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Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (15 July 2020) | Viewed by 77622

Special Issue Editor

Dr. Alessandra Ferramosca

E-Mail Website
Guest Editor
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Via Provinciale Lecce-Monteroni, I-73100 Lecce, Italy
Interests: lipid metabolism; mitochondria; cell bioenergetics; biogenesis of mitochondrial proteins; sperm metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria contain more than 1000 proteins which are encoded by both mitochondrial and nuclear genomes. Although mitochondria contain an autonomous genome (the mitochondrial DNA), the great majority of mitochondrial proteins are encoded by nuclear genes, synthesized by cytosolic ribosomes, and translocated into mitochondria by a multicomponent import machinery.

Mitochondrial proteins perform functions crucial for the viability of eukaryotic cells, as they are involved in respiration, metabolite transport, protein translocation, protein quality control, oxidoreductive homeostasis, and numerous other processes.

Interestingly, mitochondrial protein machineries, which have diverse functions, are connected in complex and dynamic networks, and the failure of these systems could lead to the development of disease.

The aim of this Special Issue is to reveal the complexity and the versatility of mitochondrial activities, integrating mitochondrial energetics and metabolism with protein biogenesis.

A deeper investigation of the functional crosstalk between mitochondrial proteins may reveal its importance in contributing to pathologies caused by dysfunctional mitochondria.

The special issue welcomes both original research articles and comprehensive reviews. Short communications will also be considered.

Prof. Alessandra Ferramosca
Guest Editor

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.

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Published Papers (15 papers)

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Editorial

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4 pages, 172 KiB  
Editorial
Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease
by Alessandra Ferramosca
Int. J. Mol. Sci. 2021, 22(1), 1; https://doi.org/10.3390/ijms22010001 - 22 Dec 2020
Cited by 7 | Viewed by 2050
Abstract
Mitochondria are double membrane-bound organelles which are essential for the viability of eukaryotic cells, because they play a crucial role in bioenergetics, metabolism and signaling [...] Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)

Research

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14 pages, 1734 KiB  
Article
Biochemical Convergence of Mitochondrial Hsp70 System Specialized in Iron–Sulfur Cluster Biogenesis
by Malgorzata Kleczewska, Aneta Grabinska, Marcin Jelen, Milena Stolarska, Brenda Schilke, Jaroslaw Marszalek, Elizabeth A. Craig and Rafal Dutkiewicz
Int. J. Mol. Sci. 2020, 21(9), 3326; https://doi.org/10.3390/ijms21093326 - 8 May 2020
Cited by 14 | Viewed by 2587
Abstract
Mitochondria play a central role in the biogenesis of iron–sulfur cluster(s) (FeS), protein cofactors needed for many cellular activities. After assembly on scaffold protein Isu, the cluster is transferred onto a recipient apo-protein. Transfer requires Isu interaction with an Hsp70 chaperone system that [...] Read more.
Mitochondria play a central role in the biogenesis of iron–sulfur cluster(s) (FeS), protein cofactors needed for many cellular activities. After assembly on scaffold protein Isu, the cluster is transferred onto a recipient apo-protein. Transfer requires Isu interaction with an Hsp70 chaperone system that includes a dedicated J-domain protein co-chaperone (Hsc20). Hsc20 stimulates Hsp70′s ATPase activity, thus stabilizing the critical Isu–Hsp70 interaction. While most eukaryotes utilize a multifunctional mitochondrial (mt)Hsp70, yeast employ another Hsp70 (Ssq1), a product of mtHsp70 gene duplication. Ssq1 became specialized in FeS biogenesis, recapitulating the process in bacteria, where specialized Hsp70 HscA cooperates exclusively with an ortholog of Hsc20. While it is well established that Ssq1 and HscA converged functionally for FeS transfer, whether these two Hsp70s possess similar biochemical properties was not known. Here, we show that overall HscA and Ssq1 biochemical properties are very similar, despite subtle differences being apparent - the ATPase activity of HscA is stimulated to a somewhat higher levels by Isu and Hsc20, while Ssq1 has a higher affinity for Isu and for Hsc20. HscA/Ssq1 are a unique example of biochemical convergence of distantly related Hsp70s, with practical implications, crossover experimental results can be combined, facilitating understanding of the FeS transfer process. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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14 pages, 3384 KiB  
Article
Cardiac Function is not Susceptible to Moderate Disassembly of Mitochondrial Respiratory Supercomplexes
by Xavier R. Chapa-Dubocq, Keishla M. Rodríguez-Graciani, Roberto A. Guzmán-Hernández, Sehwan Jang, Paul S. Brookes and Sabzali Javadov
Int. J. Mol. Sci. 2020, 21(5), 1555; https://doi.org/10.3390/ijms21051555 - 25 Feb 2020
Cited by 9 | Viewed by 3544
Abstract
Mitochondrial respiratory chain supercomplexes (RCS), particularly, the respirasome, which contains complexes I, III, and IV, have been suggested to participate in facilitating electron transport, reducing the production of reactive oxygen species (ROS), and maintaining the structural integrity of individual electron transport chain (ETC) [...] Read more.
Mitochondrial respiratory chain supercomplexes (RCS), particularly, the respirasome, which contains complexes I, III, and IV, have been suggested to participate in facilitating electron transport, reducing the production of reactive oxygen species (ROS), and maintaining the structural integrity of individual electron transport chain (ETC) complexes. Disassembly of the RCS has been observed in Barth syndrome, neurodegenerative and cardiovascular diseases, diabetes mellitus, and aging. However, the physiological role of RCS in high energy-demanding tissues such as the heart remains unknown. This study elucidates the relationship between RCS assembly and cardiac function. Adult male Sprague Dawley rats underwent Langendorff retrograde perfusion in the presence and absence of ethanol, isopropanol, or rotenone (an ETC complex I inhibitor). We found that ethanol had no effects on cardiac function, whereas rotenone reduced heart contractility, which was not recovered when rotenone was excluded from the perfusion medium. Blue native polyacrylamide gel electrophoresis revealed significant reductions of respirasome levels in ethanol- or rotenone-treated groups compared to the control group. In addition, rotenone significantly increased while ethanol had no effect on mitochondrial ROS production. In isolated intact mitochondria in vitro, ethanol did not affect respirasome assembly; however, acetaldehyde, a byproduct of ethanol metabolism, induced dissociation of respirasome. Isopropanol, a secondary alcohol which was used as an alternative compound, had effects similar to ethanol on heart function, respirasome levels, and ROS production. In conclusion, ethanol and isopropanol reduced respirasome levels without any noticeable effect on cardiac parameters, and cardiac function is not susceptible to moderate reductions of RCS. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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Review

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27 pages, 2013 KiB  
Review
Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis
by Anna M. Lenkiewicz, Magda Krakowczyk and Piotr Bragoszewski
Int. J. Mol. Sci. 2022, 23(1), 7; https://doi.org/10.3390/ijms23010007 - 21 Dec 2021
Cited by 7 | Viewed by 3404
Abstract
With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting [...] Read more.
With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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28 pages, 17870 KiB  
Review
Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease
by Fanny Eysert, Paula Fernanda Kinoshita, Arnaud Mary, Loan Vaillant-Beuchot, Frédéric Checler and Mounia Chami
Int. J. Mol. Sci. 2020, 21(24), 9521; https://doi.org/10.3390/ijms21249521 - 14 Dec 2020
Cited by 36 | Viewed by 5239
Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative pathology characterized by a progressive decline of cognitive functions. Alteration of various signaling cascades affecting distinct subcellular compartment functions and their communication likely contribute to AD progression. Among others, the alteration of the physical association between [...] Read more.
Alzheimer’s disease (AD) is a multifactorial neurodegenerative pathology characterized by a progressive decline of cognitive functions. Alteration of various signaling cascades affecting distinct subcellular compartment functions and their communication likely contribute to AD progression. Among others, the alteration of the physical association between the endoplasmic reticulum (ER) and mitochondria, also referred as mitochondria-associated membranes (MAMs), impacts various cellular housekeeping functions such as phospholipids-, glucose-, cholesterol-, and fatty-acid-metabolism, as well as calcium signaling, which are all altered in AD. Our review describes the physical and functional proteome crosstalk between the ER and mitochondria and highlights the contribution of distinct molecular components of MAMs to mitochondrial and ER dysfunctions in AD progression. We also discuss potential strategies targeting MAMs to improve mitochondria and ER functions in AD. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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26 pages, 1355 KiB  
Review
Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import
by Tian Zhao, Caitlin Goedhart, Gerald Pfeffer, Steven C Greenway, Matthew Lines, Aneal Khan, A Micheil Innes and Timothy E Shutt
Int. J. Mol. Sci. 2020, 21(21), 8327; https://doi.org/10.3390/ijms21218327 - 6 Nov 2020
Cited by 6 | Viewed by 3308
Abstract
Mitochondrial disease represents a collection of rare genetic disorders caused by mitochondrial dysfunction. These disorders can be quite complex and heterogeneous, and it is recognized that mitochondrial disease can affect any tissue at any age. The reasons for this variability are not well [...] Read more.
Mitochondrial disease represents a collection of rare genetic disorders caused by mitochondrial dysfunction. These disorders can be quite complex and heterogeneous, and it is recognized that mitochondrial disease can affect any tissue at any age. The reasons for this variability are not well understood. In this review, we develop and expand a subset of mitochondrial diseases including predominantly skeletal phenotypes. Understanding how impairment ofdiverse mitochondrial functions leads to a skeletal phenotype will help diagnose and treat patients with mitochondrial disease and provide additional insight into the growing list of human pathologies associated with mitochondrial dysfunction. The underlying disease genes encode factors involved in various aspects of mitochondrial protein homeostasis, including proteases and chaperones, mitochondrial protein import machinery, mediators of inner mitochondrial membrane lipid homeostasis, and aminoacylation of mitochondrial tRNAs required for translation. We further discuss a complex of frequently associated phenotypes (short stature, cataracts, and cardiomyopathy) potentially explained by alterations to steroidogenesis, a process regulated by mitochondria. Together, these observations provide novel insight into the consequences of impaired mitochondrial protein homeostasis. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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32 pages, 3027 KiB  
Review
The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity
by Sebastian Kreimendahl and Joachim Rassow
Int. J. Mol. Sci. 2020, 21(19), 7262; https://doi.org/10.3390/ijms21197262 - 1 Oct 2020
Cited by 36 | Viewed by 9788
Abstract
Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 [...] Read more.
Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 tetratricopeptide repeat (TPR) motifs. Tom70 serves as a docking site for cytosolic chaperone proteins and co-chaperones and is thereby involved in the uptake of newly synthesized chaperone-bound proteins in mitochondrial biogenesis. In yeast, Tom70 additionally mediates ER-mitochondria contacts via binding to sterol transporter Lam6/Ltc1. In mammalian cells, TOM70 promotes endoplasmic reticulum (ER) to mitochondria Ca2+ transfer by association with the inositol-1,4,5-triphosphate receptor type 3 (IP3R3). TOM70 is specifically targeted by the Bcl-2-related protein MCL-1 that acts as an anti-apoptotic protein in macrophages infected by intracellular pathogens, but also in many cancer cells. By participating in the recruitment of PINK1 and the E3 ubiquitin ligase Parkin, TOM70 can be implicated in the development of Parkinson’s disease. TOM70 acts as receptor of the mitochondrial antiviral-signaling protein (MAVS) and thereby participates in the corresponding system of innate immunity against viral infections. The protein encoded by Orf9b in the genome of SARS-CoV-2 binds to TOM70, probably compromising the synthesis of type I interferons. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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17 pages, 1707 KiB  
Review
Functions of Cytochrome c Oxidase Assembly Factors
by Shane A. Watson and Gavin P. McStay
Int. J. Mol. Sci. 2020, 21(19), 7254; https://doi.org/10.3390/ijms21197254 - 30 Sep 2020
Cited by 33 | Viewed by 6244
Abstract
Cytochrome c oxidase is the terminal complex of eukaryotic oxidative phosphorylation in mitochondria. This process couples the reduction of electron carriers during metabolism to the reduction of molecular oxygen to water and translocation of protons from the internal mitochondrial matrix to the inter-membrane [...] Read more.
Cytochrome c oxidase is the terminal complex of eukaryotic oxidative phosphorylation in mitochondria. This process couples the reduction of electron carriers during metabolism to the reduction of molecular oxygen to water and translocation of protons from the internal mitochondrial matrix to the inter-membrane space. The electrochemical gradient formed is used to generate chemical energy in the form of adenosine triphosphate to power vital cellular processes. Cytochrome c oxidase and most oxidative phosphorylation complexes are the product of the nuclear and mitochondrial genomes. This poses a series of topological and temporal steps that must be completed to ensure efficient assembly of the functional enzyme. Many assembly factors have evolved to perform these steps for insertion of protein into the inner mitochondrial membrane, maturation of the polypeptide, incorporation of co-factors and prosthetic groups and to regulate this process. Much of the information about each of these assembly factors has been gleaned from use of the single cell eukaryote Saccharomyces cerevisiae and also mutations responsible for human disease. This review will focus on the assembly factors of cytochrome c oxidase to highlight some of the outstanding questions in the assembly of this vital enzyme complex. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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13 pages, 1579 KiB  
Review
What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?
by Shadi Maghool, Michael T. Ryan and Megan J. Maher
Int. J. Mol. Sci. 2020, 21(19), 6983; https://doi.org/10.3390/ijms21196983 - 23 Sep 2020
Cited by 12 | Viewed by 3355
Abstract
Complex IV (cytochrome c oxidase; COX) is the terminal complex of the mitochondrial electron transport chain. Copper is essential for COX assembly, activity, and stability, and is incorporated into the dinuclear CuA and mononuclear CuB sites. Multiple assembly factors play roles [...] Read more.
Complex IV (cytochrome c oxidase; COX) is the terminal complex of the mitochondrial electron transport chain. Copper is essential for COX assembly, activity, and stability, and is incorporated into the dinuclear CuA and mononuclear CuB sites. Multiple assembly factors play roles in the biogenesis of these sites within COX and the failure of this intricate process, such as through mutations to these factors, disrupts COX assembly and activity. Various studies over the last ten years have revealed that the assembly factor COA6, a small intermembrane space-located protein with a twin CX9C motif, plays a role in the biogenesis of the CuA site. However, how COA6 and its copper binding properties contribute to the assembly of this site has been a controversial area of research. In this review, we summarize our current understanding of the molecular mechanisms by which COA6 participates in COX biogenesis. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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17 pages, 2171 KiB  
Review
Mechanisms Underlying the Regulation of Mitochondrial Respiratory Chain Complexes by Nuclear Steroid Receptors
by Ami Kobayashi, Kotaro Azuma, Kazuhiro Ikeda and Satoshi Inoue
Int. J. Mol. Sci. 2020, 21(18), 6683; https://doi.org/10.3390/ijms21186683 - 12 Sep 2020
Cited by 25 | Viewed by 5667
Abstract
Mitochondrial respiratory chain complexes play important roles in energy production via oxidative phosphorylation (OXPHOS) to drive various biochemical processes in eukaryotic cells. These processes require coordination with other cell organelles, especially the nucleus. Factors encoded by both nuclear and mitochondrial DNA are involved [...] Read more.
Mitochondrial respiratory chain complexes play important roles in energy production via oxidative phosphorylation (OXPHOS) to drive various biochemical processes in eukaryotic cells. These processes require coordination with other cell organelles, especially the nucleus. Factors encoded by both nuclear and mitochondrial DNA are involved in the formation of active respiratory chain complexes and ‘supercomplexes’, the higher-order structures comprising several respiratory chain complexes. Various nuclear hormone receptors are involved in the regulation of OXPHOS-related genes. In this article, we review the roles of nuclear steroid receptors (NR3 class nuclear receptors), including estrogen receptors (ERs), estrogen-related receptors (ERRs), glucocorticoid receptors (GRs), mineralocorticoid receptors (MRs), progesterone receptors (PRs), and androgen receptors (ARs), in the regulatory mechanisms of mitochondrial respiratory chain complex and supercomplex formation. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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27 pages, 2109 KiB  
Review
Insights into Disease-Associated Tau Impact on Mitochondria
by Leonora Szabo, Anne Eckert and Amandine Grimm
Int. J. Mol. Sci. 2020, 21(17), 6344; https://doi.org/10.3390/ijms21176344 - 1 Sep 2020
Cited by 48 | Viewed by 5219
Abstract
Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in [...] Read more.
Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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42 pages, 1168 KiB  
Review
Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers
by Rosita Curcio, Paola Lunetti, Vincenzo Zara, Alessandra Ferramosca, Federica Marra, Giuseppe Fiermonte, Anna Rita Cappello, Francesco De Leonardis, Loredana Capobianco and Vincenza Dolce
Int. J. Mol. Sci. 2020, 21(17), 6052; https://doi.org/10.3390/ijms21176052 - 22 Aug 2020
Cited by 16 | Viewed by 4753
Abstract
Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial [...] Read more.
Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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21 pages, 2157 KiB  
Review
Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment
by Luca Frattaruolo, Matteo Brindisi, Rosita Curcio, Federica Marra, Vincenza Dolce and Anna Rita Cappello
Int. J. Mol. Sci. 2020, 21(17), 6014; https://doi.org/10.3390/ijms21176014 - 21 Aug 2020
Cited by 43 | Viewed by 6956
Abstract
Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism [...] Read more.
Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism reprogramming (i.e., the Warburg effect), recently, the critical role of mitochondria in oncogenesis, tumor progression, and neoplastic dissemination has emerged. In this report, we examined the main mitochondrial metabolic pathways that are altered in cancer, which play key roles in the different stages of tumor progression. Furthermore, we reviewed the function of important molecules inhibiting the main mitochondrial metabolic processes, which have been proven to be promising anticancer candidates in recent years. In particular, inhibitors of oxidative phosphorylation (OXPHOS), heme flux, the tricarboxylic acid cycle (TCA), glutaminolysis, mitochondrial dynamics, and biogenesis are discussed. The examined mitochondrial metabolic network inhibitors have produced interesting results in both preclinical and clinical studies, advancing cancer research and emphasizing that mitochondrial targeting may represent an effective anticancer strategy. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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15 pages, 1379 KiB  
Review
SUMOylation-Mediated Response to Mitochondrial Stress
by Jianli He, Jinke Cheng and Tianshi Wang
Int. J. Mol. Sci. 2020, 21(16), 5657; https://doi.org/10.3390/ijms21165657 - 6 Aug 2020
Cited by 27 | Viewed by 4301
Abstract
Mitochondrial stress is considered as a factor that reprograms the mitochondrial biogenesis and metabolism. As known, SUMOylation occurs through a series of stress-induced biochemical reactions. During the process of SUMOylation, the small ubiquitin-like modifier (SUMO) and its specific proteases (SENPs) are key signal [...] Read more.
Mitochondrial stress is considered as a factor that reprograms the mitochondrial biogenesis and metabolism. As known, SUMOylation occurs through a series of stress-induced biochemical reactions. During the process of SUMOylation, the small ubiquitin-like modifier (SUMO) and its specific proteases (SENPs) are key signal molecules. Furthermore, they are considered as novel mitochondrial stress sensors that respond to the signals produced by various stresses. The responses are critical for mitochondrial homeostasis. The scope of this review is to provide an overview of the function of SUMOylation in the mitochondrial stress response, to delineate a SUMOylation-involved signal network diagram, and to highlight a number of key questions that remain answered. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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34 pages, 517 KiB  
Review
AMPK, Mitochondrial Function, and Cardiovascular Disease
by Shengnan Wu and Ming-Hui Zou
Int. J. Mol. Sci. 2020, 21(14), 4987; https://doi.org/10.3390/ijms21144987 - 15 Jul 2020
Cited by 122 | Viewed by 9923
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, [...] Read more.
Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function. Full article
(This article belongs to the Special Issue Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease)
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