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18 pages, 1028 KiB

Open AccessArticle

Type 2 Diabetes Related Mitochondrial Defects in Peripheral Mononucleated Blood Cells from Overweight Postmenopausal Women

by Elisa Calabria, Valentina Muollo, Valentina Cavedon, Teodora Capovin, Leonardo Saccenti, Francesco Passarotti, Laura Ghiotto, Chiara Milanese, Matteo Gelati, Doriana Rudi, Gian Luca Salvagno, Giuseppe Lippi, Enrico Tam, Federico Schena and Silvia Pogliaghi

Biomedicines 2023, 11(1), 121; https://doi.org/10.3390/biomedicines11010121 - 03 Jan 2023

Viewed by 1656

Abstract

Type 2 diabetes (T2D) is a multisystem disease that is the subject of many studies, but the earliest cause of the disease has yet to be elucidated. Mitochondrial impairment has been associated with diabetes in several tissues. To extend the association between T2D [...] Read more.

Type 2 diabetes (T2D) is a multisystem disease that is the subject of many studies, but the earliest cause of the disease has yet to be elucidated. Mitochondrial impairment has been associated with diabetes in several tissues. To extend the association between T2D and mitochondrial impairment to blood cells, we investigated T2D-related changes in peripheral mononucleated blood cells’ (PBMCs) mitochondrial function in two groups of women (CTRL vs. T2D; mean age: 54.1 ± 3.8 vs. 60.9 ± 4.8; mean BMI 25.6 ± 5.2 vs. 30.0 ± 5), together with a panel of blood biomarkers, anthropometric measurements and physiological parameters (VO_2max and strength tests). Dual-energy X-ray absorptiometry (DXA) scan analysis, cardio-pulmonary exercise test and blood biomarkers confirmed hallmarks of diabetes in the T2D group. Mitochondrial function assays performed with high resolution respirometry highlighted a significant reduction of mitochondrial respiration in the ADP-stimulated state (OXPHOS; −30%, p = 0.006) and maximal non-coupled respiration (ET; −30%, p = 0.004) in PBMCs samples from the T2D group. The total glutathione antioxidant pool (GSHt) was significantly reduced (−38%: p = 0.04) in plasma samples from the T2D group. The fraction of glycated hemoglobin (Hb1Ac) was positively associated with markers of inflammation (C-reactive protein-CRP r = 0.618; p = 0.006) and of dyslipidemia (triglycerides-TG r = 0.815; p < 0.0001). The same marker (Hb1Ac) was negatively associated with mitochondrial activity levels (OXPHOS r = −0.502; p = 0.034; ET r = −0.529; p = 0.024). The results obtained in overweight postmenopausal women from analysis of PBMCs mitochondrial respiration and their association with anthropometric and physiological parameters indicate that PBMC could represent a reliable model for studying T2D-related metabolic impairment and could be useful for testing the effectiveness of interventions targeting mitochondria. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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9 pages, 984 KiB

Open AccessArticle

Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren’s Syndrome

by Giada De Benedittis, Andrea Latini, Serena Colafrancesco, Roberta Priori, Carlo Perricone, Lucia Novelli, Paola Borgiani and Cinzia Ciccacci

Biomedicines 2022, 10(11), 2699; https://doi.org/10.3390/biomedicines10112699 - 25 Oct 2022

Cited by 4 | Viewed by 1504

Abstract

Sjögren’s syndrome (SS) is a chronic autoimmune multifactorial disease characterized by inflammation and lymphocytic infiltration of the exocrine glands. Several studies have highlighted the involvement of oxidative stress in this pathology, suggesting that it could induce mitochondrial dysfunctions. Mitochondria could have a role [...] Read more.

Sjögren’s syndrome (SS) is a chronic autoimmune multifactorial disease characterized by inflammation and lymphocytic infiltration of the exocrine glands. Several studies have highlighted the involvement of oxidative stress in this pathology, suggesting that it could induce mitochondrial dysfunctions. Mitochondria could have a role in inflammatory and immune processes. Since the mitochondrial DNA (mtDNA) copy number could change in response to physiological or environmental stimuli, this study aimed to evaluate possible alterations in the mtDNA copy number in SS. We have analyzed the amount of mtDNA in the peripheral blood of 74 SS patients and 61 healthy controls by qPCR. Then, since mitochondrial fusion and fission play a crucial role in maintaining the number of mitochondria, we investigated the expression variability of the genes most commonly involved in mitochondrial dynamics in a subgroup of SS patients and healthy controls. Interestingly, we observed a highly significant decrease in mtDNA copies in the SS patients compared to healthy controls (p = 1.44 × 10⁻¹²). Expression levels of mitochondrial fission factor (MFF), mitofusin-1 (MFN1), and mitochondrial transcription factor A (TFAM) genes were analyzed, showing a statistically significant increase in the expression of MFF (p = 0.003) and TFAM (p = 0.022) in the SS patients compared to healthy controls. These results give further insight into the possible involvement of mitochondrial dysfunctions in SS disease. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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18 pages, 2760 KiB

Open AccessArticle

Exenatide and Dapagliflozin Combination Enhances Sertoli Cell Secretion of Key Metabolites for Spermatogenesis

by João C. Ribeiro, Ana D. Martins, Ivana Jarak, Rui A. Carvalho, Marco G. Alves and Pedro F. Oliveira

Biomedicines 2022, 10(5), 1115; https://doi.org/10.3390/biomedicines10051115 - 11 May 2022

Cited by 4 | Viewed by 2207

Abstract

The incidence of metabolic diseases such as type 2 diabetes mellitus (DM) and obesity has been increasing dramatically. Both diseases are closely linked and new approaches for type 2 DM treatment aim to enable weight loss. A combined therapy of dapagliflozin and exenatide [...] Read more.

The incidence of metabolic diseases such as type 2 diabetes mellitus (DM) and obesity has been increasing dramatically. Both diseases are closely linked and new approaches for type 2 DM treatment aim to enable weight loss. A combined therapy of dapagliflozin and exenatide has been used against type 2 DM, influencing allbody glucose dynamics. Spermatogenesis is highly dependent on the metabolic cooperation established between Sertoli cells (SCs) and developing germ cells. To study the effects of dapagliflozin and exenatide on SC metabolism, mouse SCs were treated in the presence of sub-pharmacologic, pharmacologic, and supra-pharmacologic concentrations of dapagliflozin (50, 500, 5000 nM, respectively) and/or exenatide (2.5, 25, 250 pM, respectively). Cytotoxicity of these compounds was evaluated and the glycolytic profile, glycogen content assay, and lipid accumulation of SCs were determined. Dapagliflozin treatment decreased fat cellular deposits, demonstrating its anti-obesity properties at the cellular level. Polytherapy of exenatide plus dapagliflozin increased lactate production by SCs, which has been reported to improve sperm production and quality. Thus, the results herein suggest that the use of these two pharmacological agents can protect male fertility, while improving their glucose homeostasis and inducing weight loss. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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Review

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22 pages, 757 KiB

Open AccessReview

Preservation of Mitochondrial Health in Liver Ischemia/Reperfusion Injury

by Ivo F. Machado, Carlos M. Palmeira and Anabela P. Rolo

Biomedicines 2023, 11(3), 948; https://doi.org/10.3390/biomedicines11030948 - 20 Mar 2023

Cited by 9 | Viewed by 2158

Abstract

Liver ischemia-reperfusion injury (LIRI) is a major cause of the development of complications in different clinical settings such as liver resection and liver transplantation. Damage arising from LIRI is a major risk factor for early graft rejection and is associated with higher morbidity [...] Read more.

Liver ischemia-reperfusion injury (LIRI) is a major cause of the development of complications in different clinical settings such as liver resection and liver transplantation. Damage arising from LIRI is a major risk factor for early graft rejection and is associated with higher morbidity and mortality after surgery. Although the mechanisms leading to the injury of parenchymal and non-parenchymal liver cells are not yet fully understood, mitochondrial dysfunction is recognized as a hallmark of LIRI that exacerbates cellular injury. Mitochondria play a major role in glucose metabolism, energy production, reactive oxygen species (ROS) signaling, calcium homeostasis and cell death. The diverse roles of mitochondria make it essential to preserve mitochondrial health in order to maintain cellular activity and liver integrity during liver ischemia/reperfusion (I/R). A growing body of studies suggest that protecting mitochondria by regulating mitochondrial biogenesis, fission/fusion and mitophagy during liver I/R ameliorates LIRI. Targeting mitochondria in conditions that exacerbate mitochondrial dysfunction, such as steatosis and aging, has been successful in decreasing their susceptibility to LIRI. Studying mitochondrial dysfunction will help understand the underlying mechanisms of cellular damage during LIRI which is important for the development of new therapeutic strategies aimed at improving patient outcomes. In this review, we highlight the progress made in recent years regarding the role of mitochondria in liver I/R and discuss the impact of liver conditions on LIRI. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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16 pages, 776 KiB

Open AccessReview

A Mitochondrial Perspective on Noncommunicable Diseases

by Yifan Zheng, Jing Zhang, Xiaohong Zhu, Yuanjuan Wei, Wuli Zhao, Shuyi Si and Yan Li

Biomedicines 2023, 11(3), 647; https://doi.org/10.3390/biomedicines11030647 - 21 Feb 2023

Cited by 1 | Viewed by 1869

Abstract

Mitochondria are the center of energy metabolism in eukaryotic cells and play a central role in the metabolism of living organisms. Mitochondrial diseases characterized by defects in oxidative phosphorylation are the most common congenital diseases. Meanwhile, mitochondrial dysfunction caused by secondary factors such [...] Read more.

Mitochondria are the center of energy metabolism in eukaryotic cells and play a central role in the metabolism of living organisms. Mitochondrial diseases characterized by defects in oxidative phosphorylation are the most common congenital diseases. Meanwhile, mitochondrial dysfunction caused by secondary factors such as non-inherited genetic mutations can affect normal physiological functions of human cells, induce apoptosis, and lead to the development of various diseases. This paper reviewed several major factors and mechanisms that contribute to mitochondrial dysfunction and discussed the development of diseases closely related to mitochondrial dysfunction and drug treatment strategies discovered in recent years. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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21 pages, 15090 KiB

Open AccessReview

The Bidirectional Relationship of NPY and Mitochondria in Energy Balance Regulation

by Diana Sousa, Eduardo Lopes, Daniela Rosendo-Silva and Paulo Matafome

Biomedicines 2023, 11(2), 446; https://doi.org/10.3390/biomedicines11020446 - 03 Feb 2023

Viewed by 3708

Abstract

Energy balance is regulated by several hormones and peptides, and neuropeptide Y is one of the most crucial in feeding and energy expenditure control. NPY is regulated by a series of peripheral nervous and humoral signals that are responsive to nutrient sensing, but [...] Read more.

Energy balance is regulated by several hormones and peptides, and neuropeptide Y is one of the most crucial in feeding and energy expenditure control. NPY is regulated by a series of peripheral nervous and humoral signals that are responsive to nutrient sensing, but its role in the energy balance is also intricately related to the energetic status, namely mitochondrial function. During fasting, mitochondrial dynamics and activity are activated in orexigenic neurons, increasing the levels of neuropeptide Y. By acting on the sympathetic nervous system, neuropeptide Y modulates thermogenesis and lipolysis, while in the peripheral sites, it triggers adipogenesis and lipogenesis instead. Moreover, both central and peripheral neuropeptide Y reduces mitochondrial activity by decreasing oxidative phosphorylation proteins and other mediators important to the uptake of fatty acids into the mitochondrial matrix, inhibiting lipid oxidation and energy expenditure. Dysregulation of the neuropeptide Y system, as occurs in metabolic diseases like obesity, may lead to mitochondrial dysfunction and, consequently, to oxidative stress and to the white adipose tissue inflammatory environment, contributing to the development of a metabolically unhealthy profile. This review focuses on the interconnection between mitochondrial function and dynamics with central and peripheral neuropeptide Y actions and discusses possible therapeutical modulations of the neuropeptide Y system as an anti-obesity tool. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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17 pages, 1034 KiB

Open AccessReview

Exercise-Boosted Mitochondrial Remodeling in Parkinson’s Disease

by Juan Carlos Magaña, Cláudia M. Deus, Maria Giné-Garriga, Joel Montané and Susana P. Pereira

Biomedicines 2022, 10(12), 3228; https://doi.org/10.3390/biomedicines10123228 - 12 Dec 2022

Cited by 7 | Viewed by 2832

Abstract

Parkinson’s disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons resulting in dopamine deficiency in the striatum. Given the estimated escalation in the number of people with PD in the coming decades, interventions aimed at minimizing morbidity [...] Read more.

Parkinson’s disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons resulting in dopamine deficiency in the striatum. Given the estimated escalation in the number of people with PD in the coming decades, interventions aimed at minimizing morbidity and improving quality of life are crucial. Mitochondrial dysfunction and oxidative stress are intrinsic factors related to PD pathogenesis. Accumulating evidence suggests that patients with PD might benefit from various forms of exercise in diverse ways, from general health improvements to disease-specific effects and, potentially, disease-modifying effects. However, the signaling and mechanism connecting skeletal muscle-increased activity and brain remodeling are poorly elucidated. In this review, we describe skeletal muscle–brain crosstalk in PD, with a special focus on mitochondrial effects, proposing mitochondrial dysfunction as a linker in the muscle–brain axis in this neurodegenerative disease and as a promising therapeutic target. Moreover, we outline how exercise secretome can improve mitochondrial health and impact the nervous system to slow down PD progression. Understanding the regulation of the mitochondrial function by exercise in PD may be beneficial in defining interventions to delay the onset of this neurodegenerative disease. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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19 pages, 2132 KiB

Open AccessReview

Vitamin D Impacts on Skeletal Muscle Dysfunction in Patients with COPD Promoting Mitochondrial Health

by Cristina Russo, Maria Stella Valle, Antonino Casabona, Lucia Spicuzza, Gianluca Sambataro and Lucia Malaguarnera

Biomedicines 2022, 10(4), 898; https://doi.org/10.3390/biomedicines10040898 - 14 Apr 2022

Cited by 11 | Viewed by 3407

Abstract

Skeletal muscle dysfunction is frequently associated with chronic obstructive pulmonary disease (COPD), which is characterized by a permanent airflow limitation, with a worsening respiratory disorder during disease evolution. In COPD, the pathophysiological changes related to the chronic inflammatory state affect oxidant–antioxidant balance, which [...] Read more.

Skeletal muscle dysfunction is frequently associated with chronic obstructive pulmonary disease (COPD), which is characterized by a permanent airflow limitation, with a worsening respiratory disorder during disease evolution. In COPD, the pathophysiological changes related to the chronic inflammatory state affect oxidant–antioxidant balance, which is one of the main mechanisms accompanying extra-pulmonary comorbidity such as muscle wasting. Muscle impairment is characterized by alterations on muscle fiber architecture, contractile protein integrity, and mitochondrial dysfunction. Exogenous and endogenous sources of reactive oxygen species (ROS) are present in COPD pathology. One of the endogenous sources of ROS is represented by mitochondria. Evidence demonstrated that vitamin D plays a crucial role for the maintenance of skeletal muscle health. Vitamin D deficiency affects oxidative stress and mitochondrial function influencing disease course through an effect on muscle function in COPD patients. This review will focus on vitamin-D-linked mechanisms that could modulate and ameliorate the damage response to free radicals in muscle fibers, evaluating vitamin D supplementation with enough potent effect to contrast mitochondrial impairment, but which avoids potential severe side effects. Full article

(This article belongs to the Special Issue A Mitochondrial Perspective on Noncommunicable Diseases)

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