ketogenic capacity, but no impact on the capacity for fatty acid oxidation. We did not confirm the presence of oxidative stress. Mitochondria in this stage of the disease are adapted to increased substrate flux. However, inhibition of SDH can lead to the accumulation of succinate, an important signaling molecule associated with inflammation, fibrosis, and carcinogenesis. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessArticle
Independent and Combined Effects of Telomere Shortening and mtDNA4977 Deletion on Long-term Outcomes of Patients with Coronary Artery Disease
Int. J. Mol. Sci. 2019, 20(21), 5508; https://doi.org/10.3390/ijms20215508 - 05 Nov 2019
Cited by 2
Abstract
Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA4977 [...] Read more.
Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA4977), on major adverse cardiovascular events (MACEs) and all-cause mortality in patients with coronary artery disease (CAD). We studied 770 patients (673 males, 64.8 ± 8.3 years) with known or suspected stable CAD. LTL and mtDNA4977 deletion were assessed in peripheral blood using qRT-PCR. During a median follow-up of 5.4 ± 1.2 years, MACEs were 140 while 86 deaths were recorded. After adjustments for confounding risk factors, short LTLs and high mtDNA4977 deletion levels acted independently as predictors of MACEs (HR: 2.2, 95% CI: 1.2–3.9, p = 0.01 and HR: 1.7, 95% CI: 1.1–2.9, p = 0.04; respectively) and all-cause mortality events (HR: 2.1, 95% CI: 1.1–4.6, p = 0.04 and HR: 2.3, 95% CI: 1.1–4.9, p = 0.02; respectively). Patients with both short LTLs and high mtDNA4977 deletion levels had an increased risk for MACEs (HR: 4.3; 95% CI: 1.9–9.6; p = 0.0006) and all-cause mortality (HR: 6.0; 95% CI: 2.0–18.4; p = 0.001). The addition of mtDNA4977 deletion to a clinical reference model was associated with a significant net reclassification improvement (NRI = 0.18, p = 0.01). Short LTL and high mtDNA4977 deletion showed independent and joint predictive value on adverse cardiovascular outcomes and all-cause mortality in patients with CAD. These findings strongly support the importance of evaluating biomarkers of physiological/biological age, which can predict disease risk and mortality more accurately than chronological age. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Review

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Open AccessReview
Intimate Relations—Mitochondria and Ageing
Int. J. Mol. Sci. 2020, 21(20), 7580; https://doi.org/10.3390/ijms21207580 - 14 Oct 2020
Abstract
Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. We review the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their [...] Read more.
Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. We review the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessReview
Are Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance?
Int. J. Mol. Sci. 2020, 21(18), 6948; https://doi.org/10.3390/ijms21186948 - 22 Sep 2020
Cited by 3
Abstract
As a major site of glucose uptake following a meal, skeletal muscle has an important role in whole-body glucose metabolism. Evidence in humans and animal models of insulin resistance and type 2 diabetes suggests that alterations in mitochondrial characteristics accompany the development of [...] Read more.
As a major site of glucose uptake following a meal, skeletal muscle has an important role in whole-body glucose metabolism. Evidence in humans and animal models of insulin resistance and type 2 diabetes suggests that alterations in mitochondrial characteristics accompany the development of skeletal muscle insulin resistance. However, it is unclear whether changes in mitochondrial content, respiratory function, or substrate oxidation are central to the development of insulin resistance or occur in response to insulin resistance. Thus, this review will aim to evaluate the apparent conflicting information placing mitochondria as a key organelle in the development of insulin resistance in skeletal muscle. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessReview
The Significance of Mitochondrial Dysfunction in Cancer
Int. J. Mol. Sci. 2020, 21(16), 5598; https://doi.org/10.3390/ijms21165598 - 05 Aug 2020
Cited by 2
Abstract
As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of apoptosis. Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, [...] Read more.
As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of apoptosis. Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, oxidative stress, or aberrant oncogene and tumor suppressor signaling, has been observed in a wide spectrum of human cancers. In this review, we summarize mitochondrial dysfunction induced by these alterations that promote human cancers. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessReview
Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases
Int. J. Mol. Sci. 2020, 21(10), 3719; https://doi.org/10.3390/ijms21103719 - 25 May 2020
Cited by 9
Abstract
Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. [...] Read more.
Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. However, perturbations of the system due to senescence or environmental factors induce alterations of the physiological balance and lead to the impairment of mitochondrial functions. After the description of the crucial roles of mitochondria for cell survival and activity, the core of this review focuses on the “mitochondrial switch” which occurs at the onset of neuronal degeneration. We dissect the pathways related to mitochondrial dysfunctions which are shared among the most frequent or disabling neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. Can mitochondrial dysfunctions (affecting their morphology and activities) represent the early event eliciting the shift towards pathological neurobiological processes? Can mitochondria represent a common target against neurodegeneration? We also review here the drugs that target mitochondria in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessReview
Targeting Mitochondria during Cold Storage to Maintain Proteasome Function and Improve Renal Outcome after Transplantation
Int. J. Mol. Sci. 2020, 21(10), 3506; https://doi.org/10.3390/ijms21103506 - 15 May 2020
Abstract
Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD). Compared to maintenance dialysis, kidney transplantation results in improved patient survival and quality of life. Kidneys from living donors perform best; however, many patients with ESKD depend on kidneys from deceased donors. [...] Read more.
Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD). Compared to maintenance dialysis, kidney transplantation results in improved patient survival and quality of life. Kidneys from living donors perform best; however, many patients with ESKD depend on kidneys from deceased donors. After procurement, donor kidneys are placed in a cold-storage solution until a suitable recipient is located. Sadly, prolonged cold storage times are associated with inferior transplant outcomes; therefore, in most situations when considering donor kidneys, long cold-storage times are avoided. The identification of novel mechanisms of cold-storage-related renal damage will lead to the development of new therapeutic strategies for preserving donor kidneys; to date, these mechanisms remain poorly understood. In this review, we discuss the importance of mitochondrial and proteasome function, protein homeostasis, and renal recovery during stress from cold storage plus transplantation. Additionally, we discuss novel targets for therapeutic intervention to improve renal outcomes. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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Open AccessReview
Targeting Mitochondrial Network Architecture in Down Syndrome and Aging
Int. J. Mol. Sci. 2020, 21(9), 3134; https://doi.org/10.3390/ijms21093134 - 29 Apr 2020
Cited by 6
Abstract
Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears [...] Read more.
Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator PGC-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the PGC-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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