International Journal of Molecular Sciences

Editorial

4 pages, 173 KiB

Open AccessEditorial

Special Issue “Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-Communicable Diseases”

by Paola Fortini and Barbara Pascucci

Int. J. Mol. Sci. 2024, 25(7), 4004; https://doi.org/10.3390/ijms25074004 - 3 Apr 2024

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Abstract

Non-communicable diseases (NCDs) are non-infectious and non-transmissible chronic disorders [...] Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

Research

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16 pages, 3017 KiB

Open AccessArticle

Spermidine Rescues Bioenergetic and Mitophagy Deficits Induced by Disease-Associated Tau Protein

by Lauren H. Fairley, Imane Lejri, Amandine Grimm and Anne Eckert

Int. J. Mol. Sci. 2023, 24(6), 5297; https://doi.org/10.3390/ijms24065297 - 10 Mar 2023

Cited by 6 | Viewed by 2638

Abstract

Abnormal tau build-up is a hallmark of Alzheimer’s disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal [...] Read more.

Abnormal tau build-up is a hallmark of Alzheimer’s disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal tau impairs almost every aspect of mitochondrial function, from mitochondrial respiration to mitophagy. The aim of our study was to investigate the effects of spermidine, a polyamine which exerts neuroprotective effects, on mitochondrial function in a cellular model of tauopathy. Recent evidence identified autophagy as the main mechanism of action of spermidine on life-span prolongation and neuroprotection, but the effects of spermidine on abnormal tau-induced mitochondrial dysfunction have not yet been investigated. We used SH-SY5Y cells stably expressing a mutant form of human tau protein (P301L tau mutation) or cells expressing the empty vector (control cells). We showed that spermidine improved mitochondrial respiration, mitochondrial membrane potential as well as adenosine triphosphate (ATP) production in both control and P301L tau-expressing cells. We also showed that spermidine decreased the level of free radicals, increased autophagy and restored P301L tau-induced impairments in mitophagy. Overall, our findings suggest that spermidine supplementation might represent an attractive therapeutic approach to prevent/counteract tau-related mitochondrial impairments. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

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15 pages, 8711 KiB

Open AccessArticle

Disorder of Golgi Apparatus Precedes Anoxia-Induced Pathology of Mitochondria

by Yury M. Morozov and Pasko Rakic

Int. J. Mol. Sci. 2023, 24(5), 4432; https://doi.org/10.3390/ijms24054432 - 23 Feb 2023

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Abstract

Mitochondrial malfunction and morphologic disorganization have been observed in brain cells as part of complex pathological changes. However, it is unclear what may be the role of mitochondria in the initiation of pathologic processes or if mitochondrial disorders are consequences of earlier events. [...] Read more.

Mitochondrial malfunction and morphologic disorganization have been observed in brain cells as part of complex pathological changes. However, it is unclear what may be the role of mitochondria in the initiation of pathologic processes or if mitochondrial disorders are consequences of earlier events. We analyzed the morphologic reorganization of organelles in an embryonic mouse brain during acute anoxia using an immunohistochemical identification of the disordered mitochondria, followed by electron microscopic three-dimensional (3D) reconstruction. We found swelling of the mitochondrial matrix after 3 h anoxia and probable dissociation of mitochondrial stomatin-like protein 2 (SLP2)-containing complexes after 4.5 h anoxia in the neocortex, hippocampus, and lateral ganglionic eminence. Surprisingly, deformation of the Golgi apparatus (GA) was detected already after 1 h of anoxia, when the mitochondria and other organelles still had a normal ultrastructure. The disordered GA showed concentrical swirling of the cisternae and formed spherical onion-like structures with the trans-cisterna in the center of the sphere. Such disturbance of the Golgi architecture likely interferes with its function for post-translational protein modification and secretory trafficking. Thus, the GA in embryonic mouse brain cells may be more vulnerable to anoxic conditions than the other organelles, including mitochondria. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

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10 pages, 1783 KiB

Open AccessArticle

Drp1 Overexpression Decreases Insulin Content in Pancreatic MIN6 Cells

by Uma D. Kabra, Noah Moruzzi, Per-Olof Berggren and Martin Jastroch

Int. J. Mol. Sci. 2022, 23(20), 12338; https://doi.org/10.3390/ijms232012338 - 15 Oct 2022

Cited by 3 | Viewed by 1837

Abstract

Mitochondrial dynamics and bioenergetics are central to glucose-stimulated insulin secretion by pancreatic beta cells. Previously, we demonstrated that a disturbance in glucose-invoked fission impairs insulin secretion by compromising glucose catabolism. Here, we investigated whether the overexpression of mitochondrial fission regulator Drp1 in MIN6 [...] Read more.

Mitochondrial dynamics and bioenergetics are central to glucose-stimulated insulin secretion by pancreatic beta cells. Previously, we demonstrated that a disturbance in glucose-invoked fission impairs insulin secretion by compromising glucose catabolism. Here, we investigated whether the overexpression of mitochondrial fission regulator Drp1 in MIN6 cells can improve or rescue insulin secretion. Although Drp1 overexpression slightly improves the triggering mechanism of insulin secretion of the Drp1-knockdown cells and has no adverse effects on mitochondrial metabolism in wildtype MIN6 cells, the constitutive presence of Drp1 unexpectedly impairs insulin content, which leads to a reduction in the absolute values of secreted insulin. Coherent with previous studies in Drp1-overexpressing muscle cells, we found that the upregulation of ER stress-related genes (BiP, Chop, and Hsp60) possibly impacts insulin production in MIN6 cells. Collectively, we confirm the important role of Drp1 for the energy-coupling of insulin secretion but unravel off-targets effects by Drp1 overexpression on insulin content that warrant caution when manipulating Drp1 in disease therapy. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

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13 pages, 284 KiB

Open AccessArticle

Mitochondrial DNA Changes in Genes of Respiratory Complexes III, IV and V Could Be Related to Brain Tumours in Humans

by Paulina Kozakiewicz, Ludmiła Grzybowska-Szatkowska, Marzanna Ciesielka, Paulina Całka, Jacek Osuchowski, Paweł Szmygin, Bożena Jarosz and Brygida Ślaska

Int. J. Mol. Sci. 2022, 23(20), 12131; https://doi.org/10.3390/ijms232012131 - 12 Oct 2022

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Abstract

Mitochondrial DNA changes can contribute to both an increased and decreased likelihood of cancer. This process is complex and not fully understood. Polymorphisms and mutations, especially those of the missense type, can affect mitochondrial functions, particularly if the conservative domain of the protein [...] Read more.

Mitochondrial DNA changes can contribute to both an increased and decreased likelihood of cancer. This process is complex and not fully understood. Polymorphisms and mutations, especially those of the missense type, can affect mitochondrial functions, particularly if the conservative domain of the protein is concerned. This study aimed to identify the possible relationships between brain gliomas and the occurrence of specific mitochondrial DNA polymorphisms and mutations in respiratory complexes III, IV and V. The investigated material included blood and tumour material collected from 30 Caucasian patients diagnosed with WHO grade II, III or IV glioma. The mitochondrial genetic variants were investigated across the mitochondrial genome using next-generation sequencing (MiSeq/FGx system—Illumina). The study investigated, in silico, the effects of missense mutations on the biochemical properties, structure and functioning of the encoded protein, as well as their potential harmfulness. The A14793G (MTCYB), A15758G, (MT-CYB), A15218G (MT-CYB), G7444A (MT-CO1) polymorphisms, and the T15663C (MT-CYB) and G8959A (ATP6) mutations were assessed in silico as harmful alterations that could be involved in oncogenesis. The G8959A (E145K) ATP6 missense mutation has not been described in the literature so far. In light of these results, further research into the role of mtDNA changes in brain tumours should be conducted. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

Review

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21 pages, 731 KiB

Open AccessReview

Mitochondria and Oxidative Stress as a Link between Alzheimer’s Disease and Diabetes Mellitus

by Ivan M. Veselov, Daria V. Vinogradova, Andrey V. Maltsev, Pavel N. Shevtsov, Elena A. Spirkova, Sergey O. Bachurin and Elena F. Shevtsova

Int. J. Mol. Sci. 2023, 24(19), 14450; https://doi.org/10.3390/ijms241914450 - 22 Sep 2023

Cited by 1 | Viewed by 2051

Abstract

This review is devoted to the problems of the common features linking metabolic disorders and type 2 diabetes with the development of Alzheimer’s disease. The pathogenesis of Alzheimer’s disease closely intersects with the mechanisms of type 2 diabetes development, and an important risk [...] Read more.

This review is devoted to the problems of the common features linking metabolic disorders and type 2 diabetes with the development of Alzheimer’s disease. The pathogenesis of Alzheimer’s disease closely intersects with the mechanisms of type 2 diabetes development, and an important risk factor for both pathologies is aging. Common pathological mechanisms include both factors in the development of oxidative stress, neuroinflammation, insulin resistance, and amyloidosis, as well as impaired mitochondrial dysfunctions and increasing cell death. The currently available drugs for the treatment of type 2 diabetes and Alzheimer’s disease have limited therapeutic efficacy. It is important to note that drugs used to treat Alzheimer’s disease, in particular acetylcholinesterase inhibitors, show a positive therapeutic potential in the treatment of type 2 diabetes, while drugs used in the treatment of type 2 diabetes can also prevent a number of pathologies characteristic for Alzheimer’s disease. A promising direction in the search for a strategy for the treatment of type 2 diabetes and Alzheimer’s disease may be the creation of complex multi-target drugs that have neuroprotective potential and affect specific common targets for type 2 diabetes and Alzheimer’s disease. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

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22 pages, 1540 KiB

Open AccessReview

Placental Mitochondrial Function and Dysfunction in Preeclampsia

by Fahmida Jahan, Goutham Vasam, Alex E. Green, Shannon A. Bainbridge and Keir J. Menzies

Int. J. Mol. Sci. 2023, 24(4), 4177; https://doi.org/10.3390/ijms24044177 - 20 Feb 2023

Cited by 11 | Viewed by 4025

Abstract

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational parent/fetal exchange, and ultimately, fetal development and growth. Not surprisingly, in cases of placental dysfunction—where aspects of placental development or function become compromised—adverse pregnancy outcomes can result. One common placenta-mediated [...] Read more.

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational parent/fetal exchange, and ultimately, fetal development and growth. Not surprisingly, in cases of placental dysfunction—where aspects of placental development or function become compromised—adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero–placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

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21 pages, 1239 KiB

Open AccessReview

Macrophage Polarization Mediated by Mitochondrial Dysfunction Induces Adipose Tissue Inflammation in Obesity

by Long Xu, Xiaoyu Yan, Yuanxin Zhao, Jian Wang, Buhan Liu, Sihang Yu, Jiaying Fu, Yanan Liu and Jing Su

Int. J. Mol. Sci. 2022, 23(16), 9252; https://doi.org/10.3390/ijms23169252 - 17 Aug 2022

Cited by 28 | Viewed by 5714

Abstract

Obesity is one of the prominent global health issues, contributing to the growing prevalence of insulin resistance and type 2 diabetes. Chronic inflammation in adipose tissue is considered as a key risk factor for the development of insulin resistance and type 2 diabetes [...] Read more.

Obesity is one of the prominent global health issues, contributing to the growing prevalence of insulin resistance and type 2 diabetes. Chronic inflammation in adipose tissue is considered as a key risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. Macrophages are the most abundant immune cells in adipose tissue and play an important role in adipose tissue inflammation. Mitochondria are critical for regulating macrophage polarization, differentiation, and survival. Changes to mitochondrial metabolism and physiology induced by extracellular signals may underlie the corresponding state of macrophage activation. Macrophage mitochondrial dysfunction is a key mediator of obesity-induced macrophage inflammatory response and subsequent systemic insulin resistance. Mitochondrial dysfunction drives the activation of the NLRP3 inflammasome, which induces the release of IL-1β. IL-1β leads to decreased insulin sensitivity of insulin target cells via paracrine signaling or infiltration into the systemic circulation. In this review, we discuss the new findings on how obesity induces macrophage mitochondrial dysfunction and how mitochondrial dysfunction induces NLRP3 inflammasome activation. We also summarize therapeutic approaches targeting mitochondria for the treatment of diabetes. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction: A Common Trigger in Neurodegenerative and Metabolic Non-communicable Diseases)

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