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An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis.

ABSTRACT: Coenzyme Q (Q) is a key lipid electron transporter, but several aspects of its biosynthesis and redox homeostasis remain undefined. Various flavoproteins reduce ubiquinone (oxidized form of Q) to ubiquinol (QH₂); however, in eukaryotes, only oxidative phosphorylation (OXPHOS) complex III (CIII) oxidizes QH₂ to Q. The mechanism of action of CIII is still debated. Herein, we show that the Q reductase electron-transfer flavoprotein dehydrogenase (ETFDH) is essential for CIII activity in skeletal muscle. We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production. This metabolon maintains total Q levels, minimizes QH₂-reductive stress and improves OXPHOS efficiency. Muscle-specific Etfdh^-/- mice develop myopathy due to CIII dysfunction, indicating that ETFDH is a required OXPHOS component and a potential therapeutic target for mitochondrial redox medicine.

SUBMITTER: Herrero Martin JC

PROVIDER: S-EPMC10896730 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis.

Herrero Martín Juan Cruz JC Salegi Ansa Beñat B Álvarez-Rivera Gerardo G Domínguez-Zorita Sonia S Rodríguez-Pombo Pilar P Pérez Belén B Calvo Enrique E Paradela Alberto A Miguez David G DG Cifuentes Alejandro A Cuezva José M JM Formentini Laura L

Nature metabolism 20240119 2

Coenzyme Q (Q) is a key lipid electron transporter, but several aspects of its biosynthesis and redox homeostasis remain undefined. Various flavoproteins reduce ubiquinone (oxidized form of Q) to ubiquinol (QH<sub>2</sub>); however, in eukaryotes, only oxidative phosphorylation (OXPHOS) complex III (CIII) oxidizes QH<sub>2</sub> to Q. The mechanism of action of CIII is still debated. Herein, we show that the Q reductase electron-transfer flavoprotein dehydrogenase (ETFDH) is essential for CIII a ...[more]

PMID: 38243131

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Project description:Mitochondria are organelles in most human cells which release the energy required for cells to function. Oxidative phosphorylation (OXPHOS) is a key biochemical process within mitochondria required for energy production and requires a range of proteins and protein complexes. Mitochondria contain multiple copies of their own genome (mtDNA), which codes for some of the proteins and ribonucleic acids required for mitochondrial function and assembly. Pathology arises from genetic defects in mtDNA and can reduce cellular abundance of OXPHOS proteins, affecting mitochondrial function. Due to the continuous turn-over of mtDNA, pathology is random and neighbouring cells can possess different OXPHOS protein abundance. Estimating the proportion of cells where OXPHOS protein abundance is too low to maintain normal function is critical to understanding disease severity and predicting disease progression. Currently, one method to classify single cells as being OXPHOS deficient is prevalent in the literature. The method compares a patient's OXPHOS protein abundance to that of a small number of healthy control subjects. If the patient's cell displays an abundance which differs from the abundance of the controls then it is deemed deficient. However, due to the natural variation between subjects and the low number of control subjects typically available, this method is inflexible and often results in a large proportion of patient cells being misclassified. These misclassifications have significant consequences for the clinical interpretation of these data. We propose a single-cell classification method using a Bayesian hierarchical mixture model, which allows for inter-subject OXPHOS protein abundance variation. The model accurately classifies an example dataset of OXPHOS protein abundances in skeletal muscle fibres (myofibres). When comparing the proposed and existing model classifications to manual classifications performed by experts, the proposed model results in estimates of the proportion of deficient myofibres that are consistent with expert manual classifications.

Dataset Information

An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis.

Publications

An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis.

Similar Datasets

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