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Acta Neuropathologica Communications Jul 2023To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into...
To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups-WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient's mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations' impact on carcinogenesis and cancer treatment.
Topics: Humans; Female; Medulloblastoma; Mutation; DNA, Mitochondrial; Mitochondrial Diseases; Cerebellar Neoplasms
PubMed: 37501103
DOI: 10.1186/s40478-023-01602-0 -
International Journal of Molecular... May 2024Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators of neuroinflammation.... (Review)
Review
Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators of neuroinflammation. In addition to providing energy to cells, mitochondria also participate in the immunoinflammatory response of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis and epilepsy, by regulating processes such as cell death and inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, mitochondrial dynamics and calcium homeostasis imbalance may serve as underlying regulatory mechanisms for these diseases. Therefore, investigating mechanisms related to mitochondrial dysfunction may result in therapeutic strategies against chronic neuroinflammation and neurodegeneration. The present review summarizes the mechanisms of mitochondria in chronic neuroinflammatory diseases and the current treatment approaches that target mitochondrial dysfunction in these diseases.
Topics: Humans; Neuroinflammatory Diseases; Mitochondria; Neurodegenerative Diseases; Parkinson Disease; Mitochondrial Diseases
PubMed: 38577947
DOI: 10.3892/ijmm.2024.5371 -
The Biochemical Journal Nov 2023Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in... (Review)
Review
Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.
Topics: Humans; Muscle, Skeletal; Mitochondrial Myopathies; Mitochondria; Mitochondrial Turnover; Biology
PubMed: 37965929
DOI: 10.1042/BCJ20220233 -
Cells Dec 2023Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that... (Review)
Review
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor β (TR-β) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.
Topics: Humans; Metabolic Diseases; Thyroid Hormones; Non-alcoholic Fatty Liver Disease; Mitochondrial Diseases
PubMed: 38132126
DOI: 10.3390/cells12242806 -
Biochemical Society Transactions Feb 2024Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species... (Review)
Review
Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrial-derived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for age-related diseases.
Topics: Humans; Antioxidants; Reactive Oxygen Species; Carotenoids; Oxidative Stress; Mitochondrial Diseases
PubMed: 38385583
DOI: 10.1042/BST20230193 -
Neuroscience and Biobehavioral Reviews Jul 2023Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades.... (Review)
Review
Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms. This narrative review summarizes the current knowledge on neuropsychiatric impairment in SCA and FRDA. We discuss the prevalence, clinical features and treatment approaches in the most commonly reported domains of depression, anxiety, apathy, agitation and impulse dyscontrol, and psychosis. Since these symptoms have a considerable impact on patients' quality of life, we argue that further research is mandated to improve the detection and treatment options of neuropsychiatric co-morbidities in ataxia patients.
Topics: Humans; Friedreich Ataxia; Quality of Life; Spinocerebellar Ataxias; Cerebellum; Comorbidity
PubMed: 37137435
DOI: 10.1016/j.neubiorev.2023.105205 -
Frontiers in Endocrinology 2024Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass and structural deterioration of bone tissue, resulting in heightened vulnerability... (Review)
Review
Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass and structural deterioration of bone tissue, resulting in heightened vulnerability to fractures due to increased bone fragility. This condition primarily arises from an imbalance between the processes of bone resorption and formation. Mitochondrial dysfunction has been reported to potentially constitute one of the most crucial mechanisms influencing the pathogenesis of osteoporosis. In essence, mitochondria play a crucial role in maintaining the delicate equilibrium between bone formation and resorption, thereby ensuring optimal skeletal health. Nevertheless, disruption of this delicate balance can arise as a consequence of mitochondrial dysfunction. In dysfunctional mitochondria, the mitochondrial electron transport chain (ETC) becomes uncoupled, resulting in reduced ATP synthesis and increased generation of reactive oxygen species (ROS). Reinforcement of mitochondrial dysfunction is further exacerbated by the accumulation of aberrant mitochondria. In this review, we investigated and analyzed the correlation between mitochondrial dysfunction, encompassing mitochondrial DNA (mtDNA) alterations, oxidative phosphorylation (OXPHOS) impairment, mitophagy dysregulation, defects in mitochondrial biogenesis and dynamics, as well as excessive ROS accumulation, with regards to OP (). Furthermore, we explore prospective strategies currently available for modulating mitochondria to ameliorate osteoporosis. Undoubtedly, certain therapeutic strategies still require further investigation to ensure their safety and efficacy as clinical treatments. However, from a mitochondrial perspective, the potential for establishing effective and safe therapeutic approaches for osteoporosis appears promising.
Topics: Humans; Reactive Oxygen Species; Prospective Studies; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases; Osteoporosis
PubMed: 38370357
DOI: 10.3389/fendo.2024.1325317 -
International Journal of Molecular... Mar 2024Mitochondrial dysfunction and metabolic reprogramming have been extensively studied in many disorders ranging from cardiovascular to neurodegenerative disease. Obesity... (Review)
Review
Mitochondrial dysfunction and metabolic reprogramming have been extensively studied in many disorders ranging from cardiovascular to neurodegenerative disease. Obesity has previously been associated with mitochondrial fragmentation, dysregulated glycolysis, and oxidative phosphorylation, as well as increased reactive oxygen species production. Current treatments focus on reducing cellular stress to restore homeostasis through the use of antioxidants or alterations of mitochondrial dynamics. This review focuses on the role of mitochondrial dysfunction in obesity particularly for those suffering from asthma and examines mitochondrial transfer from mesenchymal stem cells to restore function as a potential therapy. Mitochondrial targeted therapy to restore healthy metabolism may provide a unique approach to alleviate dysregulation in individuals with this unique endotype.
Topics: Humans; Oxidative Stress; Metabolic Reprogramming; Neurodegenerative Diseases; Asthma; Obesity; Mitochondrial Diseases; Reactive Oxygen Species
PubMed: 38474191
DOI: 10.3390/ijms25052944 -
Annals of Neurology Oct 2023Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute...
OBJECTIVE
Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes.
METHODS
The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS.
RESULTS
The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31 of 114 GDRs curated (27%), moderate for 38 (33%), limited for 43 (38%), and disputed for 2 (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 were autosomal dominant, and 3 were X-linked.
INTERPRETATION
GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multisystem organ surveillance, recurrence risk counseling, reproductive choice, natural history studies, and determination of eligibility for interventional clinical trials. ANN NEUROL 2023;94:696-712.
Topics: Child; Humans; Leigh Disease; Mitochondrial Diseases; Mitochondria
PubMed: 37255483
DOI: 10.1002/ana.26716 -
Cells Feb 2024Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient... (Review)
Review
Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disability. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, an increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to an even greater health and economic burden as the global average life expectancy increases and consequently the world's population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction including energy starvation and oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.
Topics: Humans; Cardiovascular Diseases; Quality of Life; Cellular Senescence; Heart Failure; Myocardial Infarction; Mitochondrial Diseases
PubMed: 38391966
DOI: 10.3390/cells13040353