Recent Advances in Mitochondrial Disease

Craven, Lyndsey; Alston, Charlotte L.; Taylor, Robert W.; Turnbull, Doug M.

doi:10.1146/annurev-genom-091416-035426

Cited by 233 publications

(216 citation statements)

References 107 publications

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“…15 Our results demonstrate that phenotypic expression of the m.8993T>G mutation appears to have the lowest threshold level compared to other MT-ATP6 variants. 15 Our results demonstrate that phenotypic expression of the m.8993T>G mutation appears to have the lowest threshold level compared to other MT-ATP6 variants.…”

Section: Discussionmentioning

confidence: 55%

Pathogenic variants in MT‐ATP6: A United Kingdom–based mitochondrial disease cohort study

Martikainen

Gorman

et al. 2019

Annals of Neurology

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Distinct clinical syndromes have been associated with pathogenic MT‐ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty‐one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT‐ATP6–related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310–315

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Section: Discussionmentioning

confidence: 55%

Pathogenic variants in MT‐ATP6: A United Kingdom–based mitochondrial disease cohort study

Martikainen

Gorman

et al. 2019

Annals of Neurology

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“…2). Individual references for genes are listed in Table S1 or detailed in the following reviews (19,20,(25)(26)(27)(28)(29).…”

Section: Categorizing Oxphos Disease Genes: Direct Versus Wider Cellumentioning

confidence: 99%

“…1A), including 25 for 2017 thus far (listed in Table S1). As of November 23 2017, 289 mitochondrial disease genes have been identified (35 mtDNA encoded genes and 254 nuclear encoded disease genes); numbers refined and updated from (19,20). Recent studies of mitochondrial disease cohorts undergoing mtDNA and whole exome sequencing typically report finding a molecular diagnosis in 30 to 60% of patients (21)(22)(23)(24).…”

mentioning

confidence: 99%

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Frazier

Thorburn

Compton

2019

Journal of Biological Chemistry

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Inherited disorders of oxidative phosphorylation cause the clinically and genetically heterogeneous diseases known as mitochondrial energy generation disorders, or mitochondrial diseases. Over the last three decades, mutations causing these disorders have been identified in almost 290 genes, but many patients still remain without a molecular diagnosis. Moreover, while knowledge of the genetic causes is continually expanding, understanding into how these defects lead to cellular dysfunction and organ pathology is still incomplete. Here, we review recent developments in disease gene discovery, functional characterization, and shared pathogenic parameters influencing disease pathology that offer promising avenues towards development of effective therapies.Mitochondrial energy generation disorders (hereafter termed mitochondrial diseases) are a heterogeneous group of rare disorders involving defective oxidative phosphorylation (OXPHOS). The OXPHOS system comprises five enzyme complexes, situated in the mitochondrial inner membrane. The first four complexes and two electron carriers form the respiratory chain, which generates a proton gradient used by complex V (F 1 F o ATP synthase) to generate the majority of cellular ATP. For the purpose of this review, we have focused on genes and mechanisms that have a demonstrated defect in primary energy generation (e.g. components of the OXPHOS system) or a clear expected role in mitochondrial homeostasis and the ability to generate energy (e.g. components of the TCA cycle and pyruvate dehydrogenase complex (PDC) that feed into OXPHOS, or those affecting mitochondrial membranes and structure).

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“…The majority of these proteins are encoded by nuclear DNA (nDNA), with only 13 mitochondrial proteins encoded by mitochondrial DNA (mtDNA). Thus, mitochondria OXPHOS is under the dual control of both the mitochondrial and nuclear genomes (Craven et al, 2017). Reflecting the diverse functions occurring within mitochondria, only 150 mitochondrial proteins are directly involved in OXPHOS function and ATP production (Gorman et al, 2016).…”

Section: Environmental Toxins and Neurodegenerative Disorders With MImentioning

confidence: 99%

Clinical effects of chemical exposures on mitochondrial function

Zolkipli‐Cunningham

Falk

2017

Toxicology

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Mitochondria are critical for the provision of ATP for cellular energy requirements. Tissue and organ functions are dependent on adequate ATP production, especially when energy demand is high. Mitochondria also play a role in a vast array of important biochemical pathways including apoptosis, generation and detoxification of reactive oxygen species, intracellular calcium regulation, steroid hormone and heme synthesis, and lipid metabolism. The complexity of mitochondrial structure and function facilitates its diverse roles but also enhances its vulnerability. Primary disorders of mitochondrial bioenergetics, or Primary Mitochondrial Diseases (PMD) are due to inherited genetic defects in the nuclear or mitochondrial genomes that result in defective oxidative phosphorylation capacity and cellular energy production. Secondary mitochondrial dysfunction is observed in a wide range of diseases such as Alzheimer’s and Parkinson’s disease. Several lines of evidence suggest that environmental exposures cause substantial mitochondrial dysfunction. Whereby literature from experimental and human studies on exposures associated with Alzheimer’s and Parkinson’s diseases exist, the significance of exposures as potential triggers in Primary Mitochondrial Disease (PMD) is an emerging clinical question that has not been systematically studied.

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Recent Advances in Mitochondrial Disease

Cited by 233 publications

References 107 publications

Pathogenic variants in MT‐ATP6: A United Kingdom–based mitochondrial disease cohort study

Pathogenic variants in MT‐ATP6: A United Kingdom–based mitochondrial disease cohort study

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Clinical effects of chemical exposures on mitochondrial function

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