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Mitochondria and Brain Disease
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Mitochondria and Brain Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 84866

Special Issue Editor

Dr. Susana Cardoso

E-Mail Website
Guest Editor
Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
Interests: diabetes; Alzheimer´s disease; mental disorders; mitochondria; oxidative stress; uncoupling proteins; brain metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain diseases, which can come in different forms such as traumatic brain injuries, strokes, seizures, mental illnesses, dementia, and neurodegenerative disorders, are a significant global health issue, with the World Health Organization (WHO) estimating that over a billion people worldwide are affected with one neurological or mental health debilitating condition. In past few decades, research in brain pathologies has made great progress in clarifying the pathophysiological mechanisms contributing to disease appearance and progress. Among those, impaired mitochondrial function has taken center stage as a causative factor in brain disease pathogenesis. Apart from being a primary metabolic platform for brain cells, mitochondria biological activities also include several other processes like calcium homeostasis, reactive oxygen species (ROS) neutralization, amino-acids metabolism, neurotransmission and plasticity and so on. As the world is moving into a new era of mitochondrial medicine, currently, one of the most important focuses is on providing feasible strategies to directly manage the major insidious disturbances of mitochondrial homeostasis as well as attempts to directly or indirectly manage its consequences in the context of a brain disease. This Special Issue intends to guide readers through the multifaceted investigation of mitochondrial function and mitochondrial-directed interventions in the broad and heterogeneous field of brain diseases. For that, this Special Issue invites authors to contribute to this area of research, either with original research or with comprehensive literature reviews.

Dr. Susana Cardoso
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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

  • brain injury
  • dementia
  • mental health
  • metabolism
  • mitochondria
  • mitochondrial medicine
  • neurodegenerative disorders
  • oxidative stress
  • stroke
  • translational medicine

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Published Papers (17 papers)

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Editorial

Jump to: Research, Review

2 pages, 185 KiB  
Editorial
Special Issue “Mitochondria and Brain Disease”
by Susana Cardoso
Biomedicines 2022, 10(8), 1854; https://doi.org/10.3390/biomedicines10081854 - 01 Aug 2022
Cited by 1 | Viewed by 1075
Abstract
We are pleased to present the first Special Issue (SI) of “Mitochondria and Brain Disease” [...] Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)

Research

Jump to: Editorial, Review

33 pages, 6116 KiB  
Article
Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model
by Irina Kurokin, Anna Andrea Lauer, Daniel Janitschke, Jakob Winkler, Elena Leoni Theiss, Lea Victoria Griebsch, Sabrina Melanie Pilz, Veronika Matschke, Martin van der Laan, Heike Sabine Grimm, Tobias Hartmann and Marcus Otto Walter Grimm
Biomedicines 2021, 9(8), 1062; https://doi.org/10.3390/biomedicines9081062 - 21 Aug 2021
Cited by 11 | Viewed by 3924
Abstract
Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and [...] Read more.
Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and lipid-homeostasis exists, little is known about potential alterations in the lipid composition of mitochondria. Here, we investigate potential changes in the main mitochondrial phospholipid classes phosphatidylcholine, phosphatidylethanolamine and the corresponding plasmalogens and lyso-phospholipids of a cellular AD-model (SH-SY5Y APPswedish transfected cells), comparing these results with changes in cell-homogenates. Targeted shotgun-lipidomics revealed lipid alterations to be specific for mitochondria and cannot be predicted from total cell analysis. In particular, lipids containing three and four times unsaturated fatty acids (FA X:4), such as arachidonic-acid, are increased, whereas FA X:6 or X:5, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), are decreased. Additionally, PE plasmalogens are increased in contrast to homogenates. Results were confirmed in another cellular AD model, having a lower affinity to amyloidogenic APP processing. Besides several similarities, differences in particular in PE species exist, demonstrating that differences in APP processing might lead to specific changes in lipid homeostasis in mitochondria. Importantly, the observed lipid alterations are accompanied by changes in the carnitine carrier system, also suggesting an altered mitochondrial functionality. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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14 pages, 1889 KiB  
Article
Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients
by Ana P. Marques, Rosa Resende, Diana F. Silva, Mariana Batista, Daniela Pereira, Brigite Wildenberg, Sofia Morais, António Macedo, Cláudia Pais, Joana B. Melo, Nuno Madeira and Cláudia F. Pereira
Biomedicines 2021, 9(5), 522; https://doi.org/10.3390/biomedicines9050522 - 07 May 2021
Cited by 6 | Viewed by 3258
Abstract
This study aims to evaluate whether mitochondrial changes occur in the early stages of bipolar disorder (BD). Using fibroblasts derived from BD patients and matched controls, the levels of proteins involved in mitochondrial biogenesis and dynamics (fission and fusion) were evaluated by Western [...] Read more.
This study aims to evaluate whether mitochondrial changes occur in the early stages of bipolar disorder (BD). Using fibroblasts derived from BD patients and matched controls, the levels of proteins involved in mitochondrial biogenesis and dynamics (fission and fusion) were evaluated by Western Blot analysis. Mitochondrial membrane potential (MMP) was studied using the fluorescent probe TMRE. Mitochondrial morphology was analyzed with the probe Mitotracker Green and mitophagy was evaluated by quantifying the co-localization of HSP60 (mitochondria marker) and LC3B (autophagosome marker) by immunofluorescence. Furthermore, the activity of the mitochondrial respiratory chain and the glycolytic capacity of controls and BD patients-derived cells were also studied using the Seahorse technology. BD patient-derived fibroblasts exhibit fragmented mitochondria concomitantly with changes in mitochondrial dynamics and biogenesis in comparison with controls. Moreover, a decrease in the MMP and increased mitophagy was observed in fibroblasts obtained from BD patients when compared with control cells. Impaired energetic metabolism due to inhibition of the mitochondrial electron transport chain (ETC) and subsequent ATP depletion, associated with glycolysis stimulation, was also a feature of BD fibroblasts. Overall, these results support the fact that mitochondrial disturbance is an early event implicated in BD pathophysiology that might trigger neuronal changes and modification of brain circuitry. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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20 pages, 5515 KiB  
Article
Asiatic Acid Prevents Cognitive Deficits by Inhibiting Calpain Activation and Preserving Synaptic and Mitochondrial Function in Rats with Kainic Acid-Induced Seizure
by Cheng-Wei Lu, Tzu-Yu Lin, Tai-Long Pan, Pei-Wen Wang, Kuan-Ming Chiu, Ming-Yi Lee and Su-Jane Wang
Biomedicines 2021, 9(3), 284; https://doi.org/10.3390/biomedicines9030284 - 10 Mar 2021
Cited by 19 | Viewed by 3063
Abstract
Cognitive impairment is not only associated with seizures but also reported as an adverse effect of antiepileptic drugs. Thus, new molecules that can ameliorate seizures and maintain satisfactory cognitive function should be developed. The antiepileptic potential of asiatic acid, a triterpene derived from [...] Read more.
Cognitive impairment is not only associated with seizures but also reported as an adverse effect of antiepileptic drugs. Thus, new molecules that can ameliorate seizures and maintain satisfactory cognitive function should be developed. The antiepileptic potential of asiatic acid, a triterpene derived from the medicinal herb Centella asiatica, has already been demonstrated; however, its role in epilepsy-related cognitive deficits is yet to be determined. In this study, we evaluated the effects of asiatic acid on cognitive deficits in rats with kainic acid (KA)-induced seizure and explored the potential mechanisms underlying these effects. Our results revealed that asiatic acid administrated intraperitoneally 30 min prior to KA (15 mg/kg) injection ameliorated seizures and significantly improved KA-induced memory deficits, as demonstrated by the results of the Morris water maze test. In addition, asiatic acid ameliorated neuronal damage, inhibited calpain activation, and increased protein kinase B (AKT) activation in the hippocampus of KA-treated rats. Asiatic acid also increased the levels of synaptic proteins and the number of synaptic vesicles as well as attenuated mitochondrial morphology damage in the hippocampus of KA-treated rats. Furthermore, proteomic and Western blot analyses of hippocampal synaptosomes revealed that asiatic acid reversed KA-induced changes in mitochondria function-associated proteins, including lipoamide dehydrogenase, glutamate dehydrogenase 1 (GLUD1), ATP synthase (ATP5A), and mitochondrial deacetylase sirtuin-3 (SIRT3). Our data suggest that asiatic acid can prevent seizures and improve cognitive impairment in KA-treated rats by reducing hippocampal neuronal damage through the inhibition of calpain activation and the elevation of activated AKT, coupled with an increase in synaptic and mitochondrial function. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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20 pages, 3099 KiB  
Article
IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis
by Susana Cardoso, Icíar P. López, Sergio Piñeiro-Hermida, José G. Pichel and Paula I. Moreira
Biomedicines 2021, 9(2), 158; https://doi.org/10.3390/biomedicines9020158 - 06 Feb 2021
Cited by 19 | Viewed by 3124
Abstract
Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on [...] Read more.
Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old UBC-CreERT2; Igf1rfl/fl male mice in which Igf1r was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR/PI3K/Akt and inhibition of the MAPK/ERK1/2/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3β and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H2O2 levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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16 pages, 3433 KiB  
Article
Fatty Acid Binding Protein 5 Mediates Cell Death by Psychosine Exposure through Mitochondrial Macropores Formation in Oligodendrocytes
by An Cheng, Ichiro Kawahata and Kohji Fukunaga
Biomedicines 2020, 8(12), 635; https://doi.org/10.3390/biomedicines8120635 - 20 Dec 2020
Cited by 17 | Viewed by 3581
Abstract
Oligodendrocytes, the myelinating cells in the central nervous system (CNS), are critical for producing myelin throughout the CNS. The loss of oligodendrocytes is associated with multiple neurodegenerative disorders mediated by psychosine. However, the involvement of psychosine in the critical biochemical pathogenetic mechanism of [...] Read more.
Oligodendrocytes, the myelinating cells in the central nervous system (CNS), are critical for producing myelin throughout the CNS. The loss of oligodendrocytes is associated with multiple neurodegenerative disorders mediated by psychosine. However, the involvement of psychosine in the critical biochemical pathogenetic mechanism of the loss of oligodendrocytes and myelin in krabbe disease (KD) remains unclear. Here, we addressed how oligodendrocytes are induced by psychosine treatment in both KG-1C human oligodendroglial cells and mouse oligodendrocyte precursor cells. We found that fatty acid binding protein 5 (FABP5) expressed in oligodendrocytes accelerates mitochondria-induced glial death by inducing mitochondrial macropore formation through voltage-dependent anion channels (VDAC-1) and BAX. These two proteins mediate mitochondrial outer membrane permeabilization, thereby leading to the release of mitochondrial DNA and cytochrome C into the cytosol, and the activation of apoptotic caspases. Furthermore, we confirmed that the inhibition of FABP5 functions by shRNA and FABP5-specific ligands blocking mitochondrial macropore formation, thereby rescuing psychosine-induced oligodendrocyte death. Taken together, we identified FABP5 as a critical factor in mitochondrial injury associated with psychosine-induced apoptosis in oligodendrocytes. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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Review

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24 pages, 1772 KiB  
Review
Early Life Stress and Metabolic Plasticity of Brain Cells: Impact on Neurogenesis and Angiogenesis
by Alla B. Salmina, Yana V. Gorina, Yulia K. Komleva, Yulia A. Panina, Natalia A. Malinovskaya and Olga L. Lopatina
Biomedicines 2021, 9(9), 1092; https://doi.org/10.3390/biomedicines9091092 - 26 Aug 2021
Cited by 14 | Viewed by 3946
Abstract
Early life stress (ELS) causes long-lasting changes in brain plasticity induced by the exposure to stress factors acting prenatally or in the early postnatal ontogenesis due to hyperactivation of hypothalamic-pituitary-adrenal axis and sympathetic nervous system, development of neuroinflammation, aberrant neurogenesis and angiogenesis, and [...] Read more.
Early life stress (ELS) causes long-lasting changes in brain plasticity induced by the exposure to stress factors acting prenatally or in the early postnatal ontogenesis due to hyperactivation of hypothalamic-pituitary-adrenal axis and sympathetic nervous system, development of neuroinflammation, aberrant neurogenesis and angiogenesis, and significant alterations in brain metabolism that lead to neurological deficits and higher susceptibility to development of brain disorders later in the life. As a key component of complex pathogenesis, ELS-mediated changes in brain metabolism associate with development of mitochondrial dysfunction, loss of appropriate mitochondria quality control and mitochondrial dynamics, deregulation of metabolic reprogramming. These mechanisms are particularly critical for maintaining the pool and development of brain cells within neurogenic and angiogenic niches. In this review, we focus on brain mitochondria and energy metabolism related to tightly coupled neurogenic and angiogenic events in healthy and ELS-affected brain, and new opportunities to develop efficient therapeutic strategies aimed to restore brain metabolism and reduce ELS-induced impairments of brain plasticity. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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17 pages, 1102 KiB  
Review
Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration
by Dario Brunetti, Alessia Catania, Carlo Viscomi, Michela Deleidi, Laurence A. Bindoff, Daniele Ghezzi and Massimo Zeviani
Biomedicines 2021, 9(7), 833; https://doi.org/10.3390/biomedicines9070833 - 17 Jul 2021
Cited by 21 | Viewed by 4778
Abstract
Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control [...] Read more.
Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of PITRM1 deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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Graphical abstract

38 pages, 1358 KiB  
Review
Neuroinflammation in Alzheimer’s Disease
by Isaac G. Onyango, Gretsen V. Jauregui, Mária Čarná, James P. Bennett, Jr. and Gorazd B. Stokin
Biomedicines 2021, 9(5), 524; https://doi.org/10.3390/biomedicines9050524 - 07 May 2021
Cited by 121 | Viewed by 14762
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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14 pages, 1735 KiB  
Review
Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies
by Chantal B. Lucini and Ralf J. Braun
Biomedicines 2021, 9(4), 376; https://doi.org/10.3390/biomedicines9040376 - 02 Apr 2021
Cited by 15 | Viewed by 3401
Abstract
In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive [...] Read more.
In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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35 pages, 2183 KiB  
Review
Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases
by Nuno Santos Leal and Luís Miguel Martins
Biomedicines 2021, 9(2), 227; https://doi.org/10.3390/biomedicines9020227 - 23 Feb 2021
Cited by 25 | Viewed by 4765
Abstract
The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical [...] Read more.
The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria–ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer’s disease as well as Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer’s disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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20 pages, 1480 KiB  
Review
Energy, Entropy and Quantum Tunneling of Protons and Electrons in Brain Mitochondria: Relation to Mitochondrial Impairment in Aging-Related Human Brain Diseases and Therapeutic Measures
by James P. Bennett, Jr. and Isaac G. Onyango
Biomedicines 2021, 9(2), 225; https://doi.org/10.3390/biomedicines9020225 - 22 Feb 2021
Cited by 10 | Viewed by 4023
Abstract
Adult human brains consume a disproportionate amount of energy substrates (2–3% of body weight; 20–25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered [...] Read more.
Adult human brains consume a disproportionate amount of energy substrates (2–3% of body weight; 20–25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered by the proton gradient generated from proton-coupled electron transfer (PCET) in the multi-complex electron transport chain (ETC). ETC catalysis rates are reduced in brains from humans with neurodegenerative diseases (NDDs). Declines of ETC function in NDDs may result from combinations of nitrative stress (NS)–oxidative stress (OS) damage; mitochondrial and/or nuclear genomic mutations of ETC/OXPHOS genes; epigenetic modifications of ETC/OXPHOS genes; or defects in importation or assembly of ETC/OXPHOS proteins or complexes, respectively; or alterations in mitochondrial dynamics (fusion, fission, mitophagy). Substantial free energy is gained by direct O2-mediated oxidation of NADH. Traditional ETC mechanisms require separation between O2 and electrons flowing from NADH/FADH2 through the ETC. Quantum tunneling of electrons and much larger protons may facilitate this separation. Neuronal death may be viewed as a local increase in entropy requiring constant energy input to avoid. The ATP requirement of the brain may partially be used for avoidance of local entropy increase. Mitochondrial therapeutics seeks to correct deficiencies in ETC and OXPHOS. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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28 pages, 1799 KiB  
Review
Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion
by Marianna Carinci, Bianca Vezzani, Simone Patergnani, Peter Ludewig, Katrin Lessmann, Tim Magnus, Ilaria Casetta, Maura Pugliatti, Paolo Pinton and Carlotta Giorgi
Biomedicines 2021, 9(2), 169; https://doi.org/10.3390/biomedicines9020169 - 09 Feb 2021
Cited by 40 | Viewed by 6138
Abstract
Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen [...] Read more.
Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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13 pages, 849 KiB  
Review
Mental Health, Mitochondria, and the Battle of the Sexes
by Paola Bressan and Peter Kramer
Biomedicines 2021, 9(2), 116; https://doi.org/10.3390/biomedicines9020116 - 26 Jan 2021
Cited by 5 | Viewed by 4107
Abstract
This paper presents a broad perspective on how mental disease relates to the different evolutionary strategies of men and women and to growth, metabolism, and mitochondria—the enslaved bacteria in our cells that enable it all. Several mental disorders strike one sex more than [...] Read more.
This paper presents a broad perspective on how mental disease relates to the different evolutionary strategies of men and women and to growth, metabolism, and mitochondria—the enslaved bacteria in our cells that enable it all. Several mental disorders strike one sex more than the other; yet what truly matters, regardless of one’s sex, is how much one’s brain is “female” and how much it is “male”. This appears to be the result of an arms race between the parents over how many resources their child ought to extract from the mother, hence whether it should grow a lot or stay small and undemanding. An uneven battle alters the child’s risk of developing not only insulin resistance, diabetes, or cancer, but a mental disease as well. Maternal supremacy increases the odds of a psychosis-spectrum disorder; paternal supremacy, those of an autism-spectrum one. And a particularly lopsided struggle may invite one or the other of a series of syndromes that come in pairs, with diametrically opposite, excessively “male” or “female” characteristics. By providing the means for this tug of war, mitochondria take center stage in steadying or upsetting the precarious balance on which our mental health is built. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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26 pages, 2349 KiB  
Review
Mitochondrial Dysfunction in Alzheimer’s Disease: A Biomarker of the Future?
by Simon M. Bell, Katy Barnes, Matteo De Marco, Pamela J. Shaw, Laura Ferraiuolo, Daniel J. Blackburn, Annalena Venneri and Heather Mortiboys
Biomedicines 2021, 9(1), 63; https://doi.org/10.3390/biomedicines9010063 - 11 Jan 2021
Cited by 65 | Viewed by 9718
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterised pathologically by the accumulation of amyloid beta and tau protein aggregates. Currently, there are no approved disease modifying therapies for clearance of either of these proteins from the brain [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterised pathologically by the accumulation of amyloid beta and tau protein aggregates. Currently, there are no approved disease modifying therapies for clearance of either of these proteins from the brain of people with AD. As well as abnormalities in protein aggregation, other pathological changes are seen in this condition. The function of mitochondria in both the nervous system and rest of the body is altered early in this disease, and both amyloid and tau have detrimental effects on mitochondrial function. In this review article, we describe how the function and structure of mitochondria change in AD. This review summarises current imaging techniques that use surrogate markers of mitochondrial function in both research and clinical practice, but also how mitochondrial functions such as ATP production, calcium homeostasis, mitophagy and reactive oxygen species production are affected in AD mitochondria. The evidence reviewed suggests that the measurement of mitochondrial function may be developed into a future biomarker for early AD. Further work with larger cohorts of patients is needed before mitochondrial functional biomarkers are ready for clinical use. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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22 pages, 635 KiB  
Review
Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA
by Olga Buneeva, Valerii Fedchenko, Arthur Kopylov and Alexei Medvedev
Biomedicines 2020, 8(12), 591; https://doi.org/10.3390/biomedicines8120591 - 10 Dec 2020
Cited by 30 | Viewed by 6249
Abstract
Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source [...] Read more.
Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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Review
Environmental and Nutritional “Stressors” and Oligodendrocyte Dysfunction: Role of Mitochondrial and Endoplasmatic Reticulum Impairment
by Jessica Maiuolo, Micaela Gliozzi, Vincenzo Musolino, Cristina Carresi, Saverio Nucera, Miriam Scicchitano, Federica Scarano, Francesca Bosco, Francesca Oppedisano, Roberta Macrì and Vincenzo Mollace
Biomedicines 2020, 8(12), 553; https://doi.org/10.3390/biomedicines8120553 - 30 Nov 2020
Cited by 11 | Viewed by 2659
Abstract
Oligodendrocytes are myelinating cells of the central nervous system which are generated by progenitor oligodendrocytes as a result of maturation processes. The main function of mature oligodendrocytes is to produce myelin, a lipid-rich multi-lamellar membrane that wraps tightly around neuronal axons, insulating them [...] Read more.
Oligodendrocytes are myelinating cells of the central nervous system which are generated by progenitor oligodendrocytes as a result of maturation processes. The main function of mature oligodendrocytes is to produce myelin, a lipid-rich multi-lamellar membrane that wraps tightly around neuronal axons, insulating them and facilitating nerve conduction through saltatory propagation. The myelination process requires the consumption a large amount of energy and a high metabolic turnover. Mitochondria are essential organelles which regulate many cellular functions, including energy production through oxidative phosphorylation. Any mitochondrial dysfunction impacts cellular metabolism and negatively affects the health of the organism. If the functioning of the mitochondria is unbalanced, the myelination process is impaired. When myelination has finished, oligodendrocyte will have synthesized about 40% of the total lipids present in the brain. Since lipid synthesis occurs in the cellular endoplasmic reticulum, the dysfunction of this organelle can lead to partial or deficient myelination, triggering numerous neurodegenerative diseases. In this review, the induced malfunction of oligodendrocytes by harmful exogenous stimuli has been outlined. In particular, the effects of alcohol consumption and heavy metal intake are discussed. Furthermore, the response of the oligodendrocyte to excessive mitochondrial oxidative stress and to the altered regulation of the functioning of the endoplasmic reticulum will be explored. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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