Hallmarks of a new era in mitochondrial biochemistry

Pagliarini, David J.; Rutter, Jared

doi:10.1101/gad.229724.113

Cited by 163 publications

(135 citation statements)

References 124 publications

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“…The discovery of CoQ completed the final missing piece of the electron transport chain (ETC) machinery postulated by Warburg and Keilin (13). Following its isolation by Crane and Green in the 1950s, CoQ was established as a requisite gateway for electrons passing from CI and CII to CIII in the ETC, and has also been linked to other key antioxidant and electron transfer functions in membranes throughout the cell (40,41).…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis

Lohman¹,

Forouhar

Beebe

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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116

144

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Coenzyme Q (CoQ) is an isoprenylated quinone that is essential for cellular respiration and is synthesized in mitochondria by the combined action of at least nine proteins (COQ1-9). Although most COQ proteins are known to catalyze modifications to CoQ precursors, the biochemical role of COQ9 remains unclear. Here, we report that a disease-related COQ9 mutation leads to extensive disruption of the CoQ protein biosynthetic complex in a mouse model, and that COQ9 specifically interacts with COQ7 through a series of conserved residues. Toward understanding how COQ9 can perform these functions, we solved the crystal structure of Homo sapiens COQ9 at 2.4 Å. Unexpectedly, our structure reveals that COQ9 has structural homology to the TFR family of bacterial transcriptional regulators, but that it adopts an atypical TFR dimer orientation and is not predicted to bind DNA. Our structure also reveals a lipid-binding site, and mass spectrometry-based analyses of purified COQ9 demonstrate that it associates with multiple lipid species, including CoQ itself. The conserved COQ9 residues necessary for its interaction with COQ7 comprise a surface patch around the lipid-binding site, suggesting that COQ9 might serve to present its bound lipid to COQ7. Collectively, our data define COQ9 as the first, to our knowledge, mammalian TFR structural homolog and suggest that its lipid-binding capacity and association with COQ7 are key features for enabling CoQ biosynthesis.biquinone, also known as coenzyme Q (CoQ), is a lipophilic, redox-active small molecule that is present in nearly every cellular membrane. CoQ is a critical component of the mitochondrial electron transport chain where it shuttles electrons from complexes I and II to complex III. In addition to its vital role in cellular respiration, CoQ is instrumental in cellular antioxidation, extracellular electron transport, and membrane rigidity (1).The de novo biosynthesis of CoQ in eukaryotes takes place in the mitochondrial matrix via the collective action of at least 10 proteins (COQ1-10; Fig. S1) (2). Mutations in these proteins can cause primary CoQ deficiency-a condition associated with cerebellar ataxia, kidney disease, isolated myopathy, and severe childhood-onset multisystemic disorders (3, 4). Alteration in CoQ levels has also been associated with significant life span extensions in organisms ranging from Saccharomyces cerevisiae to mice (5-7). In S. cerevisiae (2, 8, 9), and potentially in higher eukaryotes (10, 11), most of the COQ proteins form a biosynthetic complex on the matrix face of the inner mitochondrial membrane. Although the majority of these proteins catalyze chemical modifications to CoQ precursors, the biochemical functions for COQ4, 8, and 9 have yet to be elucidated (8, 12, 13). Recently, García-Corzo et al. developed a mouse harboring a truncated version of Coq9 (Coq9 R239X)-modeled after a similar mutation observed in a human patient-that causes an encephalomyopathy associated with CoQ deficiency (11,14). A hallmark feature of these mice is a decreas...

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Section: Discussionmentioning

confidence: 99%

“…In S. cerevisiae (2,8,9), and potentially in higher eukaryotes (10,11), most of the COQ proteins form a biosynthetic complex on the matrix face of the inner mitochondrial membrane. Although the majority of these proteins catalyze chemical modifications to CoQ precursors, the biochemical functions for COQ4, 8, and 9 have yet to be elucidated (8,12,13).…”

mentioning

confidence: 99%

Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis

Lohman¹,

Forouhar

Beebe

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

116

144

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“…Mitochondria are dynamic organelles involved in a wide range of processes, such as ATP generation, cell death, immune signaling, chemotaxis, and calcium homeostasis (48). These organelles also play a central role in phospholipid metabolism and lipid exchange with the ER (49,50). Many intracellular pathogens, including T. gondii, have evolved to manipulate the surveillance or bioenergetic pathways of host mitochondria for their benefit (51-54).…”

Section: Resultsmentioning

confidence: 99%

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

et al. 2015

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Toxoplasma gondii and Neospora caninum, which cause the diseases toxoplasmosis and neosporosis, respectively, are two closely related apicomplexan parasites. They have similar heteroxenous life cycles and conserved genomes and share many metabolic features. Despite these similarities, T. gondii and N. caninum differ in their transmission strategies and zoonotic potential. Comparative analyses of the two parasites are important to identify the unique biological features that underlie the basis of host preference and pathogenicity. T. gondii and N. caninum are obligate intravacuolar parasites; in contrast to T. gondii, events that occur during N. caninum infection remain largely uncharacterized. We examined the capability of N. caninum (Liverpool isolate) to interact with host organelles and scavenge nutrients in comparison to that of T. gondii (RH strain). N. caninum reorganizes the host microtubular cytoskeleton and attracts endoplasmic reticulum (ER), mitochondria, lysosomes, multivesicular bodies, and Golgi vesicles to its vacuole though with some notable differences from T. gondii. For example, the host ER gathers around the N. caninum parasitophorous vacuole (PV) but does not physically associate with the vacuolar membrane; the host Golgi apparatus surrounds the N. caninum PV but does not fragment into ministacks. N. caninum relies on plasma lipoproteins and scavenges cholesterol from NPC1-containing endocytic organelles. This parasite salvages sphingolipids from host Golgi Rab14 vesicles that it sequesters into its vacuole. Our data highlight a remarkable degree of conservation in the intracellular infection program of N. caninum and T. gondii. The minor differences between the two parasites related to the recruitment and rearrangement of host organelles around their vacuoles likely reflect divergent evolutionary paths.

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“…This mitochondrial respiratory chain pathway consists of 89 proteins that form five multisubunit OxPhos enzyme complexes imbedded in the inner mitochondrial membrane (Hatefi 1985;Smeitink et al, 2001;Pagliarini and Rutter 2013). During OxPhos, complexes I and II accept reduction equivalents from NADH and FADH 2 respectively, and energy harvested from electron transfer drives respiratory complexes I, III, and IV to pump protons into the mitochondrial intermembrane space.…”

Section: Introductionmentioning

confidence: 99%

Effects of Anthropogenic Pollution on the Oxidative Phosphorylation Pathway of Hepatocytes from Natural Populations of Fundulus heteroclitus

Crawford

Oleksiak

2015

Aquatic Toxicology

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Hallmarks of a new era in mitochondrial biochemistry

Cited by 163 publications

References 124 publications

Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis

Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

Effects of Anthropogenic Pollution on the Oxidative Phosphorylation Pathway of Hepatocytes from Natural Populations of Fundulus heteroclitus

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