Epidemiology of Mitochondrial Disease

Schaefer, Andrew M.; Lim, Albert; Gorman, Gráinne

doi:10.1007/978-3-030-05517-2_4

Cited by 18 publications

(20 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One in 4300 people are affected by mitochondrial diseases, the most common type of genetic disorder (Schaefer et al, 2019;Ng and Turnbull, 2016). Of the 37 genes mentioned in Fig.…”

Section: Discussionmentioning

confidence: 99%

Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation

et al. 2020

View full text Add to dashboard Cite

Mitochondria are essential for energy production and although they have their own genome, many nuclear-encoded mitochondrial ribosomal proteins (MRPs) are required for proper function of the organelle. Although mutations in MRPs have been associated with human diseases, little is known about their role during development. Presented here are the null phenotypes for 21 nuclear-encoded mitochondrial proteins and in-depth characterization of mouse embryos mutant for the Mrp genes Mrpl3, Mrpl22, Mrpl44, Mrps18c and Mrps22. Loss of each MRP results in successful implantation and egg-cylinder formation, followed by severe developmental delay and failure to initiate gastrulation by embryonic day 7.5. The robust and similar single knockout phenotypes are somewhat surprising given there are over 70 MRPs and suggest little functional redundancy. Metabolic analysis reveals that Mrp knockout embryos produce significantly less ATP than controls, indicating compromised mitochondrial function. Histological and immunofluorescence analyses indicate abnormal organelle morphology and stalling at the G2/M checkpoint in Mrp null cells. The nearly identical pregastrulation phenotype observed for many different nuclear-encoded mitochondrial protein knockouts hints that distinct energy systems are crucial at specific time points during mammalian development. This article has an associated 'The people behind the papers' interview.

show abstract

“…One in 4300 people are affected by mitochondrial diseases, the most common type of genetic disorder (Schaefer et al, 2019;Ng and Turnbull, 2016). Of the 37 genes mentioned in Fig.…”

Section: Discussionmentioning

confidence: 99%

Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders (Gorman et al, 2016). These illnesses are challenging not only at the time of diagnosis but also during their medical evolution, as they involve multiple organ systems and there are limited therapeutic options (Grier et al, 2018; Parikh et al, 2017; Schaefer et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

Romero-Morales

Rastogi

Temuri

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryLeigh syndrome (LS) is a rare, inherited neuro-metabolic disorder that presents with bilateral brain lesions. This disease is caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated induced pluripotent stem cells (iPSCs) from three widely available LS fibroblast lines and identified, through whole exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS derived cell lines were viable and able to differentiate into key progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. The DLD-mutant line showed decreased neural rosette (NR) formation, and there were differences in NR lumen area in all three LS lines compared to control. LS-derived cerebral organoids showed defects in neural epithelial bud generation and reduced size when grown for 100 days. Loss of cortical architecture and markers were detected at days 30 and 100. The MT-ATP6/PDH line produced organoid neural progenitor cells with an abnormal mitochondrial morphology characterized by fragmentation and disorganization, and demonstrated increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that could be used as LS model systems.

show abstract

“…Impaired oxidative phosphorylation is a hallmark of mitochondrial disorders with progressive clinical manifestations that can vary from single organ to multisystem disorders, often affecting organs with high energetic demands [26]. Mitochondrial diseases have an estimated prevalence of one in 4300 adults, making them the most common inherited metabolic disorder [27][28][29][30]. Defects in CI are the most commonly observed respiratory chain disorder [31][32][33], making the complex a good candidate for bioenergetic testing.…”

Section: Bioenergetics Testing In Mitochondrial Disordersmentioning

confidence: 99%

Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives

Acı́n-Pérez

Benincá

Shabane

et al. 2021

Life

View full text Add to dashboard Cite

Mitochondrial bioenergetic function is a central component of cellular metabolism in health and disease. Mitochondrial oxidative phosphorylation is critical for maintaining energetic homeostasis, and impairment of mitochondrial function underlies the development and progression of metabolic diseases and aging. However, measurement of mitochondrial bioenergetic function can be challenging in human samples due to limitations in the size of the collected sample. Furthermore, the collection of samples from human cohorts is often spread over multiple days and locations, which makes immediate sample processing and bioenergetics analysis challenging. Therefore, sample selection and choice of tests should be carefully considered. Basic research, clinical trials, and mitochondrial disease diagnosis rely primarily on skeletal muscle samples. However, obtaining skeletal muscle biopsies requires an appropriate clinical setting and specialized personnel, making skeletal muscle a less suitable tissue for certain research studies. Circulating white blood cells and platelets offer a promising primary tissue alternative to biopsies for the study of mitochondrial bioenergetics. Recent advances in frozen respirometry protocols combined with the utilization of minimally invasive and non-invasive samples may provide promise for future mitochondrial research studies in humans. Here we review the human samples commonly used for the measurement of mitochondrial bioenergetics with a focus on the advantages and limitations of each sample.

show abstract

Epidemiology of Mitochondrial Disease

Cited by 18 publications

References 119 publications

Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation

Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation

Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives

Contact Info

Product

Resources

About