ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism

Desai, Rajesh K.; Frazier, Ann E.; Durigon, Romina; Patel, Harshil; Jones, Aleck W.E.; Rosa, Ilaria Dalla; Lake, Nicole J.; Compton, Alison G.; Mountford, Hayley S.; Tucker, Elena J.; Mitchell, Alice; Jackson, Deborah J.; Sesay, Abdul Karim; Re, Miriam Di; Heuvel, Lambert P. van den; Burke, Derek; Francis, David; Lunke, Sebastian; McGillivray, George; Mandelstam, Simone; Mochel, Fanny; Keren, Boris; Jardel, Claude; Turner, Anne; Andrews, Peter Ian; Smeitink, Jan A.M.; Spelbrink, Johannes N.; Heales, Simon; Kohda, Masakazu; Ohtake, Akira; Murayama, Kei; Okazaki, Yasushi; Lombès, Anne; Holt, Ian; Thorburn, David R.; Spinazzola, Antonella

doi:10.1093/brain/awx094

Cited by 118 publications

(173 citation statements)

References 53 publications

(72 reference statements)

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“…Fibroblasts derived from patients suffering from ATAD3 gene cluster deletions show impaired cholesterol metabolism and mtDNA damage, as well as impaired lipid metabolism [199] (Fig 4D). In agreement with these data, muscle ATAD3 deficiency reduces the levels of cholesterol esters in muscle, probably due to reduced Acetyl-CoA acetyltransferase [199]. The effects of ATAD3 ablation on substrate handling have not been analyzed.…”

Section: Proteins Whose Depletion Enhances Insulin Signaling and Imprmentioning

confidence: 98%

“…Proteins whose depletion alters lipid metabolism Skeletal muscle-specific Atad3 knockout mice show muscle atrophy in combination with mitochondrial abnormalities that include lack of cristae, reduced OXPHOS complexes and OPA1 expression, and progressive mtDNA depletion [198]. Fibroblasts derived from patients suffering from ATAD3 gene cluster deletions show impaired cholesterol metabolism and mtDNA damage, as well as impaired lipid metabolism [199] (Fig 4D). In agreement with these data, muscle ATAD3 deficiency reduces the levels of cholesterol esters in muscle, probably due to reduced Acetyl-CoA acetyltransferase [199].…”

Section: Proteins Whose Depletion Enhances Insulin Signaling and Imprmentioning

confidence: 99%

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Metabolic implications of organelle–mitochondria communication

2019

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Cellular organelles are not static but show dynamism—a property that is likely relevant for their function. In addition, they interact with other organelles in a highly dynamic manner. In this review, we analyze the proteins involved in the interaction between mitochondria and other cellular organelles, especially the endoplasmic reticulum, lipid droplets, and lysosomes. Recent results indicate that, on one hand, metabolic alterations perturb the interaction between mitochondria and other organelles, and, on the other hand, that deficiency in proteins involved in the tethering between mitochondria and the ER or in specific functions of the interaction leads to metabolic alterations in a variety of tissues. The interaction between organelles is an emerging field that will permit to identify key proteins, to delineate novel modulation pathways, and to elucidate their implications in human disease.

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Section: Proteins Whose Depletion Enhances Insulin Signaling and Imprmentioning

confidence: 98%

Section: Proteins Whose Depletion Enhances Insulin Signaling and Imprmentioning

confidence: 99%

Metabolic implications of organelle–mitochondria communication

2019

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“…In patient cell lines, supercomplexes consisting of OXPHOS complexes I, III and IV in various stoichiometries are destabilized, resulting in impaired OXPHOS efficiency (48,50). On the other hand, the ATAD3 locus, recently identified to underlie diverse clinical presentations often involving cerebellar defects (51)(52)(53), is linked to mitochondrial functions that include regulation of mtDNA maintenance and translation. ATAD3 patient cell lines show defects in cellular cholesterol and mtDNA homeostasis, providing a basis for the disease pathology, yet a clear link between ATAD3 and OXPHOS impairment is still lacking (52).…”

Section: Genes With a Secondary Impact On Oxphos Biogenesis As Well Amentioning

confidence: 99%

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

Frazier

Thorburn

Compton

2019

Journal of Biological Chemistry

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189

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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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“…Mutations in the ATAD3 family of proteins, which alter cholesterol metabolism, cause severe neurodegeneration, mitochondrial cristae defects, and impaired mtDNA segregation (Desai et al, 2017;Peralta et al, 2018). Aggregation and disorganization imbalance are also observed in the Niemann-Pick type C disorder, further supporting the critical role of cholesterol inserts in mitochondria by controlling the tuned segregation of the organelle DNA (Desai et al, 2017). Aggregation and disorganization imbalance are also observed in the Niemann-Pick type C disorder, further supporting the critical role of cholesterol inserts in mitochondria by controlling the tuned segregation of the organelle DNA (Desai et al, 2017).…”

Section: Role Of Cholesterol In Mitochondrial Dna Maintenancementioning

confidence: 99%

“…In the mitochondria, cholesterol is (a) a structural component of the inner and outer mitochondrial membranes, (b) a precursor of steroidogenesis (of which the first steps are conducted in the mitochondrial lumen), (c) a core to a platform of interaction with ER, lysosomes, and other compartments, and (d) a tethering element for mitochondrial DNA (mtDNA). As a consequence, alterations in mitochondrial cholesterol (mChol) occur in several diseases, including Alzheimer's disease (AD) and other neurodegenerative conditions (Desai et al, 2017;Elustondo, Martin, & Karten, 2017).…”

Section: Introductionmentioning

confidence: 99%

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Desai

Campanella

2019

British J Pharmacology

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The pharmacological targeting of cholesterol levels continues to generate interest due to the undoubted success of therapeutic agents, such as statins, in extending life expectancy by modifying the prognosis of diseases associated with the impairment of lipid metabolism. Advances in our understanding of mitochondrial dysfunction in chronic age‐related diseases of the brain have disclosed an emerging role for mitochondrial cholesterol in their pathophysiology, thus delineating an opportunity to provide mechanistic insights and explore strategies of intervention. This review draws attention to novel signalling mechanisms in conditions linked with impaired metabolism associated with impaired handling of cholesterol and its oxidized forms (oxysterols) by mitochondria. By emphasizing the role of mitochondrial cholesterol in neurological diseases, we here call for novel approaches and new means of assessment. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism

Cited by 118 publications

References 53 publications

Metabolic implications of organelle–mitochondria communication

Metabolic implications of organelle–mitochondria communication

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

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

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