Khondrion B.V.

Vital knowledge and innovative therapeutic tools
to modulate mitochondrial metabolism

Dysfunction of the mitochondria, which are responsible for the cell’s energy metabolism, is implicated in a range of serious and debilitating human diseases involving various systems and organs. Mitochondrial diseases are genetic, but can also be induced by environmental factors. There is still a gap in our understanding of why and how mitochondrial dysfunction results in variable clinical manifestations and, so far, there is no effective treatment. Khondrion B.V. has validated a quantitative platform of live mammalian cells, which provides vital knowledge about the efficacy and mechanism of action of active compounds on energy metabolism. This innovative platform is used as a second-stage drug development screening tool, and has wide industrial applications.

The energy production machinery

The aerobic production of ATP occurs in the mitochondrial matrix, and involves the cellular uptake and transport of substrates, their metabolic conversion, and a multitude of accessory ingredients such as minerals and co-factors, many of which act in a cell, tissue-, or system-dependent manner. The synthesis of ATP by the oxidative phosphorylation (OXPHOS) system is driven by the electrochemical gradient across the Inner Mitochondrial Membrane (IMM), created by the oxidation of carbohydrates, fats and amino acids. Disturbances of this energy production are involved in many conditions and diseases and can be modulated via metabolic manipulation. Both stimulation as well as repression of the system have wide applications in medicine.

Mitochondrial Medicine: From mitochondrial myopathy to common diseases

Mitochondrial diseases are rare and often lack effective treatment. Since the first description of a patient with a mitochondrial disease by Luft et al., in 1962, the role of mitochondria in health and disease has received increasing attention. Although the term mitochondrial disease, “inborn errors of energy metabolism,” strictly speaking, is much broader, it is used to describe a wide range of conditions and

Digital imaging microscopy of hormone-induced changes in mitochondrial Ca2+ concentration in human skin fibroblasts. The left image shows the absence of any specific fluorescence in the unstimulated cell. The hormone Bradykinin is known to interact with its receptor to trigger the release of Ca2+ from its intracellular store, the endoplasmic reticulum, into the cytosolic compartment. The right figure shows that this effect of Bradykinin is accompanied by a rapid increase of the Ca2+ concentration in the mitochondrial matrix. As a consequence, mitochondrial ATP production is stimulated.

diseases which cause a disturbance in the mitochondrial energy-generating system. These include type 2 diabetes; atherosclerosis; heart failure; myocardial infarction and stroke. The term also is used in reference to certain neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s disease; as well as certain types of cancers; mutations affecting mitochondrial oxidative phosphorylation genes; and ageing and trauma with multi-organ dysfunction or failure, eventually leading to death.

An area of interest that started with the anecdotal description of a sole patient with a mitochondrial dysfunction has now evolved into a new medical discipline: Mitochondrial Medicine. Despite all progress made to date, “care but not cure” is the current paradigm. Khondrion B.V. has recently filled the gap between the clinical manifestations of energy metabolism disturbance, and developing effective treatment via its unique cell panels and quantitative read-out systems, “the energy-checker system.”

Modulation of mitochondrial function by nutritional components

Proof of the value of these cell panels has been achieved by the Radboud University Nijmegen Medical Centre via funding from the European Commission, national foundations, and, most recently, by a grant from the Innovation Oriented Research Programme (IOP Genomics) of the Ministry of Economic Affairs of the Netherlands. The latter consortium runs a project entitled “New tools for the identification of nutritional modulators of mitochondrial activity: small molecules that promote health and disease.” The Dutch Science Organization has recently granted €4.5 million to Prof. Smeitink and his team for research on systems biology of bioenergetics entitled “Modelling therapeutic interventions in mitochondrial bioenergetics.” Also within this center, special attention will be paid to nutritional modulation of energy metabolism.

Khondrion B.V.

Khondrion B.V., a spin-off company of the Radboud University Nijmegen Medical Centre (RUNMC), is a mitochondrial research service company providing scientific services for academia, as well as the pharmaceutical and food industries. Khondrion has already established several collaborative efforts with companies in the medical food industry and plans to support other pharmaceutical and food companies in their search for effective treatments in mitochondrial-related diseases. The company’s CSO, Professor Jan Smeitink, is one of the world’s leading scientists in the field of mitochondrial medicine. Smeitink and his scientific staff have published more than 250 papers in peer-reviewed journals and have conducted research involving more than 1,000 patients and patient samples per year. The final aim of the Khondrion team is to make a substantial contribution to the development of a cure for mitochondrial (related) diseases. The unique knowledge and state-of-the-art technology developed over the last 25 years are available to academic and industrial stakeholders via Khondrion. Khondrion’s assets include cell panels exhibiting different energy production capacity, and more than 25 different cell biological quantitative read-outs. Their available tools and techniques have a wide range of possible applications for the pharmaceutical and food industries.

Contact Details:
Jan Smeitink, MD, PhD
Chief Scientific Officer
info@khondrion.nl
Telephone: +31-6-22933832

For further information visit Khondrion’s website
www.khondrion.nl