Attempts to understand the mechanisms of mitochondrial diseases: The reverse genetics of mouse models for mitochondrial disease

Ishikawa, Kaori; Nakada, Kazuto

doi:10.1016/j.bbagen.2020.129835

Cited by 4 publications

(6 citation statements)

References 104 publications

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“…Unfortunately, there are situations when the mouse genome manipulations that should lead to MD development do not reflect the clinical picture associated with the pathological mutation in humans [ 22 ]. On the one hand, such results are associated with a higher resistance of mice to MDs [ 23 ], and on the other, some mutations in humans can manifest themselves in combination with more complex factors, such as lifestyle and concomitant diseases [ 24 ]. In these cases, a solution may be to use another animal model.…”

Section: Animal Models Of Mitochondrial Diseasesmentioning

confidence: 99%

“…К сожалению, возникают ситуации, когда манипуляции с мышиным геномом, которые должны приводить к развитию МБ, не отражают клиническую картину этой патологической мутации у человека [22]. Такие результаты, с одной стороны, связывают с более высокой устойчивостью мышей к МБ [23], а с другой, некоторые мутации у человека могут проявляться в сочетании с более сложными факторами, такими, как образ жизни и сопутствующие заболевания [24]. Выходом в подобных случаях может стать использование другой животной модели.…”

Section: животные модели митохондриальных заболеванийunclassified

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Animal Models of Mitochondrial Diseases Associated with Nuclear Gene Mutations

Averina,

Kuznetsova,

Permyakov

et al. 2024

Acta Naturae

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Mitochondrial diseases (MDs) associated with nuclear gene mutations are part of a large group of inherited diseases caused by the suppression of energy metabolism. These diseases are of particular interest, because nuclear genes encode not only most of the structural proteins of the oxidative phosphorylation system (OXPHOS), but also all the proteins involved in the OXPHOS protein import from the cytoplasm and their assembly in mitochondria. Defects in any of these proteins can lead to functional impairment of the respiratory chain, including dysfunction of complex I that plays a central role in cellular respiration and oxidative phosphorylation, which is the most common cause of mitopathologies. Mitochondrial diseases are characterized by an early age of onset and a progressive course and affect primarily energy-consuming tissues and organs. The treatment of MDs should be initiated as soon as possible, but the diagnosis of mitopathologies is extremely difficult because of their heterogeneity and overlapping clinical features. The molecular pathogenesis of mitochondrial diseases is investigated using animal models: i.e. animals carrying mutations causing MD symptoms in humans. The use of mutant animal models opens new opportunities in the study of genes encoding mitochondrial proteins, as well as the molecular mechanisms of mitopathology development, which is necessary for improving diagnosis and developing approaches to drug therapy. In this review, we present the most recent information on mitochondrial diseases associated with nuclear gene mutations and animal models developed to investigate them.

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Section: Animal Models Of Mitochondrial Diseasesmentioning

confidence: 99%

Section: животные модели митохондриальных заболеванийunclassified

Animal Models of Mitochondrial Diseases Associated with Nuclear Gene Mutations

Averina,

Kuznetsova,

Permyakov

et al. 2024

Acta Naturae

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“…Numerous mouse models have been generated to better understand the pathogenic mechanisms underlying mitochondrial diseases (Ishikawa and Nakada, 2020). In this study we used fast-twitch muscle fiber-specific Tfam KO mice and showed that this mouse model presents a disease progression similar to that observed in mitochondrial myopathy patients; that is, an initial decline in mitochondrial oxidative capacity accompanied by a faster force decline during repeated contractions (i.e., accelerated development of muscle fatigue), which is followed by a progressive decrease in force production already in the unfatigued state (i.e., muscle weakness), reduction of body weight and premature death.…”

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 99%

“…Mitochondrial diseases are caused by genetic mutations in mitochondrial or nuclear DNA which affect the function of the mitochondrial respiratory chain thereby leading to a defective oxidative phosphorylation (Ishikawa and Nakada, 2020;Parikh et al, 2015;Thorburn, 2004). Skeletal muscles are commonly affected given that they require a high amount of energy and are highly dependent on oxidative phosphorylation for energy production.…”

Section: Introductionmentioning

confidence: 99%

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model

Chatel

Ducreux

Harhous

et al. 2021

Disease Models &Amp; Mechanisms

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Mitochondrial diseases are genetic disorders leading to an impaired mitochondrial function and resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, the fast-twitch skeletal muscle-specific Tfam deletion (Tfam KO) leads to deficit in the respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11 and 14 weeks Tfam KO mice, i.e., before and when mice are about to enter the terminal stage, respectively. While force in the unfatigued state was reduced in Tfam KO mice as compared to control littermates (WT) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in WT muscle at both ages whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy where impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.

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“…The mitochondria, colloquially known as the powerhouse of the cell, are key cellular organelles that generate energy (in the form of adenosine triphosphate, ATP) through oxidative phosphorylation to support all biochemical reactions of the cell. Prevalence estimates are variable but conservatively, mitochondrial diseases affect at least 1 in 4,300 persons in Europe [ 3 ]. MDs can be further divided into two categories, primary and secondary.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial disease registries worldwide: A scoping review

Abdul-Fatah

Esmaeilisaraji²,

Juan³

et al. 2022

PLoS ONE

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Background Mitochondrial diseases are a large group of genetically heterogeneous and clinically diverse disorders. Diagnosis often takes many years for which treatment may not exist. Registries are often used to conduct research, establish natural disease progression, engage the patient community, and develop best disease management practices. In Canada, there are limited centralized registries for mitochondrial disease patients, presenting a challenge for patients and professionals. Objective To support the creation of such a registry, a systematic scoping review was conducted to map the landscape of mitochondrial disease patient registries worldwide, with a focus on registry design and challenges. Furthermore, it addresses a knowledge gap by providing a narrative synthesis of published literature that describes these registries. Methods Arksey and O’Malley’s methodological framework was followed to systematically search English-language literature in PubMed and CINAHL describing the designs of mitochondrial disease patient registries, supplemented by a grey literature search. Data were extracted in Microsoft Excel. Stakeholder consultations were also performed with patient caregivers, advocates, and researchers to provide perspectives beyond those found in the literature. These data were thematically analyzed and were reported in accordance with the PRISMA-ScR reporting guidelines. Results A total of 17 articles were identified describing 13 unique registries located in North America, Europe, Australia, and West Asia. These papers described the registries’ designs, their strengths, and weaknesses, as well as their tangible outcomes such as facilitating recruitment for research and supporting epidemiological studies. Conclusion Based on our findings in this review, recommendations were formulated. These include establishing registry objectives, respecting patients and their roles in the registry, adopting international data standards, data evaluations, and considerations to privacy legislation, among others. These recommendations could be used to support designing a future Canadian mitochondrial disease patient registry, and to further research directly engaging these registries worldwide.

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Attempts to understand the mechanisms of mitochondrial diseases: The reverse genetics of mouse models for mitochondrial disease

Cited by 4 publications

References 104 publications

Animal Models of Mitochondrial Diseases Associated with Nuclear Gene Mutations

Animal Models of Mitochondrial Diseases Associated with Nuclear Gene Mutations

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model

Mitochondrial disease registries worldwide: A scoping review

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