A mathematical model of mitochondrial swelling

<p>Abstract</p> <p>Background</p> <p>The <it>permeabilization </it>of mitochondrial membranes is a decisive event in apoptosis or necrosis culminating in cell death. One fundamental mechanism by which such permeabilization events occur is the calcium-induced mitochondrial permeability transition. Upon Ca²⁺-uptake into mitochondria an increase in inner membrane permeability occurs by a yet unclear mechanism. This leads to a net water influx in the mitochondrial matrix, mitochondrial swelling, and finally the rupture of the outer membrane. Although already described more than thirty years ago, many unsolved questions surround this important biological phenomenon. Importantly, theoretical modeling of the mitochondrial permeability transition has only started recently and the existing mathematical models fail to characterize the swelling process throughout the whole time range.</p> <p>Results</p> <p>We propose here a new mathematical approach to the mitochondrial permeability transition introducing a specific delay equation and resulting in an optimized representation of mitochondrial swelling. Our new model is in accordance with the experimentally determined course of volume increase throughout the whole swelling process, including its initial lag phase as well as its termination. From this new model biological consequences can be deduced, such as the confirmation of a positive feedback of mitochondrial swelling which linearly depends on the Ca²⁺-concentration, or a negative exponential dependence of the average swelling time on the Ca²⁺-concentration. Finally, our model can show an initial shrinking phase of mitochondria, which is often observed experimentally before the actual swelling starts.</p> <p>Conclusions</p> <p>We present a model of the mitochondrial swelling kinetics. This model may be adapted and extended to diverse other inducing/inhibiting conditions or to mitochondria from other biological sources and thus may benefit a better understanding of the mitochondrial permeability transition.</p

Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy

MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects' fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children