scholarly journals Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 833
Author(s):  
Dario Brunetti ◽  
Alessia Catania ◽  
Carlo Viscomi ◽  
Michela Deleidi ◽  
Laurence A. Bindoff ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Fraction ◽  
Current Evidence ◽  
Mitochondrial Targeting ◽  
Therapeutic Approaches ◽  
Atp Production ◽  
Precursor Proteins ◽  
Toxic Peptides ◽  
Mitochondrial Targeting Sequences

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.

scholarly journals The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease

2019 ◽  
Vol 25 (40) ◽  
pp. 5578-5587 ◽  
Author(s):  
Claus Desler ◽  
Meryl S. Lillenes ◽  
Tone Tønjum ◽  
Lene Juel Rasmussen
Keyword(s):  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
De Novo ◽  
Oxygen Species ◽  
De Novo Synthesis ◽  
Atp Production ◽  
Essential Phospholipids

The current molecular understanding of Alzheimer’s disease (AD) has still not resulted in successful interventions. Mitochondrial dysfunction of the AD brain is currently emerging as a hallmark of this disease. One mitochondrial function often affected in AD is oxidative phosphorylation responsible for ATP production, but also for production of reactive oxygen species (ROS) and for the de novo synthesis of pyrimidines. This paper reviews the role of mitochondrial produced ROS and pyrimidines in the aetiology of AD and their proposed role in oxidative degeneration of macromolecules, synthesis of essential phospholipids and maintenance of mitochondrial viability in the AD brain.

scholarly journals The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors

2021 ◽  
Vol 12 ◽  
Author(s):  
Suzanne Gonzalez
Keyword(s):  
Bipolar Disorder ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Brain Function ◽  
Electron Flow ◽  
Mitochondrial Genes ◽  
Environmental Stressors ◽  
Atp Production ◽  
Co Morbidity

It has been postulated that mitochondrial dysfunction has a significant role in the underlying pathophysiology of bipolar disorder (BD). Mitochondrial functioning plays an important role in regulating synaptic transmission, brain function, and cognition. Neuronal activity is energy dependent and neurons are particularly sensitive to changes in bioenergetic fluctuations, suggesting that mitochondria regulate fundamental aspects of brain function. Vigorous evidence supports the role of mitochondrial dysfunction in the etiology of BD, including dysregulated oxidative phosphorylation, general decrease of energy, altered brain bioenergetics, co-morbidity with mitochondrial disorders, and association with genetic variants in mitochondrial DNA (mtDNA) or nuclear-encoded mitochondrial genes. Despite these advances, the underlying etiology of mitochondrial dysfunction in BD is unclear. A plausible evolutionary explanation is that mitochondrial-nuclear (mitonuclear) incompatibility leads to a desynchronization of machinery required for efficient electron transport and cellular energy production. Approximately 1,200 genes, encoded from both nuclear and mitochondrial genomes, are essential for mitochondrial function. Studies suggest that mitochondrial and nuclear genomes co-evolve, and the coordinated expression of these interacting gene products are essential for optimal organism function. Incompatibilities between mtDNA and nuclear-encoded mitochondrial genes results in inefficiency in electron flow down the respiratory chain, differential oxidative phosphorylation efficiency, increased release of free radicals, altered intracellular Ca2+ signaling, and reduction of catalytic sites and ATP production. This review explores the role of mitonuclear incompatibility in BD susceptibility and resilience against environmental stressors.

scholarly journals Role of laser application in endodontic treatment: a review of literature

2021 ◽  
Author(s):  
Abdulkader Abdulelah Abulhamayel ◽  
Khalid Abdulbaqi Alsulami ◽  
Ali Nasser Alshehri ◽  
Abdullah Hussain Alasmari ◽  
Faisal Ramadan Alzahrani ◽  
...  
Keyword(s):  
Surgical Procedures ◽  
The Other ◽  
Current Evidence ◽  
Selective Absorption ◽  
Laser Application ◽  
Review Of Literature ◽  
Therapeutic Approaches ◽  
Pulp Capping ◽  
Surgical Wounds

Many applications have been previously reported that laser is used in the field of endodontics. It is used in pulp diagnosis, shaping and disinfection of the root canal, endodontic surgeries, modifying the dentin structures, pulpotomy and pulp capping. Our present study aims to review some applications of laser used in the field of endodontics. According to the evidence from current studies in the literature, vital pulp therapeutic approaches for pulpotomy can significantly lead to efficacious and bloodless outcomes by using laser for the following processes: Coagulation, vaporization, and sealing of the blood vessels with potentially sterile minute wounds with no complications. Many advantages have been previously reported for using laser within endodontic surgical procedures, such as coagulation, sterilization, selective absorption, precision, lower rates of complications as inflammation and edema, getting clean, well-sealed surgical wounds, enhanced disinfection characteristics, reduced painful sensations, decreased required sutures due to better hemostasis, and reduced bleeding. On the other hand, applying some laser modalities might not be adequately efficacious according to previous studies in the literature. We recommend that further human prospective to conduct investigations for further validation of the current evidence.

Mitochondrial and nonmitochondrial citrate synthases in Saccharomyces cerevisiae are encoded by distinct homologous genes

1986 ◽  
Vol 6 (12) ◽  
pp. 4509-4515
Author(s):  
M Rosenkrantz ◽  
T Alam ◽  
K S Kim ◽  
B J Clark ◽  
P A Srere ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Citrate Synthase ◽  
Amino Terminus ◽  
Translation Product ◽  
Mitochondrial Targeting ◽  
E Coli ◽  
Homologous Genes ◽  
Primary Translation Product ◽  
Mitochondrial Targeting Sequences

Saccharomyces cerevisiae contains two genes, CIT1 and CIT2, encoding functional citrate synthase (K.-S. Kim, M. S. Rosenkrantz, and L. Guarente, Mol. Cell. Biol. 6:1936-1942, 1986). We show here that CIT2 encodes a nonmitochondrial form of citrate synthase. The DNA sequence of CIT2 presented provides a possible explanation for why the CIT2 product, unlike the CIT1 product, fails to be imported into mitochondria. While the products of these two genes are highly homologous, they diverge strikingly at their amino termini. The amino terminus of the CIT1 primary translation product extends 39 residues beyond the amino termini of Escherichia coli and porcine citrate synthases. This extension consists of a typical mitochondrial targeting motif. The amino terminus of the CIT2 primary translation product extends 20 residues beyond the amino termini of the E. coli and porcine enzymes. The CIT2-encoded extension is not homologous to that of CIT1, resulting in a nonmitochondrial localization of the product. The CIT2-encoded extension, however, does bear certain similarities to mitochondrial targeting sequences. The possible role of this sequence in targeting this CIT2 product to a nonmitochondrial organelle is discussed.

scholarly journals Mitochondrial and nonmitochondrial citrate synthases in Saccharomyces cerevisiae are encoded by distinct homologous genes.

1986 ◽  
Vol 6 (12) ◽  
pp. 4509-4515 ◽  
Author(s):  
M Rosenkrantz ◽  
T Alam ◽  
K S Kim ◽  
B J Clark ◽  
P A Srere ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Citrate Synthase ◽  
Amino Terminus ◽  
Translation Product ◽  
Mitochondrial Targeting ◽  
E Coli ◽  
Homologous Genes ◽  
Primary Translation Product ◽  
Mitochondrial Targeting Sequences

Saccharomyces cerevisiae contains two genes, CIT1 and CIT2, encoding functional citrate synthase (K.-S. Kim, M. S. Rosenkrantz, and L. Guarente, Mol. Cell. Biol. 6:1936-1942, 1986). We show here that CIT2 encodes a nonmitochondrial form of citrate synthase. The DNA sequence of CIT2 presented provides a possible explanation for why the CIT2 product, unlike the CIT1 product, fails to be imported into mitochondria. While the products of these two genes are highly homologous, they diverge strikingly at their amino termini. The amino terminus of the CIT1 primary translation product extends 39 residues beyond the amino termini of Escherichia coli and porcine citrate synthases. This extension consists of a typical mitochondrial targeting motif. The amino terminus of the CIT2 primary translation product extends 20 residues beyond the amino termini of the E. coli and porcine enzymes. The CIT2-encoded extension is not homologous to that of CIT1, resulting in a nonmitochondrial localization of the product. The CIT2-encoded extension, however, does bear certain similarities to mitochondrial targeting sequences. The possible role of this sequence in targeting this CIT2 product to a nonmitochondrial organelle is discussed.

Role of Mitochondrial Dysfunction in the Ca2+-Induced Decline of Transmitter Release at K+-Depolarized Motor Neuron Terminals

1999 ◽  
Vol 81 (2) ◽  
pp. 498-506 ◽  
Author(s):  
Michelle A. Calupca ◽  
Gregory M. Hendricks ◽  
Jean C. Hardwick ◽  
Rodney L. Parsons
Keyword(s):  
Motor Neuron ◽  
Mitochondrial Dysfunction ◽  
Transmitter Release ◽  
Synaptic Vesicles ◽  
Prolonged Exposure ◽  
Nerve Terminals ◽  
Atp Production ◽  
Neuron Terminals ◽  
Nerve Muscle

Role of mitochondrial dysfunction in the Ca2+-induced decline of transmitter release at K+-depolarized motor neuron terminals. The present study tested whether a Ca2+-induced disruption of mitochondrial function was responsible for the decline in miniature endplate current (MEPC) frequency that occurs with nerve-muscle preparations maintained in a 35 mM potassium propionate (35 mM KP) solution containing elevated calcium. When the 35 mM KP contained control Ca2+(1 mM), the MEPC frequency increased and remained elevated for many hours, and the mitochondria within twitch motor neuron terminals were similar in appearance to those in unstimulated terminals. All nerve terminals accumulated FM1–43 when the dye was present for the final 6 min of a 300-min exposure to 35 mM KP with control Ca2+. In contrast, when Ca2+ was increased to 3.6 mM in the 35 mM KP solution, the MEPC frequency initially reached frequencies >350 s− 1 but then gradually fell approaching frequencies <50 s−1. A progressive swelling and eventual distortion of mitochondria within the twitch motor neuron terminals occurred during prolonged exposure to 35 mM KP with elevated Ca2+. After ∼300 min in 35 mM KP with elevated Ca2+, only 58% of the twitch terminals accumulated FM1–43. The decline in MEPC frequency in 35 mM KP with elevated Ca2+ was less when 15 mM glucose was present or when preparations were pretreated with 10 μM oligomycin and then bathed in the 35 mM KP with glucose. When glucose was present, with or without oligomycin pretreatment, a greater percentage of twitch terminals accumulated FM1–43. However, the mitochondria in these preparations were still greatly swollen and distorted. We propose that prolonged depolarization of twitch motor neuron terminals by 35 mM KP with elevated Ca2+ produced a Ca2+-induced decrease in mitochondrial ATP production. Under these conditions, the cytosolic ATP/ADP ratio was decreased thereby compromising both transmitter release and refilling of recycled synaptic vesicles. The addition of glucose stimulated glycolysis which contributed to the maintenance of required ATP levels.

scholarly journals The Role of Extracellular Vesicles in the Hallmarks of Cancer and Drug Resistance

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1141 ◽  
Author(s):  
Cristina P. R. Xavier ◽  
Hugo R. Caires ◽  
Mélanie A. G. Barbosa ◽  
Rui Bergantim ◽  
José E. Guimarães ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Extracellular Vesicles ◽  
Genetic Material ◽  
Human Tumor ◽  
Current Evidence ◽  
Drug Resistant ◽  
Intercellular Signaling ◽  
Therapeutic Approaches ◽  
Intercellular Exchange

Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi of cancer implies the highjack of the EV signaling network to support tumor progression in many (if not all) human tumor malignancies. We have reviewed the current evidence for the role of EVs in affecting cancer hallmark traits by: (i) promoting cell proliferation and escape from apoptosis, (ii) sustaining angiogenesis, (iii) contributing to cancer cell invasion and metastasis, (iv) reprogramming energy metabolism, (v) transferring mutations, and (vi) modulating the tumor microenvironment (TME) by evading immune response and promoting inflammation. Special emphasis was given to the role of EVs in the transfer of drug resistant traits and to the EV cargo responsible for this transfer, both between cancer cells or between the microenvironment and tumor cells. Finally, we reviewed evidence for the increased release of EVs by drug resistant cells. A timely and comprehensive understanding of how tumor EVs facilitate tumor initiation, progression, metastasis and drug resistance is instrumental for the development of innovative EV-based therapeutic approaches for cancer.

scholarly journals Mechanism of insulin resistance in obesity: a role of ATP

2021 ◽  
Author(s):  
Jianping Ye
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Dysfunction ◽  
Energy Demand ◽  
Feedback Regulation ◽  
Substrate Uptake ◽  
Atp Production ◽  
Systemic Insulin Resistance ◽  
Primary Signal

AbstractObesity increases the risk of type 2 diabetes through the induction of insulin resistance. The mechanism of insulin resistance has been extensively investigated for more than 60 years, but the essential pathogenic signal remains missing. Existing hypotheses include inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperglucagonemia, glucotoxicity, and lipotoxicity. Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines. In this review, multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance. The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand, which we have named “mitochondrial overheating.” Overheating occurs because of substrate oversupply to mitochondria, leading to extra ATP production. The ATP overproduction contributes to the systemic insulin resistance through several mechanisms, such as inhibition of AMPK, induction of mTOR, hyperinsulinemia, hyperglucagonemia, and mitochondrial dysfunction. Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates. Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading. The downregulation of the mitochondrial overloading by medicines, bypass surgeries, calorie restriction, and physical exercise leads to insulin sensitization in patients. Therefore, ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply. The prevention of ATP overproduction represents a key strategy for insulin sensitization.

SECONDARY MITOCHONDRIAL DYSFUNCTION

2021 ◽  
pp. 14-19
Author(s):  
KANIKA KHAJURIA ◽  
VIJAY KHAJURIA ◽  
VINEETA SAWHNEY
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Deoxyribonucleic Acid ◽  
Muscular Atrophy ◽  
Oxygen Species ◽  
Mt Dna ◽  
Atp Production ◽  
Vital Functions ◽  
Nuclear Deoxyribonucleic Acid

Mitochondria are the most vital organelle in the cell because of its multitask properties. They are well known for the production of energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), which involves multiple complexes and cofactors. Mitochondria in addition to ATP production, also perform other vital functions like generation of reactive oxygen species (ROS), antioxidants, apoptosis, signaling and hormone actions. Because of their multiple actions, it is quite expected that their dysfunction will result in the number of effects. Since most vital organs exclusively depend on ATP to perform their functions, therefore impediment in its supply resulting from mitochondrial dysfunction will be detrimental and have a widespread spectrum. Neurodegenerative disorders, Huntington’s disease, cardiovascular disease (CVD), epilepsy, aging, metabolic syndrome, diabetes, autism, muscular atrophy, lou gehrig’s disease, neoplasia, down syndrome are few instances where mitochondrial dysfunction is the basic cause in pathogenesis. Mitochondrial disorders are either Primary or secondary disorders. Primary mitochondrial disease or disorder (PMD) has mitochondrial or nuclear deoxyribonucleic acid (mt DNA or nDNA) mutation affecting oxidative phosphorylation (OXPHOS). While Secondary mitochondrial dysfunction (SMD) does not involve OXPHOS but is the result of mutations in non OXPHOS genes. Secondary mitochondrial dysfunction (SMD) can also be acquired secondary to adverse factors those cause oxidative stress. All this highlights the role of mitochondria and makes it a new therapeutic target in managing these disorders. The present review has briefly discussed the secondary mitochondrial dysfunctional disorders and the approach to tackle it.

scholarly journals Role of dietary therapy in managing epilepsy in children

2021 ◽  
Author(s):  
Mohammed Saeed Babonji ◽  
Zahra Abdullah Alkhatir ◽  
Adel Abed Alharbi ◽  
Buthaynah Abdullah Alghasham ◽  
Ola Lateef Abumansour ◽  
...  
Keyword(s):  
Dravet Syndrome ◽  
Treatment Modalities ◽  
Current Evidence ◽  
Dietary Therapy ◽  
Therapeutic Approaches ◽  
Treatment Regimens ◽  
Ketogenic Diets ◽  
Treatment Plans ◽  
Management Approaches

Ketogenic diets have been proposed as effective management approaches that have been validated by many studies in the literature. The efficacy of administering these treatment modalities has been validated by many studies within epilepsy-related syndromes as Rett syndrome, infantile spasms, GLUT-1 deficiency and Dravet syndrome. As a result, it has been noticed that observable favorable outcomes within the first three months from starting the administration of these treatment regimens. In this literature review, we have discussed the dietary therapeutic approaches for managing epilepsy in children. The findings have been combined from different studies in the literature. Many of them are comparative investigations that have indicated the efficacy of these treatment plans in reducing both the frequency of seizures and adequately inhibiting the development of further epilepsy events. Many mechanisms have been proposed for these treatment modalities to inhibit seizures that are adequately discussed in this article. Based on the current evidence, further awareness approaches should be conducted to increase the administration of these products, especially in pharmaco-resistant cases.

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