OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis.: OPA1 isoforms in mitochondrial fusion or apoptosis.

In most eucaryote cells, release of apoptotic proteins from mitochondria involves fission of the mitochondrial network and drastic remodelling of the cristae structures. The intramitochondrial dynamin OPA1, as a potential central actor of these processes, exists as eight isoforms resulting from the alternate splicing combinations of exons (Ex) 4, 4b and 5b, which functions remain undetermined. Here, we show that Ex4 that is conserved throughout evolution confers functions to OPA1 involved in the maintenance of the DeltaPsi(m) and in the fusion of the mitochondrial network. Conversely, Ex4b and Ex5b, which are vertebrate specific, define a function involved in cytochrome c release, an apoptotic process also restricted to vertebrates. The drastic changes of OPA1 variant abundance in different organs suggest that nuclear splicing can control mitochondrial dynamic fate and susceptibility to apoptosis and pathologies

A Mathematical Analysis of Aerobic Glycolysis Triggered by Glucose Uptake in Cones

International audiencePatients affected by retinitis pigmentosa, an inherited retinal disease, experience a decline in vision due to photoreceptor degeneration leading to irreversible blindness. Rod-derived cone viability factor (RdCVF) is the most promising mutation-independent treatment today. To identify pathologic processes leading to secondary cone photoreceptor dysfunction triggering central vision loss of these patients, we model the stimulation by RdCVF of glucose uptake in cones and glucose metabolism by aerobic glycolysis. We develop a nonlinear system of enzymatic functions and differential equations to mathematically model molecular and cellular interactions in a cone. We use uncertainty and sensitivity analysis to identify processes that have the largest effect on the system and their timeframes. We consider the case of a healthy cone, a cone with low levels of glucose, and a cone with low and no RdCVF. The three key processes identified are metabolism of fructose-1,6-bisphosphate, production of glycerol-3-phosphate and competition that rods exert on cone resources. The first two processes are proportional to the partition of the carbon flux between glycolysis and the pentose phosphate pathway or the Kennedy pathway, respectively. The last process is the rods’ competition for glucose, which may explain why rods also provide the RdCVF signal to compensate