Mitochondrial Diseases Part II: Mouse models of OXPHOS deficiencies caused by defects in regulatory factors and other components required for mitochondrial function

Iommarini, Luisa; Peralta, Susana; Torraco, Alessandra; Díaz, Francisca

doi:10.1016/j.mito.2015.01.008

Cited by 22 publications

(10 citation statements)

References 254 publications

(357 reference statements)

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“…This is supported by our observation that the same proportion of digitonin released the F1 subcomplex in the KO animals, but not in the controls. The appearance of F1 subcomplex of ATP synthase is also a characteristic feature of mtDNA maintenance defects in patients (Carrozzo et al, 2006), and was reported in numerous mouse models with impaired mtDNA expression owing to mtDNA replication defects (Milenkovic et al, 2013), impaired mtDNA transcription (Metodiev et al, 2009;Mourier et al, 2014;Park et al, 2007) or impaired mitochondrial translation (Cámara et al, 2011;Dogan et al, 2014;Iommarini et al, 2015;Szczepanowska et al, 2016).…”

Section: Discussionmentioning

confidence: 95%

ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels

Peralta

Goffart

Williams

et al. 2018

Journal of Cell Science

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Mutations in the mitochondrial inner membrane ATPase result in neurological syndromes in humans. In mice, the ubiquitous disruption of (also known as ) was embryonic lethal, but a skeletal muscle-specific conditional knockout (KO) was viable. At birth, ATAD3 muscle KO mice had normal weight, but from 2 months onwards they showed progressive motor-impaired coordination and weakness. Loss of ATAD3 caused early and severe mitochondrial structural abnormalities, mitochondrial proliferation and muscle atrophy. There was dramatic reduction in mitochondrial cristae junctions and overall cristae morphology. The lack of mitochondrial cristae was accompanied by a reduction in high molecular weight mitochondrial contact site and cristae organizing system (MICOS) complexes, and to a lesser extent in OPA1. Moreover, muscles lacking ATAD3 showed altered cholesterol metabolism, accumulation of mitochondrial DNA (mtDNA) replication intermediates, progressive mtDNA depletion and deletions. Unexpectedly, decreases in the levels of some OXPHOS components occurred after cristae destabilization, indicating that ATAD3 is not crucial for mitochondrial translation, as previously suggested. Our results show a critical early role of ATAD3 in regulating mitochondrial inner membrane structure, leading to secondary defects in mtDNA replication and complex V and cholesterol levels in postmitotic tissueThis article has an associated First Person interview with the first author of the paper.

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Section: Discussionmentioning

confidence: 95%

ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels

Peralta

Goffart

Williams

et al. 2018

Journal of Cell Science

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“…Many of the models generated to date have utilized Cre/Lox technology to selectively knockout (KO) nuclear genes involved in: (i) mtDNA maintenance, replication, transcription, translation (ii) expression and assembly of OXPHOS complexes and (iii) mitochondrial dynamics to evaluate the effect on specific populations of neurons. A comprehensive description of these models is beyond the scope of the current review and we refer readers to a three part review miniseries published last year which discusses each model in detail .…”

Section: Modelling the Neurology Of Mitochondrial Diseasementioning

confidence: 99%

Review: Central nervous system involvement in mitochondrial disease

Lax

Gorman

Turnbull

2016

Neuropathology Appl Neurobio

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Mitochondrial respiratory chain defects are an important cause of inherited disorders affecting approximately 1 in 5000 people in the UK population. Collectively these disorders are termed ‘mitochondrial diseases’ and they result from either mitochondrial DNA mutations or defects in nuclear DNA. Although they are frequently multisystem disorders, neurological deficits are particularly common, wide‐ranging and disabling for patients. This review details the manifold neurological impairments associated with mitochondrial disease, and describes the efforts to understand how they arise and progressively worsen in patients with mitochondrial disease. We describe advances in our understanding of disease pathogenesis through detailed neuropathological studies and how this has spurred the development of cellular and animal models of disease. We underscore the importance of continued clinical, molecular genetic, neuropathological and animal model studies to fully characterize mitochondrial diseases and understand mechanisms of neurodegeneration. These studies are instrumental for the next phase of mitochondrial research that has a particular emphasis on finding novel ways to treat mitochondrial disease to improve patient care and quality of life.

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“…As such, this universal energy currency is synthesized at a rate of approximately 30 mM/min, with the majority originating from oxidative phosphorylation (Schmid et al, 2008 ). Defective mitochondria and decreased ATP synthesis are the hallmarks of numerous pathological conditions (Iommarini et al, 2015 ; Peralta et al, 2015 ; Torraco et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders

Auger

Alhasawi

Contavadoo

et al. 2015

Front. Cell Dev. Biol.

105

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The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids, and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis, and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS), and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity, and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.

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Mitochondrial Diseases Part II: Mouse models of OXPHOS deficiencies caused by defects in regulatory factors and other components required for mitochondrial function

Cited by 22 publications

References 254 publications

ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels

ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels

Review: Central nervous system involvement in mitochondrial disease

Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders

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