Mitochondrial Biology in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 130013

Special Issue Editors

Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
Interests: mitochondrial biology and disease; neurodegenerative disease; AMPK; TOR complex I; cellular stress signalling
Special Issues, Collections and Topics in MDPI journals
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
Interests: mitochondria; neurodegenerative disease; Parkinson’s disease; myalgic encephalomyelitis/chronic fatigue syndrome; long COVID; Dictyostelium discoideum
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Best known as the site of respiratory ATP production, the mitochondria have been revealed over the past quarter-century as being deeply embedded in all aspects of the life of the eukaryotic cell. They are the product of two genomes whose expression must be coordinated by information shared in both directions between them and the nucleus. They participate in critical central metabolic pathways and they are fully integrated into the intracellular signalling networks that regulate diverse cellular functions. It is not surprising then that mitochondrial defects or dysregulation have emerged as having key roles in ageing and in the cytopathological mechanisms underlying cancer, neurodegenerative and other diseases.

This Special Issue of Cells is devoted to all aspects of mitochondrial function and dysfunction in healthy and diseased cells. It will contain articles that collectively provide a balanced, state-of-the-art view of mitochondrial biology. We seek submissions of high quality articles on including, but not limited to, mitochondrial biogenesis, metabolism, regulation, gene expression, signalling and roles in ageing and disease. Because of the vital and powerful contributions made by model organisms to understanding human biology and disease, we encourage manuscripts that describe or include the use of simple model systems to explore mitochondrial biology in health and disease.

Prof. Paul Robert Fisher
Dr. Sarah Annesley
Guest Editors

Manuscript Submission Information

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

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • mitochondria
  • mitochondrial biogenesis
  • mitochondrial metabolism
  • mitochondrial replication
  • mitochondrial gene expression
  • mitochondrial cell death
  • mitochondrial signalling
  • mitochondrial membrane transporters
  • mitochondrial respiration
  • OXPHOS
  • neurodegenerative disease
  • cellular stress responses
  • mitophagy
  • autophagy
  • MAMs
  • apoptosis
  • ER-mitochondria interactions
  • Parkinson’s disease
  • Alzheimer’s disease
  • ALS
  • Huntington’s disease
  • cancer

Published Papers (13 papers)

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Editorial

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7 pages, 191 KiB  
Editorial
Mitochondria in Health and Disease
by Sarah J. Annesley and Paul R. Fisher
Cells 2019, 8(7), 680; https://doi.org/10.3390/cells8070680 - 05 Jul 2019
Cited by 288 | Viewed by 18860
Abstract
Mitochondria are best known as the sites for production of respiratory ATP and are essential for eukaryotic life. They have their own genome but the great majority of the mitochondrial proteins are encoded by the nuclear genome and are imported into the mitochondria. [...] Read more.
Mitochondria are best known as the sites for production of respiratory ATP and are essential for eukaryotic life. They have their own genome but the great majority of the mitochondrial proteins are encoded by the nuclear genome and are imported into the mitochondria. The mitochondria participate in critical central metabolic pathways and they are fully integrated into the intracellular signalling networks that regulate diverse cellular functions. It is not surprising then that mitochondrial defects or dysregulation have emerged as having key roles in ageing and in the cytopathological mechanisms underlying cancer, neurodegenerative and other diseases. This special issue contains 12 publications—nine review articles and three original research articles. They cover diverse areas of mitochondrial biology and function and how defects in these areas can lead to disease. In addition, the articles in this issue highlight how model organisms have contributed to our understanding of these processes. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)

Research

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19 pages, 4251 KiB  
Article
A Rise in ATP, ROS, and Mitochondrial Content upon Glucose Withdrawal Correlates with a Dysregulated Mitochondria Turnover Mediated by the Activation of the Protein Deacetylase SIRT1
by Seon Beom Song and Eun Seong Hwang
Cells 2019, 8(1), 11; https://doi.org/10.3390/cells8010011 - 27 Dec 2018
Cited by 33 | Viewed by 8636
Abstract
Glucose withdrawal has been used as a model for the study of homeostatic defense mechanisms, especially for how cells cope with a shortage of nutrient supply by enhancing catabolism. However, detailed cellular responses to glucose withdrawal have been poorly studied, and are controversial. [...] Read more.
Glucose withdrawal has been used as a model for the study of homeostatic defense mechanisms, especially for how cells cope with a shortage of nutrient supply by enhancing catabolism. However, detailed cellular responses to glucose withdrawal have been poorly studied, and are controversial. In this study, we determined how glucose withdrawal affects mitochondrial activity, and the quantity and the role of SIRT1 in these changes. The results of our study indicate a substantial increase in ATP production from mitochondria, through an elevation of mitochondrial biogenesis, mediated by SIRT1 activation that is driven by increased NAD+/NADH ratio. Moreover, mitochondria persisted in the cells as elongated forms, and apparently evaded mitophagic removal. This led to a steady increase in mitochondria content and the reactive oxygen species (ROS) generated from them, indicating failure in ATP and ROS homeostasis, due to a misbalance in SIRT1-mediated mitochondria turnover in conditions of glucose withdrawal. Our results suggest that SIRT1 activation alone cannot properly manage energy homeostasis under certain metabolic crisis conditions. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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13 pages, 2389 KiB  
Article
SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM
by Pankaj K. Bagul, Parmeshwar B. Katare, Paramesha Bugga, Amit K. Dinda and Sanjay K. Banerjee
Cells 2018, 7(12), 235; https://doi.org/10.3390/cells7120235 - 28 Nov 2018
Cited by 93 | Viewed by 7678
Abstract
Background and Purpose: Mitochondrial dysfunction remains the crucial cause for many heart diseases including diabetic cardiomyopathy (DCM). Sirtuin-3 (SIRT-3) is a protein deacetylase localized in the mitochondria and regulates mitochondrial function. Being a noteworthy mitochondrial protein deacetylase enzyme, the role of SIRT-3 in [...] Read more.
Background and Purpose: Mitochondrial dysfunction remains the crucial cause for many heart diseases including diabetic cardiomyopathy (DCM). Sirtuin-3 (SIRT-3) is a protein deacetylase localized in the mitochondria and regulates mitochondrial function. Being a noteworthy mitochondrial protein deacetylase enzyme, the role of SIRT-3 in DCM is yet to be explored. Experimental Approach: Diabetes mellitus (Type-I, T1DM) was induced using streptozotocin (STZ, 50 mg/kg) in male Sprague Dawley (SD) rats. Rats with >200 mg/dL blood glucose levels were then divided randomly into two groups, DIA and DIA + RESV, where vehicle and resveratrol (25 mg/kg/day) were administered orally in both groups, respectively. Cardiac oxidative stress, fibrosis, and mitochondrial parameters were evaluated. H9c2 cells were transfected with SIRT-3 siRNA and shRNA, and ORF plasmid for silencing and overexpression, respectively. Key Results: After eight weeks, diabetic rat heart showed reduced cardiac cell size, increased oxidative stress and reduction of the activities of enzymes involved in mitochondrial oxidative phosphorylation (OXPHOS). There was reduced expression and activity of SIRT-3 and mitochondrial transcription factor (TFAM) in diabetic heart. Reduced SIRT-3 expression is also correlated with increased acetylation, decreased mitochondrial DNA (mtDNA) binding activity of TFAM, and reduced transcription of mitochondrial DNA encoded genes. Administration of resveratrol prevented the decrease in SIRT-3 and TFAM activity, which was corresponding to the reduced acetylation status of TFAM. Silencing SIRT-3 using siRNA in H9C2 cells showed increased acetylation of TFAM. Conclusion and Implications: Together our data shows that resveratrol activates SIRT-3, regulates the acetylation status of TFAM and preserves the mitochondrial function along with cellular size in diabetic rat heart. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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15 pages, 1043 KiB  
Article
Exploring the Effect of Rotenone—A Known Inducer of Parkinson’s Disease—On Mitochondrial Dynamics in Dictyostelium discoideum
by Ethan Chernivec, Jacie Cooper and Kari Naylor
Cells 2018, 7(11), 201; https://doi.org/10.3390/cells7110201 - 08 Nov 2018
Cited by 19 | Viewed by 5838
Abstract
Current treatments for Parkinson’s disease (PD) only alleviate symptoms doing little to inhibit the onset and progression of the disease, thus we must research the mechanism of Parkinson’s. Rotenone is a known inducer of parkinsonian conditions in rats; we use rotenone to induce [...] Read more.
Current treatments for Parkinson’s disease (PD) only alleviate symptoms doing little to inhibit the onset and progression of the disease, thus we must research the mechanism of Parkinson’s. Rotenone is a known inducer of parkinsonian conditions in rats; we use rotenone to induce parkinsonian cellular conditions in Dictyostelium discoideum. In our model we primarily focus on mitochondrial dynamics. We found that rotenone disrupts the actin and microtubule cytoskeleton but mitochondrial morphology remains intact. Rotenone stimulates mitochondrial velocity while inhibiting mitochondrial fusion, increases reactive oxygen species (ROS) but has no effect on ATP levels. Antioxidants have been shown to decrease some PD symptoms thus we added ascorbic acid to our rotenone treated cells. Ascorbic acid administration suggests that rotenone effects may be specific to the disruption of the cytoskeleton rather than the increase in ROS. Our results imply that D. discoideum may be a valid cellular PD model and that the rotenone induced velocity increase and loss of fusion could prevent mitochondria from effectively providing energy and other mitochondrial products in high demand areas. The combination of these defects in mitochondrial dynamics and increased ROS could result in degeneration of neurons in PD. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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Review

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15 pages, 2698 KiB  
Review
Mitochondrial Biogenesis and Mitochondrial Reactive Oxygen Species (ROS): A Complex Relationship Regulated by the cAMP/PKA Signaling Pathway
by Cyrielle Bouchez and Anne Devin
Cells 2019, 8(4), 287; https://doi.org/10.3390/cells8040287 - 27 Mar 2019
Cited by 143 | Viewed by 11065
Abstract
Mitochondrial biogenesis is a complex process. It requires the contribution of both the nuclear and the mitochondrial genomes and therefore cross talk between the nucleus and mitochondria. Cellular energy demand can vary by great length and it is now well known that one [...] Read more.
Mitochondrial biogenesis is a complex process. It requires the contribution of both the nuclear and the mitochondrial genomes and therefore cross talk between the nucleus and mitochondria. Cellular energy demand can vary by great length and it is now well known that one way to adjust adenosine triphosphate (ATP) synthesis to energy demand is through modulation of mitochondrial content in eukaryotes. The knowledge of actors and signals regulating mitochondrial biogenesis is thus of high importance. Here, we review the regulation of mitochondrial biogenesis both in yeast and in mammalian cells through mitochondrial reactive oxygen species. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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17 pages, 6212 KiB  
Review
Lessons from the Discovery of Mitochondrial Fragmentation (Fission): A Review and Update
by Dmitry B. Zorov, Ivan A. Vorobjev, Vasily A. Popkov, Valentina A. Babenko, Ljubava D. Zorova, Irina B. Pevzner, Denis N. Silachev, Savva D. Zorov, Nadezda V. Andrianova and Egor Y. Plotnikov
Cells 2019, 8(2), 175; https://doi.org/10.3390/cells8020175 - 19 Feb 2019
Cited by 61 | Viewed by 9375
Abstract
Thirty-five years ago, we described fragmentation of the mitochondrial population in a living cell into small vesicles (mitochondrial fission). Subsequently, this phenomenon has become an object of general interest due to its involvement in the process of oxidative stress-related cell death and having [...] Read more.
Thirty-five years ago, we described fragmentation of the mitochondrial population in a living cell into small vesicles (mitochondrial fission). Subsequently, this phenomenon has become an object of general interest due to its involvement in the process of oxidative stress-related cell death and having high relevance to the incidence of a pathological phenotype. Tentatively, the key component of mitochondrial fission process is segregation and further asymmetric separation of a mitochondrial body yielding healthy (normally functioning) and impaired (incapable to function in a normal way) organelles with subsequent decomposition and removal of impaired elements through autophagy (mitophagy). We speculate that mitochondria contain cytoskeletal elements, which maintain the mitochondrial shape, and also are involved in the process of intramitochondrial segregation of waste products. We suggest that perturbation of the mitochondrial fission/fusion machinery and slowdown of the removal process of nonfunctional mitochondrial structures led to the increase of the proportion of impaired mitochondrial elements. When the concentration of malfunctioning mitochondria reaches a certain threshold, this can lead to various pathologies, including aging. Overall, we suggest a process of mitochondrial fission to be an essential component of a complex system controlling a healthy cell phenotype. The role of reactive oxygen species in mitochondrial fission is discussed. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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21 pages, 758 KiB  
Review
Mitochondrial DNA Integrity: Role in Health and Disease
by Priyanka Sharma and Harini Sampath
Cells 2019, 8(2), 100; https://doi.org/10.3390/cells8020100 - 29 Jan 2019
Cited by 132 | Viewed by 14332
Abstract
As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features [...] Read more.
As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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19 pages, 1090 KiB  
Review
The Role of Mitochondria in Reactive Oxygen Species Generation and Its Implications for Neurodegenerative Diseases
by Saima Kausar, Feng Wang and Hongjuan Cui
Cells 2018, 7(12), 274; https://doi.org/10.3390/cells7120274 - 17 Dec 2018
Cited by 202 | Viewed by 9945
Abstract
Mitochondria are dynamic cellular organelles that consistently migrate, fuse, and divide to modulate their number, size, and shape. In addition, they produce ATP, reactive oxygen species, and also have a biological role in antioxidant activities and Ca2+ buffering. Mitochondria are thought to [...] Read more.
Mitochondria are dynamic cellular organelles that consistently migrate, fuse, and divide to modulate their number, size, and shape. In addition, they produce ATP, reactive oxygen species, and also have a biological role in antioxidant activities and Ca2+ buffering. Mitochondria are thought to play a crucial biological role in most neurodegenerative disorders. Neurons, being high-energy-demanding cells, are closely related to the maintenance, dynamics, and functions of mitochondria. Thus, impairment of mitochondrial activities is associated with neurodegenerative diseases, pointing to the significance of mitochondrial functions in normal cell physiology. In recent years, considerable progress has been made in our knowledge of mitochondrial functions, which has raised interest in defining the involvement of mitochondrial dysfunction in neurodegenerative diseases. Here, we summarize the existing knowledge of the mitochondrial function in reactive oxygen species generation and its involvement in the development of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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25 pages, 4010 KiB  
Review
Mitochondrial Metabolism in Major Neurological Diseases
by Zhengqiu Zhou, Grant L. Austin, Lyndsay E. A. Young, Lance A. Johnson and Ramon Sun
Cells 2018, 7(12), 229; https://doi.org/10.3390/cells7120229 - 23 Nov 2018
Cited by 43 | Viewed by 7658
Abstract
Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is [...] Read more.
Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation–functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation and possibly disease manifestation. This review will discuss the basic functions of mitochondria and how alterations in mitochondrial activity lead to neurological disease progression. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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15 pages, 1421 KiB  
Review
AAA Proteases: Guardians of Mitochondrial Function and Homeostasis
by Magdalena Opalińska and Hanna Jańska
Cells 2018, 7(10), 163; https://doi.org/10.3390/cells7100163 - 11 Oct 2018
Cited by 32 | Viewed by 7062
Abstract
Mitochondria are dynamic, semi-autonomous organelles that execute numerous life-sustaining tasks in eukaryotic cells. Functioning of mitochondria depends on the adequate action of versatile proteinaceous machineries. Fine-tuning of mitochondrial activity in response to cellular needs involves continuous remodeling of organellar proteome. This process not [...] Read more.
Mitochondria are dynamic, semi-autonomous organelles that execute numerous life-sustaining tasks in eukaryotic cells. Functioning of mitochondria depends on the adequate action of versatile proteinaceous machineries. Fine-tuning of mitochondrial activity in response to cellular needs involves continuous remodeling of organellar proteome. This process not only includes modulation of various biogenetic pathways, but also the removal of superfluous proteins by adenosine triphosphate (ATP)-driven proteolytic machineries. Accordingly, all mitochondrial sub-compartments are under persistent surveillance of ATP-dependent proteases. Particularly important are highly conserved two inner mitochondrial membrane-bound metalloproteases known as m-AAA and i-AAA (ATPases associated with diverse cellular activities), whose mis-functioning may lead to impaired organellar function and consequently to development of severe diseases. Herein, we discuss the current knowledge of yeast, mammalian, and plant AAA proteases and their implications in mitochondrial function and homeostasis maintenance. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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26 pages, 3419 KiB  
Review
The Interplay among PINK1/PARKIN/Dj-1 Network during Mitochondrial Quality Control in Cancer Biology: Protein Interaction Analysis
by Celia Salazar, Paula Ruiz-Hincapie and Lina María Ruiz
Cells 2018, 7(10), 154; https://doi.org/10.3390/cells7100154 - 29 Sep 2018
Cited by 37 | Viewed by 9512
Abstract
PARKIN (E3 ubiquitin ligase PARK2), PINK1 (PTEN induced kinase 1) and DJ-1 (PARK7) are proteins involved in autosomal recessive parkinsonism, and carcinogenic processes. In damaged mitochondria, PINK1’s importing into the inner mitochondrial membrane is prevented, PARKIN presents a partial mitochondrial [...] Read more.
PARKIN (E3 ubiquitin ligase PARK2), PINK1 (PTEN induced kinase 1) and DJ-1 (PARK7) are proteins involved in autosomal recessive parkinsonism, and carcinogenic processes. In damaged mitochondria, PINK1’s importing into the inner mitochondrial membrane is prevented, PARKIN presents a partial mitochondrial localization at the outer mitochondrial membrane and DJ-1 relocates to mitochondria when oxidative stress increases. Depletion of these proteins result in abnormal mitochondrial morphology. PINK1, PARKIN, and DJ-1 participate in mitochondrial remodeling and actively regulate mitochondrial quality control. In this review, we highlight that PARKIN, PINK1, and DJ-1 should be regarded as having an important role in Cancer Biology. The STRING database and Gene Ontology (GO) enrichment analysis were performed to consolidate knowledge of well-known protein interactions for PINK1, PARKIN, and DJ-1 and envisage new ones. The enrichment analysis of KEGG pathways showed that the PINK1/PARKIN/DJ-1 network resulted in Parkinson disease as the main feature, while the protein DJ-1 showed enrichment in prostate cancer and p53 signaling pathway. Some predicted transcription factors regulating PINK1, PARK2 (PARKIN) and PARK7 (DJ-1) gene expression are related to cell cycle control. We can therefore suggest that the interplay among PINK1/PARKIN/DJ-1 network during mitochondrial quality control in cancer biology may occur at the transcriptional level. Further analysis, like a systems biology approach, will be helpful in the understanding of PINK1/PARKIN/DJ-1 network. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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13 pages, 1070 KiB  
Review
Mitochondrial Quality Control in COPD and IPF
by Hiromichi Hara, Kazuyoshi Kuwano and Jun Araya
Cells 2018, 7(8), 86; https://doi.org/10.3390/cells7080086 - 24 Jul 2018
Cited by 53 | Viewed by 7758
Abstract
Mitochondria play important roles in the maintenance of intracellular homeostasis; hence, the quality control of mitochondria is crucial for cell fate determination. Mitochondria dynamics and mitochondria-specific autophagy, known as mitophagy, are two main quality control systems in cells. Mitochondria fuse to increase energy [...] Read more.
Mitochondria play important roles in the maintenance of intracellular homeostasis; hence, the quality control of mitochondria is crucial for cell fate determination. Mitochondria dynamics and mitochondria-specific autophagy, known as mitophagy, are two main quality control systems in cells. Mitochondria fuse to increase energy production in response to stress, and damaged mitochondria are segregated by fission and degraded by mitophagy. Once these systems are disrupted, dysfunctional mitochondria with decreased adenosine triphosphate (ATP) production and increased reactive oxygen species (ROS) production accumulate, affecting cell fate. Recently, increasing evidence suggests that the dysregulation of mitochondria quality control is pathogenic in several age-related diseases. In this review, we outlined the role of mitochondria quality control systems in the pathogenesis of age-associated lung diseases, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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13 pages, 10763 KiB  
Review
Mitochondrial Fatty Acid Oxidation Disorders Associated with Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency
by Alice J. Sharpe and Matthew McKenzie
Cells 2018, 7(6), 46; https://doi.org/10.3390/cells7060046 - 23 May 2018
Cited by 56 | Viewed by 10718
Abstract
Mitochondrial fatty acid β-oxidation (FAO) is the primary pathway for fatty acid metabolism in humans, performing a key role in liver, heart and skeletal muscle energy homeostasis. FAO is particularly important during times of fasting when glucose supply is limited, providing energy for [...] Read more.
Mitochondrial fatty acid β-oxidation (FAO) is the primary pathway for fatty acid metabolism in humans, performing a key role in liver, heart and skeletal muscle energy homeostasis. FAO is particularly important during times of fasting when glucose supply is limited, providing energy for many organs and tissues, including the heart, liver and brain. Deficiencies in FAO can cause life-threatening metabolic disorders in early childhood that present with liver dysfunction, hypoglycemia, dilated hypertrophic cardiomyopathy and Reye-like Syndrome. Alternatively, FAO defects can also cause ‘milder’ adult-onset disease with exercise-induced myopathy and rhabdomyolysis. Short-chain enoyl-CoA hydratase (ECHS1) is a key FAO enzyme involved in the metabolism of fatty acyl-CoA esters. ECHS1 deficiency (ECHS1D) also causes human disease; however, the clinical manifestation is unlike most other FAO disorders. ECHS1D patients commonly present with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy traditionally associated with defects in oxidative phosphorylation (OXPHOS). In this article, we review the clinical, biochemical and genetic features of the ESHS1D patients described to date, and discuss the significance of the secondary OXPHOS defects associated with ECHS1D and their contribution to overall disease pathogenesis. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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