UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae

Kemmerer, Zachary A.; Robinson, Kyle; Schmitz, Jonathan M.; Manicki, Mateusz; Paulson, Brett R.; Jochem, Adam; Hutchins, Paul D.; Coon, Joshua J.; Pagliarini, David J.

doi:10.1038/s41467-021-25084-7

Cited by 33 publications

(52 citation statements)

References 67 publications

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“…How CoQ is mobilized from its site of synthesis on the inner mitochondrial membrane to other action sites remains a longstanding mystery. Recently, two highly conserved but poorly characterized mitochondrial proteins, Ypl109c (Cqd1) and Ylr253w (Cqd2), which affected this process in yeast, were identified [ 159 ].…”

Section: Mitochondrial Antioxidant Systemmentioning

confidence: 99%

Mitochondrial Management of Reactive Oxygen Species

Napolitano

Fasciolo²,

Venditti³

2021

Antioxidants

100

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Mitochondria in aerobic eukaryotic cells are both the site of energy production and the formation of harmful species, such as radicals and other reactive oxygen species, known as ROS. They contain an efficient antioxidant system, including low-molecular-mass molecules and enzymes that specialize in removing various types of ROS or repairing the oxidative damage of biological molecules. Under normal conditions, ROS production is low, and mitochondria, which are their primary target, are slightly damaged in a similar way to other cellular compartments, since the ROS released by the mitochondria into the cytosol are negligible. As the mitochondrial generation of ROS increases, they can deactivate components of the respiratory chain and enzymes of the Krebs cycle, and mitochondria release a high amount of ROS that damage cellular structures. More recently, the feature of the mitochondrial antioxidant system, which does not specifically deal with intramitochondrial ROS, was discovered. Indeed, the mitochondrial antioxidant system detoxifies exogenous ROS species at the expense of reducing the equivalents generated in mitochondria. Thus, mitochondria are also a sink of ROS. These observations highlight the importance of the mitochondrial antioxidant system, which should be considered in our understanding of ROS-regulated processes. These processes include cell signaling and the progression of metabolic and neurodegenerative disease.

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Section: Mitochondrial Antioxidant Systemmentioning

confidence: 99%

Mitochondrial Management of Reactive Oxygen Species

Napolitano

Fasciolo²,

Venditti³

2021

Antioxidants

100

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“…In eukaryotes, the COQ8 proteins are likely ATPases required for CoQ biosynthesis; however, specifics regarding how this activity is coupled to CoQ production remain unknown 21 . More recently, the yeast intermembrane space UbiB proteins were connected to CoQ distribution throughout the cell, but their precise mechanism of action also remains to be determined 49 . Here we have begun to understand how the activity of these proteins is modified by CoQ precursor mimetics at a structural level.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Modulation of the Archetypal UbiB protein COQ8

Murray

Lewis

Asquith

et al. 2022

Preprint

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Small molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize inhibitor and activator molecules for the archetypal UbiB member, COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays, and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Second, using 1H-13C HMQC NMR and hydrogen-deuterium exchange mass spectrometry, we reveal that the CoQ precursor mimetic, 2-propylphenol (2-PP), modulates the quintessential UbiB KxGQ domain to increase COQ8A nucleotide affinity and ATPase activity. Our newfound chemical tools promise to lend new mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction.

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“…Recently, in the group of Pagliarini, two proteins were identified, named Cqd1 and Cqd2, located in the inner mitochondrial membrane and involved in ubiquinone trafficking. Loss of Cqd1 favors the extramitochondrial distribution of CoQ leading to a CoQ deficient syndrome, even if the total amount of CoQ remains unchanged [ 37 ].…”

Section: Ubiquinone/coenzyme Q Biosynthesismentioning

confidence: 99%

The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions

Pallotti

Bergamini

Lamperti

et al. 2021

IJMS

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Coenzyme Q (CoQ) is a key component of the respiratory chain of all eukaryotic cells. Its function is closely related to mitochondrial respiration, where it acts as an electron transporter. However, the cellular functions of coenzyme Q are multiple: it is present in all cell membranes, limiting the toxic effect of free radicals, it is a component of LDL, it is involved in the aging process, and its deficiency is linked to several diseases. Recently, it has been proposed that coenzyme Q contributes to suppressing ferroptosis, a type of iron-dependent programmed cell death characterized by lipid peroxidation. In this review, we report the latest hypotheses and theories analyzing the multiple functions of coenzyme Q. The complete knowledge of the various cellular CoQ functions is essential to provide a rational basis for its possible therapeutic use, not only in diseases characterized by primary CoQ deficiency, but also in large number of diseases in which its secondary deficiency has been found.

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UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae

Cited by 33 publications

References 67 publications

Mitochondrial Management of Reactive Oxygen Species

Mitochondrial Management of Reactive Oxygen Species

Small Molecule Modulation of the Archetypal UbiB protein COQ8

The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions

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