Scheepers, R. | bioRxiv Science

bioRxiv2024

A distributed integral control mechanism for the regulation of cholesterol concentration in the human retina.

Tight homeostatic control of cholesterol concentration within the complex tissue microenvironment of the retina is a hallmark of the healthy eye. By contrast, dysregulation of the biochemical mechanisms governing retinal cholesterol homeostasis is thought to be a major contributor to the aetiology and progression of age-related macular degeneration (AMD) in the ageing human eye. Although the signalling mechanisms that contribute to cholesterol homeostasis at the cellular level have been studied extensively, there is currently no systems-level description of the molecular interactions that could explain cholesterol homeostasis at the level of the human retina. Here were provide a comprehensive overview of all currently-known molecular-level interactions involved in the regulation of cholesterol across all major compartments of the human retina, encompassing the retinal pigment epithelium (RPE), the photoreceptor cell layer, the Muller cell layer, and Bruchs membrane. We develop a detailed chemical reaction network (CRN) of this complex collection of biochemical interactions, comprising seventy-one (71) molecular species, which we show may be partitioned into ten (10) independent subnetworks. These ten subnetworks work together to confer robust homeostasis on thirteen different forms of cholesterol distributed through distinct cellular compartments of the retina. Remarkably, we provide compelling evidence that three independent antithetic integral controllers are responsible for the tight regulation of endoplasmic reticulum (ER) cholesterol in retinal cells, and that several additional independent mechanisms transfer this homeostatic property to other forms of cholesterol throughout the human retina. Our novel and exquisitely detailed mathematical description of retinal cholesterol regulation provides a framework for considering potential mechanisms of cholesterol dysregulation in the diseased eye, and for the study of potential therapeutic strategies against these pathologies.

systems biology↗

bioRxiv2023

Robust Homeostasis of Cellular Cholesterol via Antithetic Integral Control

Although cholesterol is essential for cellular viability and proliferation, it is highly toxic in excess. The concentration of cellular cholesterol must therefore be maintained within tight tolerances, and is thought to be subject to a stringent form of homeostasis known as Robust Perfect Adaptation (RPA). While much is known about the cellular signalling interactions involved in cholesterol regulation, the specific chemical reaction network structures that might be responsible for the robust homeostatic regulation of cellular cholesterol have been entirely unclear until now. In particular, the molecular mechanisms responsible for sensing excess whole-cell cholesterol levels have not been identified previously, and no mathematical models to date have been able to capture an integral control implementation that could impose RPA on cellular cholesterol. Here we provide a detailed mathematical description of cholesterol regulation pathways in terms of biochemical reactions, based on an extensive review of experimental and clinical literature. We are able to decompose the associated chemical reaction network structures into several independent subnetworks, one of which is responsible for conferring RPA on several intracellular forms of cholesterol. Remarkably, our analysis reveals that RPA in the cholesterol concentration in the endoplasmic reticulum (ER) is almost certainly due to a well-characterised control strategy known as antithetic integral control which, in this case, involves the high-affinity binding of a multi-molecular transcription factor complex with cholesterol molecules that are excluded from the ER membrane. Our model provides a detailed framework for exploring the necessary biochemical conditions for robust homeostatic control of essential and tightly regulated cellular molecules such as cholesterol.

biochemistry↗