Impaired Mitochondrial Bioenergetics under Pathological Conditions

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Physiology and Pathology".

Deadline for manuscript submissions: closed (19 March 2021) | Viewed by 93246

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Guest Editor
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Via Zamboni, 33, 40126 Bologna BO, Italy
Interests: mitochondria; respiratory complexes; Coenzyme Q; electron tansfer; oxidative phosphorylation; reactive oxygen species; antioxidants; mitochondrial diseases; aging

Special Issue Information

Dear colleagues,

Mitochondria, being involved in multiple metabolic functions to power life, also emerge as crucial cell components in a variety of diseases. A diffused reaction to pathology is a mitochondrial dysfunction that causes energy depletion and commits the cell to die. The mitochondrial involvement in diseases is highlighted by distinct changes in mitochondrial homeostasis. The altered metabolic pathways impair oxidative phosphorylation and the AMP/ATP ratio. Mitochondria produce ROS, resulting from the disassembly of respiratory supercomplexes and electron transfer chain disruption. The progressive dysregulation of mitochondrial homeostasis promotes Ca2+ overload in the matrix and ROS accumulation, leading to the so-called ROS-induced ROS release. When ROS levels became toxic, they damage mitochondrial and nuclear DNA and the cell cycle arrests. Moreover, elevated Ca2+ levels in the matrix and oxidative stress induce the mitochondrial permeability transition pore formation, a high-conductance channel that dissipates the mitochondrial protonomotive force resulting in mitochondrial swelling, membrane rupture, bioenergetic failure, and ultimately cell death. Lastly, the parallelism of mitochondrial dysregulation and morphological changes in mitochondria highlights the tight connection between mitochondrial membrane dynamics and pathologies.

Finally, studies on the impaired mitochondrial bioenergetics in pathology could provide molecular tools to counteract diseases associated with mitochondrial dysfunctions.

Prof. Dr. Giorgio Lenaz
Dr. Salvatore Nesci
Guest Editors

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Keywords

  • oxidative phosphorylation
  • pathological mitochondrial dysfunctions
  • permeability transition pore
  • ROS production
  • mitochondrial respiration
  • cell death

Published Papers (20 papers)

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Editorial

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3 pages, 182 KiB  
Editorial
Impaired Mitochondrial Bioenergetics under Pathological Conditions
by Salvatore Nesci and Giorgio Lenaz
Life 2022, 12(2), 205; https://doi.org/10.3390/life12020205 - 29 Jan 2022
Cited by 4 | Viewed by 1863
Abstract
Mitochondria are the powerhouses of cells; however, mitochondrial dysfunction causes energy depletion and cell death in various diseases [...] Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)

Research

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12 pages, 1431 KiB  
Article
In Vitro Assays for the Assessment of Impaired Mitochondrial Bioenergetics in Equine Atypical Myopathy
by Caroline-J. Kruse, David Stern, Ange Mouithys-Mickalad, Ariane Niesten, Tatiana Art, Hélène Lemieux and Dominique-M. Votion
Life 2021, 11(7), 719; https://doi.org/10.3390/life11070719 - 20 Jul 2021
Cited by 1 | Viewed by 1808
Abstract
Equine atypical myopathy is a seasonal intoxication of grazing equids. In Europe, this poisoning is associated with the ingestion of toxins contained in the seeds and seedlings of the sycamore maple (Acer pseudoplatanus). The toxins involved in atypical myopathy are known [...] Read more.
Equine atypical myopathy is a seasonal intoxication of grazing equids. In Europe, this poisoning is associated with the ingestion of toxins contained in the seeds and seedlings of the sycamore maple (Acer pseudoplatanus). The toxins involved in atypical myopathy are known to inhibit ß-oxidation of fatty acids and induce a general decrease in mitochondrial respiration, as determined by high-resolution respirometry applied to muscle samples taken from cases of atypical myopathy. The severe impairment of mitochondrial bioenergetics induced by the toxins may explain the high rate of mortality observed: about 74% of horses with atypical myopathy die, most within the first two days of signs of poisoning. The mechanism of toxicity is not completely elucidated yet. To improve our understanding of the pathological process and to assess therapeutic candidates, we designed in vitro assays using equine skeletal myoblasts cultured from muscle biopsies and subjected to toxins involved in atypical myopathy. We established that equine primary myoblasts do respond to one of the toxins incriminated in the disease. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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16 pages, 1572 KiB  
Article
Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus
by Vladimir Grubelnik, Jan Zmazek, Rene Markovič, Marko Gosak and Marko Marhl
Life 2020, 10(12), 348; https://doi.org/10.3390/life10120348 - 14 Dec 2020
Cited by 18 | Viewed by 5279
Abstract
Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different [...] Read more.
Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30–40% reduction in alpha cells’ mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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20 pages, 2563 KiB  
Article
Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase
by Qiuju Ding, Róża Kucharczyk, Weiwei Zhao, Alain Dautant, Shutian Xu, Katarzyna Niedzwiecka, Xin Su, Marie-France Giraud, Kewin Gombeau, Mingchao Zhang, Honglang Xie, Caihong Zeng, Marine Bouhier, Jean-Paul di Rago, Zhihong Liu, Déborah Tribouillard-Tanvier and Huimei Chen
Life 2020, 10(9), 215; https://doi.org/10.3390/life10090215 - 22 Sep 2020
Cited by 7 | Viewed by 2985
Abstract
With the advent of next generation sequencing, the list of mitochondrial DNA (mtDNA) mutations identified in patients rapidly and continuously expands. They are frequently found in a limited number of cases, sometimes a single individual (as with the case herein reported) and in [...] Read more.
With the advent of next generation sequencing, the list of mitochondrial DNA (mtDNA) mutations identified in patients rapidly and continuously expands. They are frequently found in a limited number of cases, sometimes a single individual (as with the case herein reported) and in heterogeneous genetic backgrounds (heteroplasmy), which makes it difficult to conclude about their pathogenicity and functional consequences. As an organism amenable to mitochondrial DNA manipulation, able to survive by fermentation to loss-of-function mtDNA mutations, and where heteroplasmy is unstable, Saccharomyces cerevisiae is an excellent model for investigating novel human mtDNA variants, in isolation and in a controlled genetic context. We herein report the identification of a novel variant in mitochondrial ATP6 gene, m.8909T>C. It was found in combination with the well-known pathogenic m.3243A>G mutation in mt-tRNALeu. We show that an equivalent of the m.8909T>C mutation compromises yeast adenosine tri-phosphate (ATP) synthase assembly/stability and reduces the rate of mitochondrial ATP synthesis by 20–30% compared to wild type yeast. Other previously reported ATP6 mutations with a well-established pathogenicity (like m.8993T>C and m.9176T>C) were shown to have similar effects on yeast ATP synthase. It can be inferred that alone the m.8909T>C variant has the potential to compromise human health. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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11 pages, 990 KiB  
Article
Palmitate but Not Oleate Exerts a Negative Effect on Oxygen Utilization in Myoblasts of Patients with the m.3243A>G Mutation: A Pilot Study
by Leila Motlagh Scholle, Helena Schieffers, Samiya Al-Robaiy, Annemarie Thaele, Diana Lehmann Urban and Stephan Zierz
Life 2020, 10(9), 204; https://doi.org/10.3390/life10090204 - 16 Sep 2020
Cited by 1 | Viewed by 2526
Abstract
It is known that exposure to excess saturated fatty acids, especially palmitate, can trigger cellular stress responses interpreted as lipotoxicity. The effect of excessive free fatty acids on oxidative phosphorylation capacity in myoblasts of patients with the m.3243A>G mutation was evaluated with the [...] Read more.
It is known that exposure to excess saturated fatty acids, especially palmitate, can trigger cellular stress responses interpreted as lipotoxicity. The effect of excessive free fatty acids on oxidative phosphorylation capacity in myoblasts of patients with the m.3243A>G mutation was evaluated with the mitochondrial (Mito) stress test using a Seahorse XF96 analyzer. ß-oxidation, measured with the Seahorse XF96 analyzer, was similar in patients and controls, and reduced in both patients and controls at 40 °C compared to 37 °C. Mito stress test in the absence of fatty acids showed lower values in patients compared to controls. The mitochondrial activity and ATP production rates were significantly reduced in presence of palmitate, but not of oleate in patients, showing a negative effect of excessive palmitate on mitochondrial function in patients. Diabetes mellitus is a frequent symptom in patients with m.3243A>G mutation. It can be speculated that the negative effect of palmitate on mitochondrial function might be related to diacylglycerols (DAG) and ceramides (CER) mediated insulin resistance. This might contribute to the elevated risk for diabetes mellitus in m.3243A>G patients. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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10 pages, 1602 KiB  
Article
Aging Promotes Mitochondria-Mediated Apoptosis in Rat Hearts
by Mi-Hyun No, Youngju Choi, Jinkyung Cho, Jun-Won Heo, Eun-Jeong Cho, Dong-Ho Park, Ju-Hee Kang, Chang-Ju Kim, Dae Yun Seo, Jin Han and Hyo-Bum Kwak
Life 2020, 10(9), 178; https://doi.org/10.3390/life10090178 - 5 Sep 2020
Cited by 15 | Viewed by 2864
Abstract
Aging represents a major risk for developing cardiac disease, including heart failure. The gradual deterioration of cell quality control with aging leads to cell death, a phenomenon associated with mitochondrial dysfunction in the heart. Apoptosis is an important quality control process and a [...] Read more.
Aging represents a major risk for developing cardiac disease, including heart failure. The gradual deterioration of cell quality control with aging leads to cell death, a phenomenon associated with mitochondrial dysfunction in the heart. Apoptosis is an important quality control process and a necessary phenomenon for maintaining homeostasis and normal function of the heart. However, the mechanism of mitochondria-mediated apoptosis in aged hearts remains poorly understood. Here, we used male Fischer 344 rats of various ages, representing very young (1 month), young (4 months), middle-aged (12 months), and old (20 months) rats, to determine whether mitochondria-mediated apoptotic signals and apoptosis in the left ventricle of the heart are altered notably with aging. As the rats aged, the extramyocyte space and myocyte cross-sectional area in their left ventricle muscle increased, while the number of myocytes decreased. Additionally, mitochondrion-mediated apoptotic signals and apoptosis increased remarkably during aging. Therefore, our results demonstrate that aging promotes remarkable morphological changes and increases the degree of mitochondrion-mediated apoptosis in the left ventricle of rat hearts. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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Review

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28 pages, 2810 KiB  
Review
Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives
by Rebeca Acin-Perez, Cristiane Benincá, Byourak Shabane, Orian S. Shirihai and Linsey Stiles
Life 2021, 11(9), 949; https://doi.org/10.3390/life11090949 - 10 Sep 2021
Cited by 18 | Viewed by 4776
Abstract
Mitochondrial bioenergetic function is a central component of cellular metabolism in health and disease. Mitochondrial oxidative phosphorylation is critical for maintaining energetic homeostasis, and impairment of mitochondrial function underlies the development and progression of metabolic diseases and aging. However, measurement of mitochondrial bioenergetic [...] Read more.
Mitochondrial bioenergetic function is a central component of cellular metabolism in health and disease. Mitochondrial oxidative phosphorylation is critical for maintaining energetic homeostasis, and impairment of mitochondrial function underlies the development and progression of metabolic diseases and aging. However, measurement of mitochondrial bioenergetic function can be challenging in human samples due to limitations in the size of the collected sample. Furthermore, the collection of samples from human cohorts is often spread over multiple days and locations, which makes immediate sample processing and bioenergetics analysis challenging. Therefore, sample selection and choice of tests should be carefully considered. Basic research, clinical trials, and mitochondrial disease diagnosis rely primarily on skeletal muscle samples. However, obtaining skeletal muscle biopsies requires an appropriate clinical setting and specialized personnel, making skeletal muscle a less suitable tissue for certain research studies. Circulating white blood cells and platelets offer a promising primary tissue alternative to biopsies for the study of mitochondrial bioenergetics. Recent advances in frozen respirometry protocols combined with the utilization of minimally invasive and non-invasive samples may provide promise for future mitochondrial research studies in humans. Here we review the human samples commonly used for the measurement of mitochondrial bioenergetics with a focus on the advantages and limitations of each sample. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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13 pages, 844 KiB  
Review
Accessory Subunits of the Matrix Arm of Mitochondrial Complex I with a Focus on Subunit NDUFS4 and Its Role in Complex I Function and Assembly
by Flora Kahlhöfer, Max Gansen and Volker Zickermann
Life 2021, 11(5), 455; https://doi.org/10.3390/life11050455 - 19 May 2021
Cited by 16 | Viewed by 3380
Abstract
NADH:ubiquinone-oxidoreductase (complex I) is the largest membrane protein complex of the respiratory chain. Complex I couples electron transfer to vectorial proton translocation across the inner mitochondrial membrane. The L shaped structure of complex I is divided into a membrane arm and a matrix [...] Read more.
NADH:ubiquinone-oxidoreductase (complex I) is the largest membrane protein complex of the respiratory chain. Complex I couples electron transfer to vectorial proton translocation across the inner mitochondrial membrane. The L shaped structure of complex I is divided into a membrane arm and a matrix arm. Fourteen central subunits are conserved throughout species, while some 30 accessory subunits are typically found in eukaryotes. Complex I dysfunction is associated with mutations in the nuclear and mitochondrial genome, resulting in a broad spectrum of neuromuscular and neurodegenerative diseases. Accessory subunit NDUFS4 in the matrix arm is a hot spot for mutations causing Leigh or Leigh-like syndrome. In this review, we focus on accessory subunits of the matrix arm and discuss recent reports on the function of accessory subunit NDUFS4 and its interplay with NDUFS6, NDUFA12, and assembly factor NDUFAF2 in complex I assembly. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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22 pages, 1631 KiB  
Review
Mitochondrial Bioenergetics and Dynamism in the Failing Heart
by Giampaolo Morciano, Veronica Angela Maria Vitto, Esmaa Bouhamida, Carlotta Giorgi and Paolo Pinton
Life 2021, 11(5), 436; https://doi.org/10.3390/life11050436 - 12 May 2021
Cited by 17 | Viewed by 4242
Abstract
The heart is responsible for pumping blood, nutrients, and oxygen from its cavities to the whole body through rhythmic and vigorous contractions. Heart function relies on a delicate balance between continuous energy consumption and generation that changes from birth to adulthood and depends [...] Read more.
The heart is responsible for pumping blood, nutrients, and oxygen from its cavities to the whole body through rhythmic and vigorous contractions. Heart function relies on a delicate balance between continuous energy consumption and generation that changes from birth to adulthood and depends on a very efficient oxidative metabolism and the ability to adapt to different conditions. In recent years, mitochondrial dysfunctions were recognized as the hallmark of the onset and development of manifold heart diseases (HDs), including heart failure (HF). HF is a severe condition for which there is currently no cure. In this condition, the failing heart is characterized by a disequilibrium in mitochondrial bioenergetics, which compromises the basal functions and includes the loss of oxygen and substrate availability, an altered metabolism, and inefficient energy production and utilization. This review concisely summarizes the bioenergetics and some other mitochondrial features in the heart with a focus on the features that become impaired in the failing heart. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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44 pages, 1901 KiB  
Review
Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration
by Hope I. Needs, Margherita Protasoni, Jeremy M. Henley, Julien Prudent, Ian Collinson and Gonçalo C. Pereira
Life 2021, 11(5), 432; https://doi.org/10.3390/life11050432 - 11 May 2021
Cited by 16 | Viewed by 8345
Abstract
The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required [...] Read more.
The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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21 pages, 2376 KiB  
Review
The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology
by Mariona Jové, Natàlia Mota-Martorell, Pascual Torres, Victoria Ayala, Manuel Portero-Otin, Isidro Ferrer and Reinald Pamplona
Life 2021, 11(5), 388; https://doi.org/10.3390/life11050388 - 25 Apr 2021
Cited by 19 | Viewed by 4029
Abstract
Current shreds of evidence point to the entorhinal cortex (EC) as the origin of the Alzheimer’s disease (AD) pathology in the cerebrum. Compared with other cortical areas, the neurons from this brain region possess an inherent selective vulnerability derived from particular oxidative stress [...] Read more.
Current shreds of evidence point to the entorhinal cortex (EC) as the origin of the Alzheimer’s disease (AD) pathology in the cerebrum. Compared with other cortical areas, the neurons from this brain region possess an inherent selective vulnerability derived from particular oxidative stress conditions that favor increased mitochondrial molecular damage with early bioenergetic involvement. This alteration of energy metabolism is the starting point for subsequent changes in a multitude of cell mechanisms, leading to neuronal dysfunction and, ultimately, cell death. These events are induced by changes that come with age, creating the substrate for the alteration of several neuronal pathways that will evolve toward neurodegeneration and, consequently, the development of AD pathology. In this context, the present review will focus on description of the biological mechanisms that confer vulnerability specifically to neurons of the entorhinal cortex, the changes induced by the aging process in this brain region, and the alterations at the mitochondrial level as the earliest mechanism for the development of AD pathology. Current findings allow us to propose the existence of an altered allostatic mechanism at the entorhinal cortex whose core is made up of mitochondrial oxidative stress, lipid metabolism, and energy production, and which, in a positive loop, evolves to neurodegeneration, laying the basis for the onset and progression of AD pathology. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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25 pages, 1203 KiB  
Review
Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences
by Michela Rugolo, Claudia Zanna and Anna Maria Ghelli
Life 2021, 11(4), 351; https://doi.org/10.3390/life11040351 - 17 Apr 2021
Cited by 4 | Viewed by 3025
Abstract
The mitochondrial respiratory chain encompasses four oligomeric enzymatic complexes (complex I, II, III and IV) which, together with the redox carrier ubiquinone and cytochrome c, catalyze electron transport coupled to proton extrusion from the inner membrane. The protonmotive force is utilized by [...] Read more.
The mitochondrial respiratory chain encompasses four oligomeric enzymatic complexes (complex I, II, III and IV) which, together with the redox carrier ubiquinone and cytochrome c, catalyze electron transport coupled to proton extrusion from the inner membrane. The protonmotive force is utilized by complex V for ATP synthesis in the process of oxidative phosphorylation. Respiratory complexes are known to coexist in the membrane as single functional entities and as supramolecular aggregates or supercomplexes (SCs). Understanding the assembly features of SCs has relevant biomedical implications because defects in a single protein can derange the overall SC organization and compromise the energetic function, causing severe mitochondrial disorders. Here we describe in detail the main types of SCs, all characterized by the presence of complex III. We show that the genetic alterations that hinder the assembly of Complex III, not just the activity, cause a rearrangement of the architecture of the SC that can help to preserve a minimal energetic function. Finally, the major metabolic disturbances associated with severe SCs perturbation due to defective complex III are discussed along with interventions that may circumvent these deficiencies. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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20 pages, 1101 KiB  
Review
Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview
by Valentina Brillo, Leonardo Chieregato, Luigi Leanza, Silvia Muccioli and Roberto Costa
Life 2021, 11(4), 332; https://doi.org/10.3390/life11040332 - 10 Apr 2021
Cited by 94 | Viewed by 7577
Abstract
Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute [...] Read more.
Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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21 pages, 1399 KiB  
Review
The ATP Synthase Deficiency in Human Diseases
by Chiara Galber, Stefania Carissimi, Alessandra Baracca and Valentina Giorgio
Life 2021, 11(4), 325; https://doi.org/10.3390/life11040325 - 8 Apr 2021
Cited by 28 | Viewed by 6021
Abstract
Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocognitive disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations [...] Read more.
Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocognitive disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations of genes encoding mitochondrial protein. Under physiological conditions, the mitochondrial ATP synthase provides the most energy of the cell via the oxidative phosphorylation. Alterations of oxidative phosphorylation mainly affect the tissues characterized by a high-energy metabolism, such as nervous, cardiac and skeletal muscle tissues. In this review, we focus on human diseases caused by altered expressions of ATP synthase genes of both mitochondrial and nuclear origin. Moreover, we describe the contribution of ATP synthase to the pathophysiological mechanisms of other human diseases such as cardiovascular, neurodegenerative diseases or neurocognitive disorders. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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53 pages, 4522 KiB  
Review
Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology
by Salvatore Nesci, Fabiana Trombetti, Alessandra Pagliarani, Vittoria Ventrella, Cristina Algieri, Gaia Tioli and Giorgio Lenaz
Life 2021, 11(3), 242; https://doi.org/10.3390/life11030242 - 15 Mar 2021
Cited by 42 | Viewed by 5932
Abstract
Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled [...] Read more.
Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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15 pages, 1510 KiB  
Review
Role of Mitochondria in Viral Infections
by Srikanth Elesela and Nicholas W. Lukacs
Life 2021, 11(3), 232; https://doi.org/10.3390/life11030232 - 11 Mar 2021
Cited by 53 | Viewed by 7716
Abstract
Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect [...] Read more.
Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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10 pages, 1103 KiB  
Review
Mitochondrial Functionality in Inflammatory Pathology-Modulatory Role of Physical Activity
by Rafael A. Casuso and Jesús R. Huertas
Life 2021, 11(1), 61; https://doi.org/10.3390/life11010061 - 15 Jan 2021
Cited by 16 | Viewed by 5035
Abstract
The incidence and severity of metabolic diseases can be reduced by introducing healthy lifestyle habits including moderate exercise. A common observation in age-related metabolic diseases is an increment in systemic inflammation (the so-called inflammaging) where mitochondrial reactive oxygen species (ROS) production may have [...] Read more.
The incidence and severity of metabolic diseases can be reduced by introducing healthy lifestyle habits including moderate exercise. A common observation in age-related metabolic diseases is an increment in systemic inflammation (the so-called inflammaging) where mitochondrial reactive oxygen species (ROS) production may have a key role. Exercise prevents these metabolic pathologies, at least in part, due to its ability to alter immunometabolism, e.g., reducing systemic inflammation and by improving immune cell metabolism. Here, we review how exercise regulates immunometabolism within contracting muscles. In fact, we discuss how circulating and resident macrophages alter their function due to mitochondrial signaling, and we propose how these effects can be triggered within skeletal muscle in response to exercise. Finally, we also describe how exercise-induced mitochondrial adaptations can help to fight against virus infection. Moreover, the fact that moderate exercise increases circulating immune cells must be taken into account by public health agencies, as it may help prevent virus spread. This is of interest in order to face not only acute respiratory-related coronavirus (SARS-CoV) responsible for the COVID-19 pandemic but also for future virus infection challenges. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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42 pages, 1049 KiB  
Review
Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae
by Leticia V. R. Franco, Luca Bremner and Mario H. Barros
Life 2020, 10(11), 304; https://doi.org/10.3390/life10110304 - 23 Nov 2020
Cited by 9 | Viewed by 4126
Abstract
The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in [...] Read more.
The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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35 pages, 4744 KiB  
Review
Analysis of Human Mutations in the Supernumerary Subunits of Complex I
by Quynh-Chi L. Dang, Duong H. Phan, Abigail N. Johnson, Mukund Pasapuleti, Hind A. Alkhaldi, Fang Zhang and Steven B. Vik
Life 2020, 10(11), 296; https://doi.org/10.3390/life10110296 - 20 Nov 2020
Cited by 10 | Viewed by 4418
Abstract
Complex I is the largest member of the electron transport chain in human mitochondria. It comprises 45 subunits and requires at least 15 assembly factors. The subunits can be divided into 14 “core” subunits that carry out oxidation–reduction reactions and proton translocation, as [...] Read more.
Complex I is the largest member of the electron transport chain in human mitochondria. It comprises 45 subunits and requires at least 15 assembly factors. The subunits can be divided into 14 “core” subunits that carry out oxidation–reduction reactions and proton translocation, as well as 31 additional supernumerary (or accessory) subunits whose functions are less well known. Diminished levels of complex I activity are seen in many mitochondrial disease states. This review seeks to tabulate mutations in the supernumerary subunits of humans that appear to cause disease. Mutations in 20 of the supernumerary subunits have been identified. The mutations were analyzed in light of the tertiary and quaternary structure of human complex I (PDB id = 5xtd). Mutations were found that might disrupt the folding of that subunit or that would weaken binding to another subunit. In some cases, it appeared that no protein was made or, at least, could not be detected. A very common outcome is the lack of assembly of complex I when supernumerary subunits are mutated or missing. We suggest that poor assembly is the result of disrupting the large network of subunit interactions that the supernumerary subunits typically engage in. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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23 pages, 1686 KiB  
Review
Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies
by Christina Wasmus and Jan Dudek
Life 2020, 10(11), 277; https://doi.org/10.3390/life10110277 - 11 Nov 2020
Cited by 24 | Viewed by 4624
Abstract
The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial [...] Read more.
The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies. Full article
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
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