About

Catherine F. Clarke joined the Department of Chemistry and Biochemistry at UCLA in 1993. Her research focuses on how cells synthesize coenzyme Q, also known as ubiquinone, which functions as a redox-active coenzyme in mitochondrial and plasma membrane electron transport, as well as an essential lipid-soluble antioxidant. She studies the biosynthesis, transport, regulation, and enzymology of coenzyme Q, aiming to characterize the polypeptides involved and how their activity can be modulated for health benefits. Her work has identified eight of the eleven polypeptides required for Q biosynthesis and has contributed to understanding the pathways and mechanisms underlying Q production, including a newly discovered biosynthetic pathway involving para-aminobenzoic acid (pABA). Clarke's research also explores the impact of Q deficiency on diseases, the role of Q as an antioxidant, and the effects of dietary and environmental factors on longevity and aging. In 2016, she became the first woman to lead the UCLA Department of Chemistry and Biochemistry, and in 2019, she was appointed Dean of Special Projects in the UCLA Division of Physical Sciences.

Research topics

• Biochemistry
• Biology
• Chemistry

Selected publications

• Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q

  Contact · 2025-01-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  Coenzyme Q (CoQ) is an essential redox-active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. In Saccharomyces cerevisiae (yeast), CoQ biosynthesis occurs exclusively in the mitochondrial matrix via a large protein-lipid complex, the CoQ synthome, comprised of CoQ itself, late-stage CoQ-intermediates, and the polypeptides Coq3-Coq9 and Coq11. Coq11 is suggested to act as a negative modulator of CoQ synthome assembly and CoQ synthesis, as its deletion enhances Coq polypeptide content, produces an enlarged CoQ synthome, and restores respiration in mutants lacking the CoQ chaperone polypeptide, Coq10. The CoQ synthome resides in specific niches within the inner mitochondrial membrane, termed CoQ domains, that are often located adjacent to the endoplasmic reticulum-mitochondria encounter structure (ERMES). Loss of ERMES destabilizes the CoQ synthome and renders CoQ biosynthesis less efficient. Here we show that deletion of COQ11 suppresses the respiratory deficient phenotype of select ERMES mutants, results in repair and reorganization of the CoQ synthome, and enhances mitochondrial CoQ domains. Given that ER-mitochondrial contact sites coordinate CoQ biosynthesis, we used a Split-MAM (Mitochondrial Associated Membrane) artificial tether consisting of an ER-mitochondrial contact site reporter, to evaluate the effects of artificial membrane tethers on CoQ biosynthesis in both wild-type and ERMES mutant yeast strains. Overall, this work identifies the deletion of COQ11 as a novel suppressor of phenotypes associated with ERMES deletion mutants and indicates that ER-mitochondria tethers influence CoQ content and turnover, highlighting the role of membrane contact sites in regulating mitochondrial respiratory homeostasis.

  PublisherDOI

• Abstract 2641 An enzymology approach to understanding CoQ deficiency: unraveling the structure-function relationship of COQ5

  Journal of Biological Chemistry · 2025-05-01

  articleOpen accessSenior author

  Coenzyme Q (CoQ) is an essential lipid that functions as an electron carrier in the mitochondrial electron transport chain. In its reduced form (CoQH2), it can also act as a chain-terminating antioxidant providing protection against lipid peroxidation and ferroptosis. Genetic defects in the CoQ biosynthetic pathway in humans can cause a wide array of illnesses, including cardiovascular, kidney, and neurodegenerative disorders, through a condition known as primary CoQ deficiency. We focus on COQ5, a gene encoding an S-adenosylmethionine (AdoMet)-dependent C-methyltransferase in the CoQ biosynthetic pathway.

  PublisherOA PDFDOI

• Abstract 2384 Active Site Residues of Coq11, an Atypical Short-Chain Dehydrogenase/Reductase, are Essential for Efficient Coenzyme Q Biosynthesis

  Journal of Biological Chemistry · 2025-05-01

  articleOpen accessSenior author

  Coenzyme Q (CoQ or ubiquinone) is a redox-active lipid molecule that acts as an electron carrier in the mitochondrial electron transport chain, aiding in energy metabolism. CoQ is synthesized in the mitochondrial matrix by a multi-subunit, high-molecular-mass protein-lipid complex termed the CoQ Synthome in Saccharomyces cerevisiae (yeast). Recently, the polypeptide Coq11 was identified as a novel member of the yeast CoQ Synthome. Deletion of COQ11 has been shown to significantly reduce, but not abolish, de novo CoQ biosynthesis.

  PublisherOA PDFDOI

• Nonfunctional coq10 mutants maintain the ERMES complex and reveal true phenotypes associated with the loss of the coenzyme Q chaperone protein Coq10

  Journal of Biological Chemistry · 2024-09-27 · 4 citations

  articleOpen accessSenior author

  Coenzyme Q (CoQ) is a redox-active lipid molecule that acts as an electron carrier in the mitochondrial electron transport chain. In Saccharomyces cerevisiae, CoQ is synthesized in the mitochondrial matrix by a multisubunit protein-lipid complex termed the CoQ synthome, the spatial positioning of which is coordinated by the endoplasmic reticulum-mitochondria encounter structure (ERMES). The MDM12 gene encoding the cytosolic subunit of ERMES is coexpressed with COQ10, which encodes the putative CoQ chaperone Coq10, via a shared bidirectional promoter. Deletion of COQ10 results in respiratory deficiency, impaired CoQ biosynthesis, and reduced spatial coordination between ERMES and the CoQ synthome. While Coq10 protein content is maintained upon deletion of MDM12, we show that deletion of COQ10 by replacement with a HIS3 marker results in diminished Mdm12 protein content. Since deletion of individual ERMES subunits prevents ERMES formation, we asked whether some or all of the phenotypes associated with COQ10 deletion result from ERMES dysfunction. To identify the phenotypes resulting solely due to the loss of Coq10, we constructed strains expressing a functionally impaired (coq10-L96S) or truncated (coq10-R147∗) Coq10 isoform using CRISPR-Cas9. We show that both coq10 mutants preserve Mdm12 protein content and exhibit impaired respiratory capacity like the coq10Δ mutant, indicating that Coq10's function is vital for respiration regardless of ERMES integrity. Moreover, the maintenance of CoQ synthome stability and efficient CoQ biosynthesis observed for the coq10-R147∗ mutant suggests these deleterious phenotypes in the coq10Δ mutant result from ERMES disruption. Overall, this study clarifies the role of Coq10 in modulating CoQ biosynthesis.

  PublisherOA PDFDOI

• Resurrecting an ancient coenzyme Q metabolon

  Nature Catalysis · 2024-02-27

  articleSenior author
  PublisherDOI

• Abstract 2648: Can we predict coenzyme Q deficiency in patients? The case of COQ5, a C-methyltransferase in coenzyme Q biosynthesis

  Journal of Biological Chemistry · 2023-01-01

  articleOpen accessSenior author
  PublisherDOI

• New Insights on the Uptake and Trafficking of Coenzyme Q

  Antioxidants · 2023-07-06 · 16 citations

  reviewOpen accessSenior authorCorresponding

  Coenzyme Q (CoQ) is an essential lipid with many cellular functions, such as electron transport for cellular respiration, antioxidant protection, redox homeostasis, and ferroptosis suppression. Deficiencies in CoQ due to aging, genetic disease, or medication can be ameliorated by high-dose supplementation. As such, an understanding of the uptake and transport of CoQ may inform methods of clinical use and identify how to better treat deficiency. Here, we review what is known about the cellular uptake and intracellular distribution of CoQ from yeast, mammalian cell culture, and rodent models, as well as its absorption at the organism level. We discuss the use of these model organisms to probe the mechanisms of uptake and distribution. The literature indicates that CoQ uptake and distribution are multifaceted processes likely to have redundancies in its transport, utilizing the endomembrane system and newly identified proteins that function as lipid transporters. Impairment of the trafficking of either endogenous or exogenous CoQ exerts profound effects on metabolism and stress response. This review also highlights significant gaps in our knowledge of how CoQ is distributed within the cell and suggests future directions of research to better understand this process.

  PublisherOA PDFDOI

• Carbonyl Post-Translational Modification Associated with Early Onset Type 1 Diabetes Autoimmunity

  2022-06-22

  preprintOpen access

  <p>Inflammation and oxidative stress in pancreatic islets amplify the appearance of various post-translational modifications (PTMs) to self-proteins. Herein, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in non-obese diabetic mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase beta subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found the carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin to insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes. </p>

  PublisherDOI

• Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity

  Diabetes · 2022-06-22 · 25 citations

  articleOpen access

  Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.

  PublisherOA PDFDOI

• Respiratory defects caused by mutations affecting the Endoplasmic Reticulum‐Mitochondria Encounter Structure (ERMES) can be rescued by the deletion of <i>COQ11</i>

  The FASEB Journal · 2022-05-01

  articleSenior author

  Coenzyme Q (CoQ) is an essential redox‐active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. Deficiency of CoQ causes a wide range of clinical deficiencies, highlighting the need to study the biosynthesis of this lipid to design therapeutics to treat these symptoms. In Saccharomyces cerevisiae , CoQ biosynthesis takes place exclusively in the mitochondrial matrix using a multi‐subunit protein‐lipid complex, the CoQ Synthome, that includes the polypeptides Coq3‐Coq9 and Coq11. A recently identified regulator of CoQ Synthome assembly and CoQ production is the ER‐mitochondria encounter structure (ERMES). ERMES is a tethering complex that bridges the ER and mitochondria, and the CoQ Synthome resides in specific membrane niches or domains directly adjacent to this complex. Loss of ERMES results in transcriptionally upregulated expression of COQ genes, yet inefficient synthesis of CoQ due to a destabilized CoQ Synthome. In this work, ERMESΔcoq11Δ mutants have been generated in an effort to correct this defect. Deletion of COQ11 has been shown to promote mitochondrial CoQ content, enhance CoQ Synthome stability, and rescue the respiratory deficiency of the coq10Δ mutant. We seek to investigate the functional roles of Coq11 and ERMES to better understand the regulation of CoQ biosynthesis and aid in the development of more effective therapeutics for diseases linked to CoQ deficiencies.

  PublisherDOI

Recent grants

• NIH Grant R01GM045952

  NIH · $4.6M · 2011

• Metabolism of Aromatic Ring Precursors in Coenzyme Q Biosynthesis

  NSF · $645k · 2009–2014

• NIH Grant R03AG018085

  NIH · $77k · 2002

• Metabolism of Aromatic Ring Precursors in Coenzyme Q Biosynthesis

  NSF · $833k · 2013–2018

• NIH Grant R25GM055052

  NIH · $10.7M · 2023

Frequent coauthors

• Beth N. Marbois

  33 shared

• Tanya Jonassen

  University of California, Los Angeles

  20 shared

• Carlos Santos‐Ocaña

  Instituto de Salud Carlos III

  19 shared

• Lucía Fernández-del-Río

  19 shared

• Plácido Navas

  Centre for Biomedical Network Research on Rare Diseases

  17 shared

• Letian X. Xie

  Xi’an Jiaotong-Liverpool University

  17 shared

• Hui S. Tsui

  15 shared

• Michelle C. Bradley

  University of California, Los Angeles

  14 shared

Education

• Postdoctoral Fellow, Molecular Biology

  Princeton University

• PhD, Biological Chemistry

  UCLA Graduate Medical Education

  1985

• B.S., Chemistry & Biochemistry

  UCLA Division of Physical Sciences

  1979

Awards & honors

• Ellison Medical Foundation Senior Scholar Award (2001)
• WHS Hall of Fame, Whittier High School (2018)
• BSF Research Grant Award (2019)
• Career Development Award (2021)