Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

Stefely, Jonathan A.; Licitra, Floriana; Laredj, Leila; Reidenbach, Andrew G.; Kemmerer, Zachary A.; Grangeray, Anais; Jaeg-Ehret, Tiphaine; Minogue, Catherine E.; Ulbrich, Arne; Hutchins, Paul D.; Wilkerson, Emily M.; Ruan, Zheng; Aydin, Deniz; Hebert, Alexander S.; Guo, Xiao; Freiberger, Elyse C.; Reutenauer, Laurence; Jochem, Adam; Chergova, Maya; Johnson, Isabel E.; Lohman, Danielle C.; Rush, Matthew J. P.; Kwiecien, Nicholas W.; Singh, Pankaj Kumar; Schlagowski, Anna I.; Floyd, Brendan J.; Forsman, Ulrika; Šindelář, Pavel; Westphall, Michael S.; Pierrel, Fabien; Zoll, Joffrey; Peraro, Matteo Dal; Kannan, Natarajan; Bingman, C.A.; Coon, Joshua J.; Isope, Philippe; Puccio, Hélène; Pagliarini, David J.

doi:10.1016/j.molcel.2016.06.030

Cited by 105 publications

(156 citation statements)

References 54 publications

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“…Why mutations in different COQ genes have such distinct effects remains unclear. Tissue-specific differences in gene expression or metabolism-regulated protein-protein interactions may play a role [87, 117]. …”

Section: Functions Of Coenzyme Q and An Overview Of Its Biosynthesismentioning

confidence: 99%

“…Delivering CoQ to specific cells in need, such as cerebellar Purkinje cells [87], is a major challenge. Exogenous CoQ is efficiently taken up by liver [174, 175], ovarian [176], and brown adipose tissues [177].…”

Section: Functions Of Coenzyme Q and An Overview Of Its Biosynthesismentioning

confidence: 99%

“…Biochemical fractionation studies localized yeast Coq3p–Coq9p to the mitochondrial matrix and, importantly, showed that they are peripherally associated with the matrix face of the inner membrane [59, 73–84]. An exception to this peripheral association is COQ8A, which has a transmembrane helix [85–87], although its yeast ortholog Coq8p may be peripherally associated [59, 81]. …”

Section: The Terminal Stage Of Coq Biosynthesis – Head Group Modificamentioning

confidence: 99%

“…Additionally, the COQ2 homolog UBIAD1 localizes to the Golgi membrane, where it supports Golgi CoQ production [28]. Whether the downstream CoQ biosynthesis proteins (COQ3–9) also localize to the Golgi is unclear, but, interestingly, Golgi dysmorphology was observed in mice that lack COQ8A [87]. …”

Section: The Terminal Stage Of Coq Biosynthesis – Head Group Modificamentioning

confidence: 99%

“…Global mass spectrometry proteomics studies demonstrated that deletion of Coq8a or Coq9 in mice causes selective and significant depletion of numerous COQ proteins [87, 116], not just that encoded by the deleted gene. Furthermore, a mitochondria-focused affinity enrichment mass spectrometry (AE-MS) study revealed a dynamic network of protein-protein interactions between COQ3–COQ9 [117].…”

Section: The Coq Biosynthetic Complexmentioning

confidence: 99%

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Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Stefely

Pagliarini

2017

Trends in Biochemical Sciences

243

290

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Coenzyme Q (CoQ, ubiquinone) is a redox active lipid produced across all domains of life that functions in electron transport and oxidative phosphorylation and whose deficiency causes human diseases. Yet, CoQ biosynthesis has not been fully defined in any organism. Several proteins with unclear molecular functions facilitate CoQ biosynthesis through unknown means, and multiple steps in the pathway are catalyzed by currently unidentified enzymes. Here we highlight recent progress toward filling these knowledge gaps through both traditional biochemistry and cutting-edge “omics” approaches. To help fill the remaining gaps, we present questions framed by the recently discovered CoQ biosynthetic complex and by putative biophysical barriers. Mapping CoQ biosynthesis, metabolism, and transport pathways has great potential to enhance treatment of numerous human diseases.

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Section: Functions Of Coenzyme Q and An Overview Of Its Biosynthesismentioning

confidence: 99%

Section: Functions Of Coenzyme Q and An Overview Of Its Biosynthesismentioning

confidence: 99%

Section: The Terminal Stage Of Coq Biosynthesis – Head Group Modificamentioning

confidence: 99%

Section: The Terminal Stage Of Coq Biosynthesis – Head Group Modificamentioning

confidence: 99%

Section: The Coq Biosynthetic Complexmentioning

confidence: 99%

See 3 more Smart Citations

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Stefely

Pagliarini

2017

Trends in Biochemical Sciences

243

290

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Clinico‐Genetic, Imaging and Molecular Delineation of COQ8A‐Ataxia: A Multicenter Study of 59 Patients

Traschütz

Schirinzi

Laugwitz

et al. 2020

Annals of Neurology

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Objective To foster trial‐readiness of coenzyme Q8A (COQ8A)‐ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A‐ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods Cross‐modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D‐protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results Fifty‐nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A‐ataxia presented as variable multisystemic, early‐onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss‐of‐function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross‐sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild‐to‐moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation This study provides a deeper understanding of the disease, and paves the way toward large‐scale natural history studies and treatment trials in COQ8A‐ataxia. ANN NEUROL 2020;88:251–263

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Functional analysis of Aarf domain‐containing kinase 1 in Drosophila melanogaster

Wisidagama

Thomas

Lam

et al. 2019

Developmental Dynamics

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Background: The ADCK proteins are predicted mitochondrial kinases. Most studies of these proteins have focused on the Abc1/Coq8 subfamily, which contributes to Coenzyme Q biosynthesis. In contrast, little is known about ADCK1 despite its evolutionary conservation in yeast, Drosophila, Caenorhabditis elegans and mammals. Results: We show that Drosophila ADCK1 mutants die as second instar larvae with double mouth hooks and tracheal breaks. Tissue-specific genetic rescue and RNAi studies show that ADCK1 is necessary and sufficient in the trachea for larval viability. In addition, tracheal-rescued ADCK1 mutant adults have reduced lifespan, are developmentally delayed, have reduced body size, and normal levels of basic metabolites. Conclusion: The larval lethality and double mouth hooks seen in ADCK1 mutants are often associated with reduced levels of the steroid hormone ecdysone, suggesting that this gene could contribute to controlling ecdysone levels or bioavailability. Similarly, the tracheal defects in these animals could arise from defects in intracellular lipid trafficking. These studies of ADCK1 provide a new context to define the physiological functions of this poorly understood member of the ADCK family of predicted mitochondrial proteins. K E Y W O R D Smetabolism, mitochondria, molting, trachea

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Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

Cited by 105 publications

References 54 publications

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Clinico‐Genetic, Imaging and Molecular Delineation of COQ8A‐Ataxia: A Multicenter Study of 59 Patients

Functional analysis of Aarf domain‐containing kinase 1 in Drosophila melanogaster

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