When enzymes join forces: unmasking a mitochondrial biosynthetic engine

Informazioni relative al progetto

MetaQ

ID dell’accordo di sovvenzione: 101094471

DOI

10.3030/101094471

Data della firma CE 2 Maggio 2023

Data di avvio 1 Ottobre 2023

Data di completamento 30 Settembre 2028

Finanziato da

• European Research Council (ERC)

Costo totale

€ 2 107 750,00

Contributo UE

€ 2 107 750,00

Coordinato da

UNIVERSITA DEGLI STUDI DI PAVIA
Italy

Periodic Reporting for period 1 - MetaQ (When enzymes join forces: unmasking a mitochondrial biosynthetic engine)

Periodo di rendicontazione: 2023-10-01 al 2026-03-31

Sintesi del contesto e degli obiettivi generali del progetto

Life would not be sustainable in the absence of enzymes. These biological catalysts underpin every chemical transformation required for the maintenance and propagation of living systems. Within the cellular milieu, an immense network of biochemical reactions generates the molecules essential for structure, energy production, and regulation. Each of these reactions depends on enzymes to proceed at rates compatible with life, as the uncatalyzed processes would occur too slowly to meet physiological demands. Enzymes function by stabilizing transition states and reducing activation energies, thereby accelerating reaction rates by several orders of magnitude. Through these mechanisms, they facilitate processes fundamental to existence, including respiration, digestion, biosynthesis, and cellular signalling. Advances in molecular imaging, structural biology, and systems-level modelling now provide unprecedented opportunities to elucidate how enzymes achieve such precise coordination at the molecular level.
The MetaQ project addresses these questions through the investigation of coenzyme Q (ubiquinone), a lipid-soluble redox-active molecule that plays a pivotal role in cellular metabolism. While coenzyme Q is widely recognized in commercial contexts, particularly in cosmetic and nutraceutical formulations, it is fundamentally a ubiquitous and indispensable component of biological systems. It functions as an essential electron carrier within the mitochondrial respiratory chain, enabling ATP production through oxidative phosphorylation. In addition, coenzyme Q acts as a potent antioxidant, protecting cellular membranes from oxidative stress. Perturbations in its biosynthetic pathway or cellular distribution have been implicated in a variety of pathological conditions, including neurodegenerative diseases, mitochondrial disorders, and cardiovascular dysfunctions. Given its biochemical complexity, essential physiological functions, and clinical relevance, the biosynthesis of coenzyme Q constitutes an exemplary model for investigating the spatial and temporal coordination of enzymatic processes. The MetaQ project aims to answer key mechanistic questions: How do enzymes within this pathway ensure efficient substrate channelling and minimize metabolic leakage? What molecular interactions prevent premature degradation of intermediates? And by what principles are specific enzymes selectively recruited to distinct metabolic networks?

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Since its launch in October 2023, the MetaQ project has achieved significant advances in the understanding of coenzyme Q (CoQ) biosynthesis within human cells. The research has uncovered several previously uncharacterized chemical steps in the CoQ biosynthetic pathway, representing a fundamental breakthrough in mitochondrial biochemistry. These discoveries have filled long-standing gaps in the mapping of this essential metabolic process, providing a more comprehensive view of how cells produce and regulate one of their most critical molecular components. A major outcome of the project has been the discovery of how the enzymes responsible for CoQ biosynthesis do not operate as isolated entities dispersed throughout the cellular environment. Instead, they assemble into a dynamic and loosely organized multi-enzyme complex that functions analogously to a molecular factory. Within this assembly, each enzyme performs its specific catalytic step in a defined sequence, thereby enabling a highly efficient handover of intermediate metabolites. This organization minimizes the diffusion and potential accumulation of unstable or reactive intermediates, many of which could otherwise exert cytotoxic effects. Such spatial and temporal coordination ensures both the fidelity and the safety of this vital metabolic pathway.
These findings challenge the traditional perception of the cell as a homogeneous “soup of enzymes,” in which each catalytic protein functions independently. Instead, MetaQ has provided compelling evidence that metabolic processes are governed by higher-order organizational principles. Enzymes can physically associate, co-localize within subcellular domains, and coordinate their activities to achieve enhanced catalytic efficiency while minimizing wasteful or deleterious by-products. This concept offers important insights into how cellular metabolism attains both precision and adaptability, even under fluctuating physiological conditions. The results being obtained are also demonstrating that this fundamental knowledge on biochemical processes can advance the discovery of drugs and therapeutics. Using modern AI-based computational tools, our data have enabled the discovery of molecules able to interfere with coenzyme Q metabolism and a potential beneficial effect to halt tumour cells propagation.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Despite their centrality to life, the mechanisms by which enzymes coordinate their activities within the highly organized and crowded environment of the cell remain incompletely understood. Metabolic pathways typically consist of multiple enzymes that must operate in a defined temporal and spatial sequence to ensure efficient flux through the pathway. For these systems to function optimally, enzymes must exchange intermediates rapidly and specifically, minimizing the loss or degradation of reaction products and avoiding interference from competing pathways. The next phase of the MetaQ project focuses on developing and applying advanced experimental methodologies to characterize the structural and functional dynamics of enzymes’s coordinated functions. These include state-of-the-art imaging, proximity-labelling, and proteomic approaches aimed at elucidating how the enzymes associate, how their interactions are regulated, and how their spatial proximity influences overall pathway performance. By dissecting the molecular organization and regulatory dynamics underlying coenzyme Q biosynthesis, MetaQ seeks to uncover generalizable principles governing enzymatic cooperation within cells. Insights derived from this research are expected to contribute not only to fundamental biochemistry but also to applied fields such as metabolic engineering, synthetic biology, and drug and therapeutic design. Through understanding how enzymatic systems orchestrate their activities with such precision, the project aspires to deepen our comprehension of life’s molecular architecture.

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