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Orphanet Journal of Rare Diseases Mar 2015Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a... (Review)
Review
BACKGROUND
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia.
METHODS
A systematic review of publications reporting patients with HHH syndrome was performed.
RESULTS
We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life.
CONCLUSIONS
This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
Topics: Aging; Humans; Hyperammonemia; Mutation; Origin Recognition Complex; Ornithine; Protein Conformation; Urea Cycle Disorders, Inborn
PubMed: 25874378
DOI: 10.1186/s13023-015-0242-9 -
Mitochondrion May 2022Mitochondrial permeability transition pore (mPTP) is a channel that opens at the inner mitochondrial membrane under conditions of stress. Sirtuin 3 (Sirt3) is a... (Review)
Review
Mitochondrial permeability transition pore (mPTP) is a channel that opens at the inner mitochondrial membrane under conditions of stress. Sirtuin 3 (Sirt3) is a mitochondrial deacetylase known to play a major role in stress resistance and a regulatory role in cell death. This systematic review aims to elucidate the role of Sirt3 in mPTP inhibition. Electronic databases, including PubMed, EMBASE, Web of Science and Cochrane Library were searched up to May 2020. Original studies that investigated the relationship between Sirt3 and mPTP were included. Two reviewers independently extracted data on study characteristics, methods and outcomes. A total of 194 articles were found. Twenty-nine articles, which met criteria were included in the systematic review. Twenty-three studies provided evidence of the inhibitory effect of Sirt3 on the mPTP aperture. This review summarizes up-to-date evidence of the protective and inhibitory role of Sirt3 through deacetylating Cyclophilin D (CypD) on the mPTP aperture. Furthermore, we discuss the implications of this effect in disease.
Topics: Peptidyl-Prolyl Isomerase F; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Sirtuin 3
PubMed: 35346868
DOI: 10.1016/j.mito.2022.03.004 -
Frontiers in Aging Neuroscience 2023Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial...
Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aβ) plaques. probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in the human brain. Phosphorus-magnetic resonance spectroscopy (P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of P-MRS measures as biomarkers for the early detection of AD.
PubMed: 37273652
DOI: 10.3389/fnagi.2023.1183228 -
Reviews in Medical Virology Nov 2021Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization... (Review)
Review
Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization reports. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins into the complexes of the electron transport chain; (ii) impact on mitochondrial genome (depletion, deletions and point mutations) and mitochondrial dynamics (fusion and fission); (iii) membrane potential impairment; (iv) apoptotic regulation; and (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with considerable impact on the quality of life of the children and could even cause death. Herein, we use a systematic review to explore the association between mitochondrial alterations in paediatric infections including human immunodeficiency virus, cytomegalovirus, herpes viruses, various forms of hepatitis, adenovirus, T-cell lymphotropic virus and influenza. We analyse how these paediatric viral infectious processes may cause mitochondrial deterioration in this especially vulnerable population, with consideration for the principal aspects of research and diagnosis leading to improved disease understanding, management and surveillance.
Topics: Antiviral Agents; Child; Communicable Diseases; DNA, Mitochondrial; Humans; Mitochondria; Pediatrics; Virus Diseases
PubMed: 33792105
DOI: 10.1002/rmv.2232 -
Biomolecules Nov 2023Mitochondria are ancient endosymbiotic double membrane organelles that support a wide range of eukaryotic cell functions through energy, metabolism, and cellular... (Review)
Review
Mitochondria are ancient endosymbiotic double membrane organelles that support a wide range of eukaryotic cell functions through energy, metabolism, and cellular control. There are over 1000 known proteins that either reside within the mitochondria or are transiently associated with it. These mitochondrial proteins represent a functional subcellular protein network (mtProteome) that is encoded by mitochondrial and nuclear genomes and significantly varies between cell types and conditions. In neurons, the high metabolic demand and differential energy requirements at the synapses are met by specific modifications to the mtProteome, resulting in alterations in the expression and functional properties of the proteins involved in energy production and quality control, including fission and fusion. The composition of mtProteomes also impacts the localization of mitochondria in axons and dendrites with a growing number of neurodegenerative diseases associated with changes in mitochondrial proteins. This review summarizes the findings on the composition and properties of mtProteomes important for mitochondrial energy production, calcium and lipid signaling, and quality control in neural cells. We highlight strategies in mass spectrometry (MS) proteomic analysis of mtProteomes from cultured cells and tissue. The research into mtProteome composition and function provides opportunities in biomarker discovery and drug development for the treatment of metabolic and neurodegenerative disease.
Topics: Humans; Proteome; Neurodegenerative Diseases; Proteomics; Mitochondria; Neurons; Mitochondrial Proteins
PubMed: 38002320
DOI: 10.3390/biom13111638 -
Scientific Reports Aug 2016Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus... (Review)
Review
Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease.
Topics: Aged; Biopsy; DNA, Mitochondrial; Female; Humans; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Muscle, Skeletal; Mutation; Young Adult
PubMed: 27506553
DOI: 10.1038/srep30610 -
Biomedicine & Pharmacotherapy =... Sep 2023Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs... (Review)
Review
Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.
Topics: Humans; Neurodegenerative Diseases; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Kaempferols; Alzheimer Disease; Parkinson Disease; Huntington Disease
PubMed: 37494786
DOI: 10.1016/j.biopha.2023.115215 -
Journal of Translational Medicine May 2021Mitochondria are essential organelles that provide energy for cellular functions, participate in cellular signaling and growth, and facilitate cell death. Based on their... (Review)
Review
BACKGROUND
Mitochondria are essential organelles that provide energy for cellular functions, participate in cellular signaling and growth, and facilitate cell death. Based on their multifactorial roles, mitochondria are also critical in the progression of critical illnesses. Transplantation of mitochondria has been reported as a potential promising approach to treat critical illnesses, particularly ischemia reperfusion injury (IRI). However, a systematic review of the relevant literature has not been conducted to date. Here, we systematically reviewed the animal and human studies relevant to IRI to summarize the evidence for mitochondrial transplantation.
METHODS
We searched MEDLINE, the Cochrane library, and Embase and performed a systematic review of mitochondrial transplantation for IRI in both preclinical and clinical studies. We developed a search strategy using a combination of keywords and Medical Subject Heading/Emtree terms. Studies including cell-mediated transfer of mitochondria as a transfer method were excluded. Data were extracted to a tailored template, and data synthesis was descriptive because the data were not suitable for meta-analysis.
RESULTS
Overall, we identified 20 animal studies and two human studies. Among animal studies, 14 (70%) studies focused on either brain or heart IRI. Both autograft and allograft mitochondrial transplantation were used in 17 (85%) animal studies. The designs of the animal studies were heterogeneous in terms of the route of administration, timing of transplantation, and dosage used. Twelve (60%) studies were performed in a blinded manner. All animal studies reported that mitochondrial transplantation markedly mitigated IRI in the target tissues, but there was variation in biological biomarkers and pathological changes. The human studies were conducted with a single-arm, unblinded design, in which autologous mitochondrial transplantation was applied to pediatric patients who required extracorporeal membrane oxygenation (ECMO) for IRI-associated myocardial dysfunction after cardiac surgery.
CONCLUSION
The evidence gathered from our systematic review supports the potential beneficial effects of mitochondrial transplantation after IRI, but its clinical translation remains limited. Further investigations are thus required to explore the mechanisms of action and patient outcomes in critical settings after mitochondrial transplantation. Systematic review registration The study was registered at UMIN under the registration number UMIN000043347.
Topics: Animals; Cell Death; Child; Humans; Mitochondria; Reperfusion Injury
PubMed: 34001191
DOI: 10.1186/s12967-021-02878-3 -
Molecular Neurobiology Apr 2016Mitochondrial dysfunction has been reported to be involved in the pathophysiology of autism spectrum disorder (ASD). Studies investigating the possible association... (Meta-Analysis)
Meta-Analysis Review
Mitochondrial dysfunction has been reported to be involved in the pathophysiology of autism spectrum disorder (ASD). Studies investigating the possible association between ASD and polymorphism in SLC25A12, which encodes the mitochondrial aspartate/glutamate carrier, have yielded inconsistent results. We conducted a systematic review and meta-analysis of such studies to elucidate if and which SLC25A12 single nucleotide polymorphisms (SNPs) are associated with ASD. We searched PubMed, Ovid, Web of Science, and ERIC databases through September 20th, 2014. Odds ratios (ORs) were aggregated using random effect models. Sensitivity analyses were conducted based on study design (family-based or case-control). Fifteen out of 79 non-duplicate records were retained for qualitative synthesis. We pooled 10 datasets from 9 studies with 2001 families, 735 individuals with ASD and 632 typically developing (TD) individuals for the meta-analysis of rs2292813, as well as 11 datasets from 10 studies with 2016 families, 852 individuals with ASD and 1058 TD individuals for the meta-analysis of rs2056202. We found a statistically significant association between ASD and variant in rs2292813 (OR = 1.190, 95% CI 1.052-1.346, P = 0.006) as well as in rs2056202 (OR = 1.206, 95% CI 1.035-1.405, P = 0.016). Sensitivity analyses including only studies with family-based design demonstrated significant association between ASD and polymorphism in rs2292813 (OR = 1.216, 95% CI 1.075-1.376, P = 0.002) and rs2056202 (OR = 1.267, 95% CI 1.041-1.542, P = 0.018). In contrast, sensitivity analyses including case-control design studies only failed to find a significant association. Further research on the role of SLC25A12 and ASD may pave the way for potential innovative therapeutic interventions.
Topics: Autism Spectrum Disorder; Case-Control Studies; Datasets as Topic; Family Health; Genotype; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Polymorphism, Single Nucleotide
PubMed: 25663199
DOI: 10.1007/s12035-015-9116-3 -
Molecular Biology Reports Apr 2023FF adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes.... (Review)
Review
FF adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes. FF ATP synthase also regulates the central metabolic processes in the human body driven by proton motive force (Δp). Numerous studies have immensely contributed toward highlighting its regulation in improving energy homeostasis and maintaining mitochondrial integrity, which otherwise gets compromised in illnesses. Yet, its role in the implication of non-communicable diseases remains unknown. FF ATP synthase dysregulation at gene level leads to reduced activity and delocalization in the cristae and plasma membranes, which is directly associated with non-communicable diseases: cardiovascular diseases, diabetes, neurodegenerative disorders, cancer, and renal diseases. Individual subunits of the FF ATP synthase target ligand-based competitive or non-competitive inhibition. After performing a systematic literature review to understand its specific functions and its novel drug targets, the present article focuses on the central role of FF ATP synthase in primary non-communicable diseases. Next, it discusses its involvement through various pathways and the effects of multiple inhibitors, activators, and modulators specific to non-communicable diseases with a futuristic outlook.
Topics: Humans; Adenosine Triphosphate; Glycogen Synthase; Noncommunicable Diseases; Mitochondria; Mitochondrial Membranes; Mitochondrial Proton-Translocating ATPases
PubMed: 36715790
DOI: 10.1007/s11033-023-08299-3