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

Abstract

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.