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Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0
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Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0

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 (28 February 2023) | Viewed by 20723

Special Issue Editors

Dr. Anna Atlante

E-Mail Website
Guest Editor
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM)-CNR, Via G. Amendola122/O, 70126 Bari, Italy
Interests: mitochondrial bioenergetics; oxidative phosphorylation; mitochondrial dysfunction; metabolic regulation; oxidative stress; apoptosis; Alzheimer’s disease; cystic fibrosis
Special Issues, Collections and Topics in MDPI journals
Dr. Daniela Valenti

E-Mail Website
Guest Editor
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Council of Research, Bari, Italy
Interests: mitochondrial bioenergetics; mitochondrial metabolism; mitochondrial transport; mitochondrial signaling pathways; mitochondrial dysfunction; neurodevelopmental diseases; oxidative stress; reactive oxygen species; programmed cell death
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are central actors in the bioenergetics of cellular life. They are maternally inherited, multifunctional organelles widely known for generating energy in the form of ATP through the inner membrane mitochondrial respiratory chain complexes that form the functional respirasome. Besides the oxidative phosphorylation process, mitochondrial transport, inter-organelle crosstalk, mitochondrial dynamics, biogenesis and degradation all play a critical role in the efficiency and homeostasis of mitochondrial bioenergetics. Damage to these highly energetic and redox-sensitive organelles can result in an increase in the autophagic removal of the mitochondria (mitophagy) and disruption to the mitochondrial network. Mitochondrial dysfunction is now emerging as a major contributor to the pathogenesis of a broad range of human diseases, directly or indirectly, through a wide spectrum of signaling pathways.

Contributions to this Special Issue will provide new insights into mitochondrial bioenergetics to deepen our understanding of its role in health and disease and reveal novel mitochondria-targeting therapeutic opportunities. Original research articles and topical reviews on these and related topics are welcome in this Special Issue.

Due to the success of the first and second editions, we would like to add more results and new insights from recent research projects.

https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/Mitochondrial_Bioenergetics

https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/Mitochondrial_Bioenergetics_2

Dr. Anna Atlante
Dr. Daniela Valenti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • mitochondrial ATP generation
  • oxidative phosphorylation machinery
  • mitochondrial quality control
  • mitochondrial dynamic network
  • mitogenesis/mitophagy
  • mitochondrial signaling
  • inter-organelle crosstalk
  • mitochondrial dysfunction
  • mitochondria-targeting therapeutic strategies

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Published Papers (9 papers)

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Research

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19 pages, 4913 KiB  
Article
Bioenergetic and Cytokine Profiling May Help to Rescue More DCD Livers for Transplantation
by Julia Hofmann, Andras T. Meszaros, Madita L. Buch, Florian Nardin, Verena Hackl, Carola J. Strolz, Bettina Zelger, Margot Fodor, Benno Cardini, Rupert Oberhuber, Thomas Resch, Annemarie Weissenbacher, Jakob Troppmair, Stefan Schneeberger and Theresa Hautz
Int. J. Mol. Sci. 2023, 24(11), 9536; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119536 - 31 May 2023
Viewed by 1042
Abstract
The majority of organs used for liver transplantation come from brain-dead donors (DBD). In order to overcome the organ shortage, increasingly donation after circulatory death (DCD) organs are also considered. Since normothermic machine perfusion (NMP) restores metabolic activity and allows for in-depth assessment [...] Read more.
The majority of organs used for liver transplantation come from brain-dead donors (DBD). In order to overcome the organ shortage, increasingly donation after circulatory death (DCD) organs are also considered. Since normothermic machine perfusion (NMP) restores metabolic activity and allows for in-depth assessment of organ quality and function prior to transplantation, such organs may benefit from NMP. We herein compare the bioenergetic performance through a comprehensive evaluation of mitochondria by high-resolution respirometry in tissue biopsies and the inflammatory response in DBD and DCD livers during NMP. While livers were indistinguishable by perfusate biomarker assessment and histology, our findings revealed a greater impairment of mitochondrial function in DCD livers after static cold storage compared to DBD livers. During subsequent NMPs, DCD organs recovered and eventually showed a similar performance as DBD livers. Cytokine expression analysis showed no differences in the early phase of NMP, while towards the end of NMP, significantly elevated levels of IL-1β, IL-5 and IL-6 were found in the perfusate of DCD livers. Based on our results, we find it worthwhile to reconsider more DCD organs for transplantation to further extend the donor pool. Therefore, donor organ quality criteria must be developed, which may include an assessment of bioenergetic function and cytokine quantification. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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18 pages, 3696 KiB  
Article
Pathway and Network Analyses Identify Growth Factor Signaling and MMP9 as Potential Mediators of Mitochondrial Dysfunction in Severe COVID-19
by Ya Wang, Klaus Schughart, Tiana Maria Pelaia, Tracy Chew, Karan Kim, Thomas Karvunidis, Ben Knippenberg, Sally Teoh, Amy L. Phu, Kirsty R. Short, Jonathan Iredell, Irani Thevarajan, Jennifer Audsley, Stephen Macdonald, Jonathon Burcham, PREDICT-19 Consortium, Benjamin Tang, Anthony McLean and Maryam Shojaei
Int. J. Mol. Sci. 2023, 24(3), 2524; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032524 - 28 Jan 2023
Cited by 2 | Viewed by 1978
Abstract
Patients with preexisting metabolic disorders such as diabetes are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Mitochondrion, the very organelle that controls cellular metabolism, holds the key to understanding disease progression at the cellular level. Our current study aimed [...] Read more.
Patients with preexisting metabolic disorders such as diabetes are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Mitochondrion, the very organelle that controls cellular metabolism, holds the key to understanding disease progression at the cellular level. Our current study aimed to understand how cellular metabolism contributes to COVID-19 outcomes. Metacore pathway enrichment analyses on differentially expressed genes (encoded by both mitochondrial and nuclear deoxyribonucleic acid (DNA)) involved in cellular metabolism, regulation of mitochondrial respiration and organization, and apoptosis, was performed on RNA sequencing (RNASeq) data from blood samples collected from healthy controls and patients with mild/moderate or severe COVID-19. Genes from the enriched pathways were analyzed by network analysis to uncover interactions among them and up- or downstream genes within each pathway. Compared to the mild/moderate COVID-19, the upregulation of a myriad of growth factor and cell cycle signaling pathways, with concomitant downregulation of interferon signaling pathways, were observed in the severe group. Matrix metallopeptidase 9 (MMP9) was found in five of the top 10 upregulated pathways, indicating its potential as therapeutic target against COVID-19. In summary, our data demonstrates aberrant activation of endocrine signaling in severe COVID-19, and its implication in immune and metabolic dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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16 pages, 3191 KiB  
Article
Effect of Quercetin on mitoBKCa Channel and Mitochondrial Function in Human Bronchial Epithelial Cells Exposed to Particulate Matter
by Adrianna Dabrowska, Miroslaw Zajac, Piotr Bednarczyk and Agnieszka Lukasiak
Int. J. Mol. Sci. 2023, 24(1), 638; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010638 - 30 Dec 2022
Cited by 4 | Viewed by 1557
Abstract
Particulate matter (PM) exposure increases reactive oxygen species (ROS) levels. It can lead to inflammatory responses and damage of the mitochondria thus inducing cell death. Recently, it has been shown that potassium channels (mitoK) located in the inner mitochondrial membrane are involved in [...] Read more.
Particulate matter (PM) exposure increases reactive oxygen species (ROS) levels. It can lead to inflammatory responses and damage of the mitochondria thus inducing cell death. Recently, it has been shown that potassium channels (mitoK) located in the inner mitochondrial membrane are involved in cytoprotection, and one of the mechanisms involves ROS. To verify the cytoprotective role of mitoBKCa, we performed a series of experiments using a patch-clamp, transepithelial electrical resistance assessment (TEER), mitochondrial respiration measurements, fluorescence methods for the ROS level and mitochondrial membrane potential assessment, and cell viability measurements. In the human bronchial epithelial cell model (16HBE14σ), PM < 4 μm in diameter (SRM-PM4.0) was used. We observed that PM decreased TEER of HBE cell monolayers. The effect was partially abolished by quercetin, a mitoBKCa opener. Consequently, quercetin decreased the mitochondrial membrane potential and increased mitochondrial respiration. The reduction of PM-induced ROS level occurs both on cellular and mitochondrial level. Additionally, quercetin restores HBE cell viability after PM administration. The incubation of cells with PM substantially reduced the mitochondrial function. Isorhamnetin had no effect on TEER, the mitoBKCa activity, respiratory rate, or mitochondrial membrane potential. Obtained results indicate that PM has an adverse effect on HBE cells at the cellular and mitochondrial level. Quercetin is able to limit the deleterious effect of PM on barrier function of airway epithelial cells. We show that the effect in HBE cells involves mitoBKCa channel-activation. However, quercetin’s mechanism of action is not exclusively determined by modulation of the channel activity. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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13 pages, 2413 KiB  
Article
ATP8B1 Deficiency Results in Elevated Mitochondrial Phosphatidylethanolamine Levels and Increased Mitochondrial Oxidative Phosphorylation in Human Hepatoma Cells
by Valentina E. Gómez-Mellado, Jung-Chin Chang, Kam S. Ho-Mok, Carmen Bernardino Morcillo, Remco H. J. Kersten, Ronald P. J. Oude Elferink, Arthur J. Verhoeven and Coen C. Paulusma
Int. J. Mol. Sci. 2022, 23(20), 12344; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012344 - 15 Oct 2022
Cited by 2 | Viewed by 1583
Abstract
ATP8B1 is a phospholipid flippase that is deficient in patients with progressive familial intrahepatic cholestasis type 1 (PFIC1). PFIC1 patients suffer from severe liver disease but also present with dyslipidemia, including low plasma cholesterol, of yet unknown etiology. Here we show that ATP8B1 [...] Read more.
ATP8B1 is a phospholipid flippase that is deficient in patients with progressive familial intrahepatic cholestasis type 1 (PFIC1). PFIC1 patients suffer from severe liver disease but also present with dyslipidemia, including low plasma cholesterol, of yet unknown etiology. Here we show that ATP8B1 knockdown in HepG2 cells leads to a strong increase in the mitochondrial oxidative phosphorylation (OXPHOS) without a change in glycolysis. The enhanced OXPHOS coincides with elevated low-density lipoprotein receptor protein and increased mitochondrial fragmentation and phosphatidylethanolamine levels. Furthermore, expression of phosphatidylethanolamine N-methyltransferase, an enzyme that catalyzes the conversion of mitochondrial-derived phosphatidylethanolamine to phosphatidylcholine, was reduced in ATP8B1 knockdown cells. We conclude that ATP8B1 deficiency results in elevated mitochondrial PE levels that stimulate mitochondrial OXPHOS. The increased OXPHOS leads to elevated LDLR levels, which provides a possible explanation for the reduced plasma cholesterol levels in PFIC1 disease. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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15 pages, 1770 KiB  
Article
Sex as Biological Variable in Cardiac Mitochondrial Bioenergetic Responses to Acute Stress
by Susan R. Scott, Kanhaiya Singh, Qing Yu, Chandan K. Sen and Meijing Wang
Int. J. Mol. Sci. 2022, 23(16), 9312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169312 - 18 Aug 2022
Cited by 8 | Viewed by 1948
Abstract
Cardiac dysfunction/damage following trauma, shock, sepsis, and ischemia impacts clinical outcomes. Acute inflammation and oxidative stress triggered by these injuries impair mitochondria, which are critical to maintaining cardiac function. Despite sex dimorphisms in consequences of these injuries, it is unclear whether mitochondrial bioenergetic [...] Read more.
Cardiac dysfunction/damage following trauma, shock, sepsis, and ischemia impacts clinical outcomes. Acute inflammation and oxidative stress triggered by these injuries impair mitochondria, which are critical to maintaining cardiac function. Despite sex dimorphisms in consequences of these injuries, it is unclear whether mitochondrial bioenergetic responses to inflammation/oxidative stress are sex-dependent. We hypothesized that sex disparity in mitochondrial bioenergetics following TNFα or H2O2 exposure is responsible for reported sex differences in cardiac damage/dysfunction. Methods and Results: Cardiomyocytes isolated from age-matched adult male and female mice were subjected to 1 h TNFα or H2O2 challenge, followed by detection of mitochondrial respiration capacity using the Seahorse XF96 Cell Mito Stress Test. Mitochondrial membrane potential (ΔΨm) was analyzed using JC-1 in TNFα-challenged cardiomyocytes. We found that cardiomyocytes isolated from female mice displayed a better mitochondrial bioenergetic response to TNFα or H2O2 than those isolated from male mice did. TNFα decreased ΔΨm in cardiomyocytes isolated from males but not from females. 17β-estradiol (E2) treatment improved mitochondrial metabolic function in cardiomyocytes from male mice subjected to TNFα or H2O2 treatment. Conclusions: Cardiomyocyte mitochondria from female mice were more resistant to acute stress than those from males. The female sex hormone E2 treatment protected cardiac mitochondria against acute inflammatory and oxidative stress. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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Review

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22 pages, 1569 KiB  
Review
Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes
by Daniela Valenti and Rosa Anna Vacca
Int. J. Mol. Sci. 2023, 24(15), 12488; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241512488 - 06 Aug 2023
Cited by 3 | Viewed by 1791
Abstract
Mitochondria, far beyond their prominent role as cellular powerhouses, are complex cellular organelles active as central metabolic hubs that are capable of integrating and controlling several signaling pathways essential for neurological processes, including neurogenesis and neuroplasticity. On the other hand, mitochondria are themselves [...] Read more.
Mitochondria, far beyond their prominent role as cellular powerhouses, are complex cellular organelles active as central metabolic hubs that are capable of integrating and controlling several signaling pathways essential for neurological processes, including neurogenesis and neuroplasticity. On the other hand, mitochondria are themselves regulated from a series of signaling proteins to achieve the best efficiency in producing energy, in establishing a network and in performing their own de novo synthesis or clearance. Dysfunctions in signaling processes that control mitochondrial biogenesis, dynamics and bioenergetics are increasingly associated with impairment in brain development and involved in a wide variety of neurodevelopmental disorders. Here, we review recent evidence proving the emerging role of mitochondria as master regulators of brain bioenergetics, highlighting their control skills in brain neurodevelopment and cognition. We analyze, from a mechanistic point of view, mitochondrial bioenergetic dysfunction as causally interrelated to the origins of typical genetic intellectual disability-related neurodevelopmental disorders, such as Down, Rett and Fragile X syndromes. Finally, we discuss whether mitochondria can become therapeutic targets to improve brain development and function from a holistic perspective. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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23 pages, 2906 KiB  
Review
Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives
by Marco D’Amato, Francesca Morra, Ivano Di Meo and Valeria Tiranti
Int. J. Mol. Sci. 2023, 24(3), 1969; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031969 - 19 Jan 2023
Cited by 11 | Viewed by 4301
Abstract
Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, [...] Read more.
Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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20 pages, 4497 KiB  
Review
Mitochondria and Cancer Recurrence after Liver Transplantation—What Is the Benefit of Machine Perfusion?
by Alessandro Parente, Mauricio Flores Carvalho, Janina Eden, Philipp Dutkowski and Andrea Schlegel
Int. J. Mol. Sci. 2022, 23(17), 9747; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179747 - 28 Aug 2022
Cited by 3 | Viewed by 2255
Abstract
Tumor recurrence after liver transplantation has been linked to multiple factors, including the recipient’s tumor burden, donor factors, and ischemia-reperfusion injury (IRI). The increasing number of livers accepted from extended criteria donors has forced the transplant community to push the development of dynamic [...] Read more.
Tumor recurrence after liver transplantation has been linked to multiple factors, including the recipient’s tumor burden, donor factors, and ischemia-reperfusion injury (IRI). The increasing number of livers accepted from extended criteria donors has forced the transplant community to push the development of dynamic perfusion strategies. The reason behind this progress is the urgent need to reduce the clinical consequences of IRI. Two concepts appear most beneficial and include either the avoidance of ischemia, e.g., the replacement of cold storage by machine perfusion, or secondly, an endischemic organ improvement through perfusion in the recipient center prior to implantation. While several concepts, including normothermic perfusion, were found to reduce recipient transaminase levels and early allograft dysfunction, hypothermic oxygenated perfusion also reduced IRI-associated post-transplant complications and costs. With the impact on mitochondrial injury and subsequent less IRI-inflammation, this endischemic perfusion was also found to reduce the recurrence of hepatocellular carcinoma after liver transplantation. Firstly, this article highlights the contributing factors to tumor recurrence, including the surgical and medical tissue trauma and underlying mechanisms of IRI-associated inflammation. Secondly, it focuses on the role of mitochondria and associated interventions to reduce cancer recurrence. Finally, the role of machine perfusion technology as a delivery tool and as an individual treatment is discussed together with the currently available clinical studies. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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25 pages, 626 KiB  
Review
Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview
by Vlad Florian Avram, Adrian Petru Merce, Iasmina Maria Hâncu, Alina Doruța Bătrân, Gabrielle Kennedy, Mariana Georgeta Rosca and Danina Mirela Muntean
Int. J. Mol. Sci. 2022, 23(16), 8852; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168852 - 09 Aug 2022
Cited by 15 | Viewed by 3173
Abstract
Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and [...] Read more.
Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 3.0)
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