On Thursday (19.11) we will host Prof. dr. Werner J.H. Koopman (Radboudumc, The Netherlands). His lecture will be entitled: "Mitochondrial disease - Mechanisms and Intervention". The lecture will take place at 3 p.m. in the CN lecture hall and it will be followed by a get together.

Background

Research in Koopman’s team is performed across two universities: the Radboud University Medical Center (Radboudumc) and Wageningen University (WU). This work primarily focuses on rare mitochondrial diseases (MDs) including Leigh Syndrome (LS) but also studies mitochondrial (dys)function in other pathologies (e.g. melanoma, Parkinson’s, immunity, neurodevelopmental disorders) and human aging. In this context, research efforts pursue four main goals: (1) To develop, apply and make available novel technologies and models for (single) live-cell analysis, (2) to provide new fundamental insights into cellular and mitochondrial bioenergetics, (3), to understand the (patho)physiology of MDs driving novel intervention strategies, and (4) to disseminate (basic) knowledge and provide counselling to relevant stakeholders (e.g. students, researchers, industry).

Abstract

This lecture will focus on a recent collaborative study with Prof. Mariusz Wieckowski in which we studied the LS pathomechanism and thermal intervention in whole-body (WB) Ndufs4^-/- (KO) mice. These mice are a widely used animal model of pediatric LS. We compared Ndufs4^-/- mice housed at 26 ^oC (KO26 mice) and 20 ^oC (KO20 mice), and demonstrate that KO26 mice live longer. This life extension was paralleled by lower energy expenditure, increased glucose oxidation, higher brain temperature, decreased food intake, increased food efficiency, and prevention of elevated serum lactate/glucose ratios. Moreover, thermal intervention normalized increased GFAP levels (brain inflammation) in the hippocampus and motor cortex of KO mice. This normalization was paralleled by increased voluntary locomotor activity. In contrast, thermal intervention did not improve body weight gain, lean mass gain and fat mass gain in KO mice. In addition, brain protein oxidation, OXPHOS subunit levels or mitochondrial fission/fusion protein expression were not affected in KO26 mice. Subsequent mechanistic analyses in human NDUFS4-mutated neuronal progenitor cells demonstrated that thermal intervention increased mitochondrial ATP production, without affecting membrane potential (Dy), lactate production, OXPHOS subunit levels or mitochondrial fission/fusion protein expression. Moreover, NDUFS4 mutations induced defective calcium handling, which was mitigated by thermal intervention. Taken together, our results suggest that thermal intervention lowers ATP demand for heat-generation and stimulates mitochondrial ATP production to extend life and mitigate specific brain pathology in Ndufs4^-/- mice. Since LS patients display reduced mitochondrial ATP production and a disturbed thermoregulation, thermal intervention might be of therapeutic value and/or contribute to an improved quality of life. In a broader sense, our results advocate avoiding sub-thermoneutral housing conditions in murine models of human disease, especially when mitochondrial ATP production is compromised.