On the cutting edge: perspectives in bioenergetics

Abstract

The field of bioenergetics is rapidly expanding with new discoveries of mechanisms and potential therapeutic targets. The 2023 Keystone symposium on ‘Bioenergetics in Health and Disease’, which was jointly held with the symposium ‘Adipose Tissue: Energizing Good Fat’, consisted of a powerhouse line-up of researchers who shared their insights.

What do we think about when we think of bioenergetics? The truth is that there are many probable answers to this question. It concerns the way that our cells communicate both intrinsically and extrinsically, it governs the rhythm of our days and it is, at its core, critical to all facets of life itself. Over a week in January, researchers from all over the world gathered in Keystone, CO, USA, for the 2023 Keystone symposium on ‘Bioenergetics in Health and Disease’ to share their perspectives on what bioenergetics means to them. The organizers (Shingo Kajimura, Anna Krook and Jared Rutter) composed a multifaceted symposium, including sessions on metabolic flux, interorganelle communication, exercise physiology, circadian rhythms and many more. The conference was jointly held with a related Keystone symposium (‘Adipose Tissue: Energizing Good Fat’), organized by Silvia Corvera, Kendra Bence and Rana Gupta. The overarching goal of both meetings was similar: to address emerging questions in bioenergetics and adipose tissue, from the molecular to organismal level, in the context of metabolic diseases and in relation to human health. In addition to high-quality presentations in which speakers generously shared their latest research, the conference ran several workshops that were focused on early-career researchers and that covered topics including novel technologies and recent insights into bioenergetics, how to efficiently bridge basic and clinical science, and research career opportunities. The organizers and conference staff together succeeded not only in composing a scientifically rigorous programme, but also in providing an environment in which collaborations and new interactions were encouraged.

To holistically understand the determinants of health and mechanisms of metabolic disease, one must consider biological scale — ranging from the smallest of molecules to population-level dynamics. The first of two keynote addresses, given by Peter Tontonoz, focused on the molecular and cellular end of this spectrum, and discussed the mechanisms of cholesterol transport via crosstalk between the endoplasmic reticulum and plasma membrane. A particular focus was on the biological function of aster, a recently identified cholesterol carrier protein that is required for cholesterol transport across the plasma membrane to the endoplasmic reticulum¹. As hypercholesterolaemia is one of the most prevalent metabolic diseases and one for which only a few treatments exist, Tontonoz encouraged further critical thought regarding therapeutic avenues for cholesterol absorption. The second keynote address, by Joshua Joseph, examined metabolic disease from a different perspective by looking at the social determinants of health as risk factors for diseases such as obesity and diabetes mellitus, which disproportionately affect vulnerable communities. Joseph then explored cellular-level to systems-level mechanisms of psychosocial stress and their contributions to increases in risk factors for developing metabolic disease, and considered how these mechanisms are affected by the social determinants of health. A comprehensive understanding of these upstream and downstream elements of system complexity should be considered as we strive to create equitable health outcomes.

Metabolic flux is a critical avenue of research and is centred around the rate of turnover of molecules through a metabolic pathway, which was the key theme of the first session. As technologies are being improved, many novel methods to measure mechanisms of metabolic flux are emerging^2,3. Owing to these advances, new ideas about lactate flux, and the rebranding of lactate as not only a cellular waste product but also a major carbohydrate fuel, were spoken about at length. Lactate is abundantly shuttled through many metabolic pathways and research was presented that showed that lactate can directly influence mechanisms of cell-cycle progression and even act as a sensor for glycolytic flux. Similarly, researchers have used ¹³C-glucose labelling and pulse chase experiments to reveal that red muscle is a major site of whole-body glycolysis — one that secretes lactate to be used in whole-body energy homeostasis⁴. As some speakers highlighted, it is important to assess potential sex-specific, or even individual, differences in metabolic flux in both healthy and disease states, which is an active area of further investigation. As such, attendees were encouraged to creatively think about ways to assess how many metabolites might have roles beyond their currently known function.

Typically, we can think of metabolism as the study of how nutrients are broken down and subsequently used as fuel. Complementary to this idea, however, is the question of precisely how these nutrients are sensed in various cells, tissue types and disease states. AMP-activated protein kinase (AMPK) is a highly conserved sensor of intracellular levels of ATP that acts as a master regulator of whole-body energy homeostasis. Therefore, activation of AMPK has been suggested to be a potential therapeutic strategy for broadly promoting metabolic health⁵. The steps of ATP generation are obviously multifaceted and are highly dependent on the presence of NAD⁺. After the identification of SLC25A51 as the mitochondrial NAD⁺ transporter, the way in which mitochondria obtain NAD⁺ no longer remains a mystery and there is therapeutic potential for the many metabolic diseases in which NAD⁺ metabolism is dysfunctional⁶. However, critical questions remain as to how boosting levels of these essential energy molecules will translate into humans: for example, what the adverse effects (if any) will be of increasing the levels of these molecules that are involved in nearly every regulatory pathway within the cell, or whether there are high levels of individual variation in the response to therapeutic agents targeting these pathways. These questions and others merit extensive further analyses.

Bioenergetic mechanisms exist in harmony to maintain homeostasis within the cell; a careful investigation of these mechanisms is therefore necessary to understand their contributions to physiology, as well as how they might be used to mitigate metabolic disorders. As such, mechanisms of adaptive non-shivering thermogenesis were a highlight of the conference. Although UCP1 is the most well-characterized contributor to thermogenesis in adipose tissue, the existence of UCP1-independent mechanisms of thermogenesis has been sufficiently shown. For example, thermogenic adipose tissue has been shown to use substrates such as creatine to drive the futile cycling of substrates to promote non-shivering thermogenesis⁷. Furthermore, the futile creatine cycle has been shown to be regulated by coordinated α-adrenergic receptor and β₃-adrenergic receptor signalling⁸. In beige adipose tissue, calcium cycling (that is, the process of futile cycling of Ca²⁺ ions from the endoplasmic reticulum) has been shown to contribute to whole-body energy homeostasis through the ATP-dependent SERCA2b Ca²⁺ pump⁹. An active area of ongoing investigation is centred around understanding the mechanisms of how agonism of the glucagon-like peptide 1 receptor (GLP1R) can serve as a treatment for type 2 diabetes mellitus by improving insulin sensitivity and promoting weight loss. Of note, activation of GLP1R can trigger increased energy expenditure independently of UCP1 in animal models, which suggests the involvement of UCP1-independent pathways¹⁰. Consequently, current work suggests that Ca²⁺ cycling in adipose tissue can be activated by targeting GLP1R, which provides further evidence that Ca²⁺ cycling may be implicated in promoting systemic metabolic health.

As additional mechanisms of energy homeostasis are revealed, there is increasing potential for therapeutic advancement in the treatment of metabolic diseases, which currently place a massive burden on health-care systems. Targeting these pathways in animal models has conferred resistance against classic metabolic disease phenotypes, such as the development of obesity and adipose tissue fibrosis, glucose intolerance, and insulin resistance. However, much remains to be uncovered, as translational work attempts to bridge the gap from bench to bedside. As such, attendees of the conference were challenged to consider creative ways in which their research could contribute to clinically important discoveries. Overall, the organizers and attendees agreed that there has never been a more exciting time for our field than now. Looking forward, there is a considerable need for further therapeutic interventions for metabolic disease. Furthermore, an emphasis should be placed on continuing to use new technologies and iterating on pre-existing technologies to determine novel metabolic mechanisms in health and disease.