Mitochondrial Metabolism

Project 1:

Nutritional approaches to preserve and improve mitochondrial health and physical function in the elderly (Mitochondrial Health)

Mitochondria, the cell’s powerhouses, are essential organelles in all cells relying on aerobic metabolism to maintain cellular ATP (=energy) levels necessary for all vital processes in the cell and human body. Healthy mitochondria are characterized by a large capacity to generate energy, while keeping reactive oxygen species production controlled. Furthermore, over the last decade it has become increasingly clear that mitochondria are not single organelles, but combine into tightly regulated, dynamic networks that are constantly built, renewed and subjected to quality control mechanisms . To maintain proper mitochondrial morphology and overall function, dysfunctional parts of mitochondria can be split off (fission) and degraded via a process called mitophagy. Furthermore, new functional mitochondria can fuse with other mitochondria (fusion) in order to adapt to changes in cellular energy demand.

It is well documented that with aging muscle mitochondrial function declines, which is paralleled by a decline in muscle health, as reflected by a decline in muscle strength and physical function, oxidative capacity, endurance and fatigue, insulin sensitivity and metabolism, and muscle mass. Importantly, this reduction in muscle health translates into declined performance in daily activities, such as walking short distances, climbing stairs, lifting groceries or standing from a chair. Although several animal studies have shown that changes in mitochondrial function are directly linked to parameters of physical function, such as muscle mass, human data on the relation between skeletal muscle mitochondrial metabolism and muscle health are scarce.

Interestingly from a food perspective, while physical exercise and calorie restriction are perhaps the best-known strategies to boost mitochondrial capacity, accumulating evidence also suggests that mitochondria are very sensitive to various nutritional signals . Again however, data from human (intervention) studies is largely lacking. The aim of the project Mitochondrial Health is to increase our understanding on the relationship between muscle mitochondrial function and muscle health/function, and to investigate whether muscle mitochondrial function and physical function can be improved by nutritional interventions in humans.

This project is financed by a partnership between the Top Institute for Food and Nutrition (TIFN) and the Netherlands Scientific Organization (NWO)
PhD Students: Niels Connell, Lotte Grevendonk

Project 2:

The Might of MicroRNA in Muscle Mitochondrial Metabolism

A diminished mitochondrial oxidative capacity in skeletal muscle tissue has frequently been reported in human type 2 diabetes mellitus (T2DM) and insulin resistance. Moreover, interventions improving muscle oxidative capacity, such as exercise training and caloric restriction, are among the most potent strategies to revert the insulin resistant state. However, a sustained increase in physical activity or restriction of caloric intake is not easily achieved in a generally obese population and additional strategies are needed to improve mitochondrial oxidative capacity.

In this context, we recently published the involvement of specific microRNAs – posttranscriptional regulators of gene expression – in the regulation of mitochondrial capacity in cardiac tissue. If and how microRNAs also affect mitochondrial metabolism in skeletal muscle has however not been studied so far. To explore this concept, we recently finalized a pilot study in which we performed a high-throughput silencing screen on the near complete genome content of mammalian microRNAs in muscle cells and detected ~60 microRNAs that are putatively involved in the regulation of skeletal muscle mitochondrial capacity.

In this project we intend to target top candidate microRNAs both in vitro (C2C12 myotubes) and in vivo (in microRNA knockout mice) and assess the functional effects on mitochondrial capacity and insulin sensitivity. To translate these findings to the human situation, the effect of silencing these microRNAs on mitochondrial capacity/insulin sensitivity will also be tested in human primary myotubes, derived from both T2DM patients and BMI- and age-matched controls. We anticipate that this project will reveal novel microRNAs that are involved in the regulation of skeletal muscle mitochondrial oxidative capacity and may uncover novel drug targets to improve metabolic health.

This project is financed by a VIDI grant from the Netherlands Organization for Scientific Research (NWO) and a Senior Fellowship from the Dutch Diabetes Research Foundation (DFN), granted to Dr. Joris Hoeks
PhD Students: Dennis Dahlmans, Alex Houzelle
Collaborators: Prof. Dr. Johan Auwerx, EPFL Lausanne, Switzerland

Project 3:

The fate of incomplete amino acid metabolism in type 2 diabetes

Recent high impact research identified clusters of circulating branched-chain amino acids (BCAA), aromatic amino acids (AAA) and amino acid-derived short-chain acylcarnitines in insulin resistant humans, as risk factors in the development of type 2 diabetes. The elevated amino acid clusters may derive from elevated amino acid supply or incomplete amino acid catabolism. These findings shed new light in the etiology of diabetes, which for long time was considered to be related only to disturbances in fat and glucose metabolism, underlying the development of insulin resistance and mitochondrial dysfunction. Here, the hypothesis will be tested that type 2 diabetes (T2DM) is linked to dysregulated amino acid metabolism, resulting in elevated clusters of BCAA, AAA and acylcarnitines causing insulin resistance, and that impaired amino acid metabolism underlies impaired mitochondrial oxidative capacity in T2DM via diminished delivery and flux of amino acid-derived tricarboxylic acid cycle (TCA) intermediates. The experiments include metabolic profiling of amino acid metabolism-derived intermediates in plasma and muscle of patients with T2DM and in first-degree relatives, which has never been explored before (experiment 1). In addition, we will investigate the direct effects of excess BCAA availability on the development of insulin resistance and mitochondrial function (experiment 2). Finally, we will investigate whether sustained lowering of BCAA availability via a dietary intervention will reverse possible detrimental effects of BCAA in T2DM (experiment 3). With this project, we hope to reveal the fate of dysregulated amino acid metabolism in T2DM.

This project is financed by a VENI grant from the Netherlands Organisation for Scientific Research (NWO), granted to Dr. Esther Phielix
PostDoc: Esther Phielix

Project 4:

The role of cardiac mitochondrial function and lipid accumulation in the development of cardiac insulin resistance; etiology and treatment strategies.

Cardiovascular diseases remain the major cause of death in type 2 diabetes. Although atherosclerosis remains the main factor, the prevalence of cardiac dysfunction is rising in type 2 diabetes. So far, however, the aetiology of this diabetic cardiac dysfunction is not completely understood, but it has been suggested that cardiac fat accumulation and mitochondrial dysfunction might be involved. From animal studies, it has been suggested that an altered PPAR and PGC1 expression is involved in the development of reduced cardiac mitochondrial function. In humans, however, data on cardiac mitochondrial function, substrate handling and storage and the interplay with cardiac function in the human diabetic and pre-diabetic heart is scarce. In this research proposal, we aim to map changes in cardiac metabolism and its relations with cardiac function in the pre-diabetic state, as these patients may already be at increased risk of a decreased cardiac function. We will do so by using state-of-the-art imaging techniques, but also will perform molecular analysis to unravel underlying mechanisms in cardiac tissue obtained during surgery. Furthermore, we will investigate if boosting cardiac mitochondrial function is beneficial for cardiac function. The outcome of our project may shape future interventions to prevent cardiac dysfunction in type 2 diabetes.

This project is financed by a Junior Fellowship from the Dutch Diabetes Research Foundation (DFN), granted to Dr. Tineke van de Weijer
PostDoc: Tineke van de Weijer