Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family

Reidenbach, Andrew G.; Kemmerer, Zachary A.; Aydin, Deniz; Jochem, Adam; McDevitt, Molly T.; Hutchins, Paul D.; Stark, Jaime L.; Stefely, Jonathan A.; Reddy, Thiru R.; Hebert, Alex S.; Wilkerson, Emily M.; Johnson, Isabel E.; Bingman, C.A.; Markley, John L.; Coon, Joshua J.; Peraro, Matteo Dal; Pagliarini, David J.

doi:10.1016/j.chembiol.2017.11.001

Cited by 64 publications

(84 citation statements)

References 88 publications

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“…22,23 Our We propose that COQ9 acts as a lipid chaperone that helps to withdraw CoQ intermediates from the membrane and present them to soluble enzymes within complex Q. After Stefely et al, 19,20 Reidenbach et al, 21 and Lohman et al 24 structure of COQ9 unexpectedly revealed that it adopts an ancient TetR (tetracycline resistance) fold typically used by nutrient-sensing bacterial transcription factors [ Fig. 3(B)].…”

Section: Structural Genomicsmentioning

confidence: 88%

“…We propose that COQ9 acts as a lipid chaperone that helps to withdraw CoQ intermediates from the membrane and present them to soluble enzymes within complex Q. After Stefely et al, Reidenbach et al, and Lohman et al…”

Section: Finding Homes For the Orphansmentioning

confidence: 90%

“…(A)]. This work, and the mechanistic follow‐up biochemistry that it motivated, suggests a model whereby COQ8 assists CoQ biosynthesis by coupling ATP hydrolysis to the formation of a CoQ‐related metabolon and/or by the extraction of hydrophobic CoQ intermediates from the mitochondrial membrane.…”

Section: Finding Homes For the Orphansmentioning

confidence: 94%

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A path to the powerhouse: systems‐to‐structure approaches for studying mitochondrial proteins

Pagliarini

2018

Protein Science

Self Cite

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The young investigator award from the Protein Society was a special honor for me because, at its essence, the goal of my laboratory is to define what obscure proteins do. Years ago, I stumbled into mitochondria as a venue for this work, and these organelles continue to define the biological theme of my laboratory. Our approaches are fairly broad, reflecting my own somewhat unorthodox training among diverse scientific fields spanning organic synthesis, chemical biology, mechanistic biochemistry, signal transduction, and systems biology. Yet, whatever the theme or the discipline, we aim to understand how proteins work-especially those that hide in the dark corners of mitochondria. Below, I recount my own path into this arena of protein science, and describe how my experiences along the way have shaped our current multi-disciplinary efforts to define the inner workings of this complex biological system.

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Section: Structural Genomicsmentioning

confidence: 88%

Section: Finding Homes For the Orphansmentioning

confidence: 90%

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A path to the powerhouse: systems‐to‐structure approaches for studying mitochondrial proteins

Pagliarini

2018

Protein Science

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“…Recent studies have revealed that ADCK3 lacks canonical protein kinase activity in the trans form; instead, it binds to lipid CoQ 10 intermediates and exhibits ATPase activity(Reidenbach, Kemmerer et al, 2018, Stefely et al, 2016). In the present study, GO analysis also revealed that interactors of ADCK4, especially in the mitochondria, are significantly associated with oxidoreductase activity, which can be related to the antioxidant property of CoQ 10 .…”

Section: Discussionmentioning

confidence: 99%

ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment

Widmeier

Nag³

et al. 2019

Preprint

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AbstractADCK4 mutations usually manifest as steroid-resistant nephrotic syndrome, and cause coenzyme Q10 (CoQ10) deficiency. However, the function of ADCK4 remains obscure. We investigated ADCK4 function using mouse and cell models. Podocyte-specific Adck4 deletion in mice significantly reduced survival and caused severe focal segmental glomerular sclerosis with extensive interstitial fibrosis and tubular atrophy, which were prevented by treatment with 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of CoQ10 precursor molecule. ADCK4 knockout podocytes exhibited significantly decreased CoQ10 level, respiratory chain activity, mitochondrial potential, and dysmorphic mitochondria with loss of cristae formation, which were rescued by 2,4-diHB treatment, thus attributing these phenotypes to decreased CoQ10 levels. ADCK4 interacted with mitochondrial proteins including COQ5, and also cytoplasmic proteins including myosin and heat shock proteins. ADCK4 knockout decreased COQ complex levels, and the COQ5 level was rescued by ADCK4 overexpression in ADCK4 knockout podocytes. Overall, ADCK4 is required for CoQ10 biosynthesis and mitochondrial function in podocytes.

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“…This observation has prompted speculation that Coq10 acts as a Q 6 chaperone protein required for delivery of Q 6 from its synthesis site to sites where Q 6 functions as an antioxidant and to the respiratory complexes, thereby bridging efficient de novo Q 6 biosynthesis with respiration (17). Recent studies have shown a spatial compartmentalization of the mitochondrial inner membrane with the identification of different sites, such as the inner boundary membrane, the cristae membrane, and the ER-mitochondrial contact sites (22)(23)(24)(25). Thus, for optimal respiratory competence, newly synthesized Q 6 must move from its site of synthesis (i.e.…”

mentioning

confidence: 99%

COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10

Bradley¹,

Yang²,

Fernández-del-Rio³

et al. 2020

Journal of Biological Chemistry

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Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because “fused” proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.

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Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family

Cited by 64 publications

References 88 publications

A path to the powerhouse: systems‐to‐structure approaches for studying mitochondrial proteins

A path to the powerhouse: systems‐to‐structure approaches for studying mitochondrial proteins

ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment

COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10

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