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Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0
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Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 53864

Special Issue Editors

Dr. Anna Atlante

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

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

Special Issue Information

Dear Colleagues,

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

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

Dr. Anna Atlante
Dr. Daniela Valenti
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

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Published Papers (16 papers)

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Editorial

Jump to: Research, Review

5 pages, 209 KiB  
Editorial
Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0
by Daniela Valenti and Anna Atlante
Int. J. Mol. Sci. 2022, 23(10), 5552; https://doi.org/10.3390/ijms23105552 - 16 May 2022
Cited by 1 | Viewed by 1436
Abstract
Mitochondria, traditionally identified as the powerhouses of eukaryotic cells, constitute a dynamic network of signaling platforms with multifaceted key roles in cell metabolism, proliferation and survival [...] Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)

Research

Jump to: Editorial, Review

21 pages, 4317 KiB  
Article
Proline Oxidation Supports Mitochondrial ATP Production When Complex I Is Inhibited
by Gergely Pallag, Sara Nazarian, Dora Ravasz, David Bui, Timea Komlódi, Carolina Doerrier, Erich Gnaiger, Thomas N. Seyfried and Christos Chinopoulos
Int. J. Mol. Sci. 2022, 23(9), 5111; https://doi.org/10.3390/ijms23095111 - 4 May 2022
Cited by 12 | Viewed by 2923
Abstract
The oxidation of proline to pyrroline-5-carboxylate (P5C) leads to the transfer of electrons to ubiquinone in mitochondria that express proline dehydrogenase (ProDH). This electron transfer supports Complexes CIII and CIV, thus generating the protonmotive force. Further catabolism of P5C forms glutamate, which fuels [...] Read more.
The oxidation of proline to pyrroline-5-carboxylate (P5C) leads to the transfer of electrons to ubiquinone in mitochondria that express proline dehydrogenase (ProDH). This electron transfer supports Complexes CIII and CIV, thus generating the protonmotive force. Further catabolism of P5C forms glutamate, which fuels the citric acid cycle that yields the reducing equivalents that sustain oxidative phosphorylation. However, P5C and glutamate catabolism depend on CI activity due to NAD+ requirements. NextGen-O2k (Oroboros Instruments) was used to measure proline oxidation in isolated mitochondria of various mouse tissues. Simultaneous measurements of oxygen consumption, membrane potential, NADH, and the ubiquinone redox state were correlated to ProDH activity and F1FO-ATPase directionality. Proline catabolism generated a sufficiently high membrane potential that was able to maintain the F1FO-ATPase operation in the forward mode. This was observed in CI-inhibited mouse liver and kidney mitochondria that exhibited high levels of proline oxidation and ProDH activity. This action was not observed under anoxia or when either CIII or CIV were inhibited. The duroquinone fueling of CIII and CIV partially reproduced the effects of proline. Excess glutamate, however, could not reproduce the proline effect, suggesting that processes upstream of the glutamate conversion from proline were involved. The ProDH inhibitors tetrahydro-2-furoic acid and, to a lesser extent, S-5-oxo-2-tetrahydrofurancarboxylic acid abolished all proline effects. The data show that ProDH-directed proline catabolism could generate sufficient CIII and CIV proton pumping, thus supporting ATP production by the F1FO-ATPase even under CI inhibition. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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22 pages, 4017 KiB  
Article
Cytopathological Outcomes of Knocking down Expression of Mitochondrial Complex II Subunits in Dictyostelium discoideum
by Sui Lay, Xavier Pearce, Oana Sanislav, Paul Robert Fisher and Sarah Jane Annesley
Int. J. Mol. Sci. 2022, 23(9), 5039; https://doi.org/10.3390/ijms23095039 - 1 May 2022
Cited by 1 | Viewed by 1691
Abstract
Mitochondrial Complex II is composed of four core subunits and mutations to any of the subunits result in lowered Complex II activity. Surprisingly, although mutations in any of the subunits can yield similar clinical outcomes, there are distinct differences in the patterns of [...] Read more.
Mitochondrial Complex II is composed of four core subunits and mutations to any of the subunits result in lowered Complex II activity. Surprisingly, although mutations in any of the subunits can yield similar clinical outcomes, there are distinct differences in the patterns of clinical disease most commonly associated with mutations in different subunits. Thus, mutations to the SdhA subunit most often result in mitochondrial disease phenotypes, whilst mutations to the other subunits SdhB-D more commonly result in tumour formation. The reason the clinical outcomes are so different is unknown. Here, we individually antisense-inhibited three of the Complex II subunits, SdhA, SdhB or SdhC, in the simple model organism Dictyostelium discoideum. Whilst SdhB and SdhC knockdown resulted in growth defects on bacterial lawns, antisense inhibition of SdhA expression resulted in a different pattern of phenotypic defects, including impairments of growth in liquid medium, enhanced intracellular proliferation of the bacterial pathogen Legionella pneumophila and phagocytosis. Knockdown of the individual subunits also produced different abnormalities in mitochondrial function with only SdhA knockdown resulting in broad mitochondrial dysfunction. Furthermore, these defects were shown to be mediated by the chronic activation of the cellular energy sensor AMP-activated protein kinase. Our results are in agreement with a role for loss of function of SdhA but not the other Complex II subunits in impairing mitochondrial oxidative phosphorylation and they suggest a role for AMP-activated protein kinase in mediating the cytopathological outcomes. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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19 pages, 5178 KiB  
Article
The Mitochondrial Epigenome: An Unexplored Avenue to Explain Unexplained Myopathies?
by Archibold Mposhi, Lin Liang, Kevin P. Mennega, Dilemin Yildiz, Crista Kampert, Ingrid H. Hof, Pytrick G. Jellema, Tom J. de Koning, Klaas Nico Faber, Marcel H. J. Ruiters, Klary E. Niezen-Koning and Marianne G. Rots
Int. J. Mol. Sci. 2022, 23(4), 2197; https://doi.org/10.3390/ijms23042197 - 16 Feb 2022
Cited by 7 | Viewed by 2478
Abstract
Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical [...] Read more.
Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies. The present study set out to assess whether mtDNA methylation could explain impaired mitochondrial function in patients diagnosed with myopathy without known underlying genetic mutations. Enhanced mtDNA methylation was indicated by pyrosequencing for muscle biopsies of 14 myopathy patients compared to four healthy controls, at selected cytosines in the Cytochrome B (CYTB) gene, but not within the displacement loop (D-loop) region. The mtDNA methylation patterns of the four healthy muscle biopsies were highly consistent and showed intriguing tissue-specific differences at particular cytosines with control skin fibroblasts cultured in vitro. Within individual myopathy patients, the overall mtDNA methylation pattern correlated well between muscle and skin fibroblasts. Despite this correlation, a pilot analysis of four myopathy and five healthy fibroblast samples did not reveal a disease-associated difference in mtDNA methylation. We did, however, detect increased expression of solute carrier family 25A26 (SLC25A26), encoding the importer of S-adenosylmethionine, together with enhanced mtDNA copy numbers in myopathy fibroblasts compared to healthy controls. To confirm that pyrosequencing indeed reflected DNA methylation and not bisulfite accessibility, mass spectrometry was employed. Although no myopathy-related differences in total amount of methylated cytosines were detected at this stage, a significant contribution of contaminating nuclear DNA (nDNA) was revealed, and steps to improve enrichment for mtDNA are reported. In conclusion, in this explorative study we show that analyzing the mitochondrial genome beyond its sequence opens novel avenues to identify potential molecular biomarkers assisting in the diagnosis of unexplained myopathies. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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24 pages, 6185 KiB  
Article
Combining Metabolomics and Experimental Evolution Reveals Key Mechanisms Underlying Longevity Differences in Laboratory Evolved Drosophila melanogaster Populations
by Mark A. Phillips, Kenneth R. Arnold, Zer Vue, Heather K. Beasley, Edgar Garza-Lopez, Andrea G. Marshall, Derrick J. Morton, Melanie R. McReynolds, Thomas T. Barter and Antentor Hinton, Jr.
Int. J. Mol. Sci. 2022, 23(3), 1067; https://doi.org/10.3390/ijms23031067 - 19 Jan 2022
Cited by 4 | Viewed by 3195
Abstract
Experimental evolution with Drosophila melanogaster has been used extensively for decades to study aging and longevity. In recent years, the addition of DNA and RNA sequencing to this framework has allowed researchers to leverage the statistical power inherent to experimental evolution to study [...] Read more.
Experimental evolution with Drosophila melanogaster has been used extensively for decades to study aging and longevity. In recent years, the addition of DNA and RNA sequencing to this framework has allowed researchers to leverage the statistical power inherent to experimental evolution to study the genetic basis of longevity itself. Here, we incorporated metabolomic data into to this framework to generate even deeper insights into the physiological and genetic mechanisms underlying longevity differences in three groups of experimentally evolved D. melanogaster populations with different aging and longevity patterns. Our metabolomic analysis found that aging alters mitochondrial metabolism through increased consumption of NAD+ and increased usage of the TCA cycle. Combining our genomic and metabolomic data produced a list of biologically relevant candidate genes. Among these candidates, we found significant enrichment for genes and pathways associated with neurological development and function, and carbohydrate metabolism. While we do not explicitly find enrichment for aging canonical genes, neurological dysregulation and carbohydrate metabolism are both known to be associated with accelerated aging and reduced longevity. Taken together, our results provide plausible genetic mechanisms for what might be driving longevity differences in this experimental system. More broadly, our findings demonstrate the value of combining multiple types of omic data with experimental evolution when attempting to dissect mechanisms underlying complex and highly polygenic traits such as aging. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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14 pages, 2357 KiB  
Article
Inducing Energetic Switching Using Klotho Improves Vascular Smooth Muscle Cell Phenotype
by Craig K. Docherty, Anastasiya Strembitska, Christa P. Baker, Fiona F. Schmidt, Kieran Reay and John R. Mercer
Int. J. Mol. Sci. 2022, 23(1), 217; https://doi.org/10.3390/ijms23010217 - 25 Dec 2021
Cited by 7 | Viewed by 3512
Abstract
The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant [...] Read more.
The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox’d Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Methods: Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Results: Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Conclusions: Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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18 pages, 5591 KiB  
Article
A New Strategy to Preserve and Assess Oxygen Consumption in Murine Tissues
by Jerome Kluza, Victoriane Peugnet, Blanche Daunou, William Laine, Gwenola Kervoaze, Gaëlle Rémy, Anne Loyens, Patrice Maboudou, Quentin Fovez, Corinne Grangette, Isabelle Wolowczuk, Philippe Gosset, Guillaume Garçon, Philippe Marchetti, Florence Pinet, Muriel Pichavant and Emilie Dubois-Deruy
Int. J. Mol. Sci. 2022, 23(1), 109; https://doi.org/10.3390/ijms23010109 - 22 Dec 2021
Cited by 5 | Viewed by 4329
Abstract
Mitochondrial dysfunctions are implicated in several pathologies, such as metabolic, cardiovascular, respiratory, and neurological diseases, as well as in cancer and aging. These metabolic alterations are usually assessed in human or murine samples by mitochondrial respiratory chain enzymatic assays, by measuring the oxygen [...] Read more.
Mitochondrial dysfunctions are implicated in several pathologies, such as metabolic, cardiovascular, respiratory, and neurological diseases, as well as in cancer and aging. These metabolic alterations are usually assessed in human or murine samples by mitochondrial respiratory chain enzymatic assays, by measuring the oxygen consumption of intact mitochondria isolated from tissues, or from cells obtained after physical or enzymatic disruption of the tissues. However, these methodologies do not maintain tissue multicellular organization and cell-cell interactions, known to influence mitochondrial metabolism. Here, we develop an optimal model to measure mitochondrial oxygen consumption in heart and lung tissue samples using the XF24 Extracellular Flux Analyzer (Seahorse) and discuss the advantages and limitations of this technological approach. Our results demonstrate that tissue organization, as well as mitochondrial ultrastructure and respiratory function, are preserved in heart and lung tissues freshly processed or after overnight conservation at 4 °C. Using this method, we confirmed the repeatedly reported obesity-associated mitochondrial dysfunction in the heart and extended it to the lungs. We set up and validated a new strategy to optimally assess mitochondrial function in murine tissues. As such, this method is of great potential interest for monitoring mitochondrial function in cohort samples. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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11 pages, 1832 KiB  
Article
Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome
by Sofia Barbosa-Gouveia, Maria E. Vázquez-Mosquera, Emiliano Gonzalez-Vioque, Álvaro Hermida-Ameijeiras, Laura L. Valverde, Judith Armstrong-Moron, Maria del Carmen Fons-Estupiña, Liesbeth T. Wintjes, Antonia Kappen, Richard J. Rodenburg and Maria L. Couce
Int. J. Mol. Sci. 2021, 22(24), 13484; https://doi.org/10.3390/ijms222413484 - 15 Dec 2021
Cited by 7 | Viewed by 2509
Abstract
Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex [...] Read more.
Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous AGK variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient’s DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the AGK cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient’s fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient’s fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel AGK variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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16 pages, 4058 KiB  
Article
Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
by Luca X. Zampieri, Martina Sboarina, Andrea Cacace, Debora Grasso, Léopold Thabault, Loïc Hamelin, Thibaut Vazeille, Elodie Dumon, Rodrigue Rossignol, Raphaël Frédérick, Etienne Sonveaux, Florence Lefranc and Pierre Sonveaux
Int. J. Mol. Sci. 2021, 22(21), 11938; https://doi.org/10.3390/ijms222111938 - 3 Nov 2021
Cited by 9 | Viewed by 3147
Abstract
Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, [...] Read more.
Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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22 pages, 19673 KiB  
Article
Bee Venom Melittin Disintegrates the Respiration of Mitochondria in Healthy Cells and Lymphoblasts, and Induces the Formation of Non-Bilayer Structures in Model Inner Mitochondrial Membranes
by Edward Gasanoff, Yipeng Liu, Feng Li, Paul Hanlon and Győző Garab
Int. J. Mol. Sci. 2021, 22(20), 11122; https://doi.org/10.3390/ijms222011122 - 15 Oct 2021
Cited by 9 | Viewed by 1711
Abstract
In this paper, we examined the effects of melittin, a bee venom membrane-active peptide, on mitochondrial respiration and cell viability of healthy human lymphocytes (HHL) and Jurkat cells, as well as on lymphoblasts from acute human T cell leukemia. The viability of melittin-treated [...] Read more.
In this paper, we examined the effects of melittin, a bee venom membrane-active peptide, on mitochondrial respiration and cell viability of healthy human lymphocytes (HHL) and Jurkat cells, as well as on lymphoblasts from acute human T cell leukemia. The viability of melittin-treated cells was related to changes in O2 consumption and in the respiratory control index (RCI) of mitochondria isolated from melittin-pretreated cells as well as of mitochondria first isolated from cells and then directly treated with melittin. It was shown that melittin is three times more cytotoxic to Jurkat cells than to HHL, but O2 consumption and RCI values of mitochondria from both cell types were equally affected by melittin when melittin was directly added to mitochondria. To elucidate the molecular mechanism of melittin’s cytotoxicity to healthy and cancer cells, the effects of melittin on lipid-packing and on the dynamics in model plasma membranes of healthy and cancer cells, as well as of the inner mitochondrial membrane, were studied by EPR spin probes. The affinity of melittin binding to phosphatidylcholine, phosphatidylserine, phosphatidic acid and cardiolipin, and binding sites of phospholipids on the surface of melittin were studied by 31P-NMR, native PAGE and AutoDock modeling. It is suggested that the melittin-induced decline of mitochondrial bioenergetics contributes primarily to cell death; the higher cytotoxicity of melittin to cancer cells is attributed to its increased permeability through the plasma membrane. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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20 pages, 1882 KiB  
Article
Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity
by Ajibola B. Bakare, Joseph Dean, Qun Chen, Vedant Thorat, Yimin Huang, Thomas LaFramboise, Edward J. Lesnefsky and Shilpa Iyer
Int. J. Mol. Sci. 2021, 22(19), 10344; https://doi.org/10.3390/ijms221910344 - 26 Sep 2021
Cited by 5 | Viewed by 2382
Abstract
Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood. To better understand this [...] Read more.
Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood. To better understand this relationship, we computed a glycolytic bioenergetics health index (BHI) for measuring mitochondrial dysfunction in LS patient fibroblast cells harboring varying percentages of pathogenic mutant mtDNA (T8993G, T9185C) exhibiting deficiency in complex V or complex I (T10158C, T12706C). A high percentage (>90%) of pathogenic mtDNA in cells affecting complex V and a low percentage (<39%) of pathogenic mtDNA in cells affecting complex I was quantified. Levels of defective enzyme activities of the electron transport chain correlated with the percentage of pathogenic mtDNA. Subsequent bioenergetics assays showed cell lines relied on both OXPHOS and glycolysis for meeting energy requirements. Results suggest that whereas the precise mechanism of LS has not been elucidated, a multi-pronged approach taking into consideration the specific pathogenic mtDNA variant, glycolytic BHI, and the composite BHI (average ratio of oxphos to glycolysis) can aid in better understanding the factors influencing disease severity in LS. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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15 pages, 2513 KiB  
Article
An Inducible and Vascular Smooth Muscle Cell-Specific Pink1 Knockout Induces Mitochondrial Energetic Dysfunction during Atherogenesis
by Craig K. Docherty, Jordan Bresciani, Andy Carswell, Amrita Chanderseka, Elaine Friel, Marianna Stasi and John R. Mercer
Int. J. Mol. Sci. 2021, 22(18), 9993; https://doi.org/10.3390/ijms22189993 - 16 Sep 2021
Cited by 5 | Viewed by 2914
Abstract
DNA damage and mitochondrial dysfunction are defining characteristics of aged vascular smooth muscle cells (VSMCs) found in atherosclerosis. Pink1 kinase regulates mitochondrial homeostasis and recycles dysfunctional organelles critical for maintaining energetic homeostasis. Here, we generated a new vascular-specific Pink1 knockout and assessed its [...] Read more.
DNA damage and mitochondrial dysfunction are defining characteristics of aged vascular smooth muscle cells (VSMCs) found in atherosclerosis. Pink1 kinase regulates mitochondrial homeostasis and recycles dysfunctional organelles critical for maintaining energetic homeostasis. Here, we generated a new vascular-specific Pink1 knockout and assessed its effect on VSMC-dependent atherogenesis in vivo and VSMC energetic metabolism in vitro. A smooth muscle cell-specific and MHC-Cre-inducible flox’d Pink1f/f kinase knockout was made on a ROSA26+/0 and ApoE−/− C57Blk6/J background. Mice were high fat fed for 10 weeks and vasculature assessed for physiological and pathogical changes. Mitochondrial respiratory activity was then assessed in wild-type and knockout animals vessels and isolated cells for their reliance on oxidative and glycolytic metabolism. During atherogenesis, we find that Pink1 knockout affects development of plaque quality rather than plaque quantity by decreasing VSMC and extracellular matrix components, collagen and elastin. Pink1 protein is important in the wild-type VSMC response to metabolic stress and induced a compensatory increase in hexokinase II, which catalyses the first irreversible step in glycolysis. Pink1 appears to play an important role in VSMC energetics during atherogenesis but may also provide insight into the understanding of mitochondrial energetics in other diseases where the regulation of energetic switching between oxidative and glycolytic metabolism is found to be important. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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18 pages, 2602 KiB  
Article
Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis
by Mikhail V. Dubinin, Vlada S. Starinets, Eugeny Yu. Talanov, Irina B. Mikheeva, Natalia V. Belosludtseva and Konstantin N. Belosludtsev
Int. J. Mol. Sci. 2021, 22(18), 9780; https://doi.org/10.3390/ijms22189780 - 10 Sep 2021
Cited by 23 | Viewed by 2955
Abstract
Mitigation of calcium-dependent destruction of skeletal muscle mitochondria is considered as a promising adjunctive therapy in Duchenne muscular dystrophy (DMD). In this work, we study the effect of intraperitoneal administration of a non-immunosuppressive inhibitor of calcium-dependent mitochondrial permeability transition (MPT) pore alisporivir on [...] Read more.
Mitigation of calcium-dependent destruction of skeletal muscle mitochondria is considered as a promising adjunctive therapy in Duchenne muscular dystrophy (DMD). In this work, we study the effect of intraperitoneal administration of a non-immunosuppressive inhibitor of calcium-dependent mitochondrial permeability transition (MPT) pore alisporivir on the state of skeletal muscles and the functioning of mitochondria in dystrophin-deficient mdx mice. We show that treatment with alisporivir reduces inflammation and improves muscle function in mdx mice. These effects of alisporivir were associated with an improvement in the ultrastructure of mitochondria, normalization of respiration and oxidative phosphorylation, and a decrease in lipid peroxidation, due to suppression of MPT pore opening and an improvement in calcium homeostasis. The action of alisporivir was associated with suppression of the activity of cyclophilin D and a decrease in its expression in skeletal muscles. This was observed in both mdx mice and wild-type animals. At the same time, alisporivir suppressed mitochondrial biogenesis, assessed by the expression of Ppargc1a, and altered the dynamics of organelles, inhibiting both DRP1-mediated fission and MFN2-associated fusion of mitochondria. The article discusses the effects of alisporivir administration and cyclophilin D inhibition on mitochondrial reprogramming and networking in DMD and the consequences of this therapy on skeletal muscle health. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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Review

Jump to: Editorial, Research

17 pages, 905 KiB  
Review
ATP Synthase and Mitochondrial Bioenergetics Dysfunction in Alzheimer’s Disease
by Somya Patro, Sujay Ratna, Hianny A. Yamamoto, Andrew T. Ebenezer, Dillon S. Ferguson, Amanpreet Kaur, Brendan C. McIntyre, Ryan Snow and Maria E. Solesio
Int. J. Mol. Sci. 2021, 22(20), 11185; https://doi.org/10.3390/ijms222011185 - 17 Oct 2021
Cited by 25 | Viewed by 4464
Abstract
Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in our society, as the population ages, its incidence is expected to increase in the coming decades. The etiopathology of this disease still remains largely unclear, probably because of the highly complex and multifactorial [...] Read more.
Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in our society, as the population ages, its incidence is expected to increase in the coming decades. The etiopathology of this disease still remains largely unclear, probably because of the highly complex and multifactorial nature of AD. However, the presence of mitochondrial dysfunction has been broadly described in AD neurons and other cellular populations within the brain, in a wide variety of models and organisms, including post-mortem humans. Mitochondria are complex organelles that play a crucial role in a wide range of cellular processes, including bioenergetics. In fact, in mammals, including humans, the main source of cellular ATP is the oxidative phosphorylation (OXPHOS), a process that occurs in the mitochondrial electron transfer chain (ETC). The last enzyme of the ETC, and therefore the ulterior generator of ATP, is the ATP synthase. Interestingly, in mammalian cells, the ATP synthase can also degrade ATP under certain conditions (ATPase), which further illustrates the crucial role of this enzyme in the regulation of cellular bioenergetics and metabolism. In this collaborative review, we aim to summarize the knowledge of the presence of dysregulated ATP synthase, and of other components of mammalian mitochondrial bioenergetics, as an early event in AD. This dysregulation can act as a trigger of the dysfunction of the organelle, which is a clear component in the etiopathology of AD. Consequently, the pharmacological modulation of the ATP synthase could be a potential strategy to prevent mitochondrial dysfunction in AD. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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42 pages, 1593 KiB  
Review
Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain
by Paola Zanfardino, Stefano Doccini, Filippo M. Santorelli and Vittoria Petruzzella
Int. J. Mol. Sci. 2021, 22(15), 8325; https://doi.org/10.3390/ijms22158325 - 3 Aug 2021
Cited by 5 | Viewed by 5645
Abstract
Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge [...] Read more.
Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as ‘mitoexome’, ‘mitoproteome’ and ‘mitointeractome’ have entered the field of ‘mitochondrial medicine’. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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23 pages, 2914 KiB  
Review
Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer
by Daniela Valenti, Rosa Anna Vacca, Loredana Moro and Anna Atlante
Int. J. Mol. Sci. 2021, 22(15), 8312; https://doi.org/10.3390/ijms22158312 - 2 Aug 2021
Cited by 59 | Viewed by 6037
Abstract
Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, [...] Read more.
Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis. Full article
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Different Pathophysiological Conditions 2.0)
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