Brugada phenocopy associated with diabetic ketoacidosis in two pediatric patients.

Two patients without cardiac history demonstrated type 1 Brugada pattern during hospitalization for diabetic ketoacidosis (DKA). Both patients had normalization of their ECGs after treatment of marked electrolyte abnormalities and metabolic acidosis. In this report, we describe two cases of Brugada phenocopy associated with DKA in children.

Preventing permeability transition pore opening increases mitochondrial maturation, myocyte differentiation and cardiac function in the neonatal mouse heart.

BACKGROUND: In embryonic myocytes, closure of the mitochondrial permeability transition pore (PTP) drives mitochondrial maturation and cardiac myocyte differentiation. Since neonatal cardiac myocytes remain relatively immature, we hypothesized that inducing PTP closure at this age, by inhibiting the PTP regulator, cyclophilin D (CyPD), genetically or with Cyclosporin A (CsA) and NIM811, would increase cardiac function by increasing mitochondrial maturation and myocyte differentiation. METHODS: Cultured neonatal myocytes or neonatal mice were treated for 5 d with vehicle, CsA or NIM811. Mitochondrial function and structure were measured in vitro. Myocyte differentiation was assessed by immunolabeling for contractile proteins. Cardiac function was determined using echocardiography. RESULTS: The probability of PTP opening was high in WT neonatal myocytes. Treatment with CsA or NIM811 in vitro increased mitochondrial structural complexity and membrane potential, decreased reactive oxygen species levels, and increased myocyte differentiation. WT mice treated with either CsA or NIM811 in vivo for the first 5 d of life had higher ejection fractions. Deleting CyPD had similar effects as CsA and NIM811 on all parameters. CONCLUSIONS: It may be feasible to inhibit the PTP using available drugs to increase mitochondrial maturation, myocyte differentiation, and cardiac function in neonates.

Cyclophilin D regulates the dynamic assembly of mitochondrial ATP synthase into synthasomes.

Mitochondrial electron transport is essential for oxidative phosphorylation (OXPHOS). Electron transport chain (ETC) activity generates an electrochemical gradient that is used by the ATP synthase to make ATP. ATP synthase is organized into supramolecular units called synthasomes that increase the efficiency of ATP production, while within ATP synthase is the cyclophilin D (CypD) regulated mitochondrial permeability transition pore (PTP). We investigated whether synthasomes are dynamic structures that respond to metabolic demands and whether CypD regulates this dynamic. Isolated heart mitochondria from wild-type (WT) and CypD knockout (KO) mice were treated to either stimulate OXPHOS or open the PTP. The presence and dynamics of mitochondrial synthasomes were investigated by native electrophoresis, immunoprecipitation, and sucrose density centrifugation. We show that stimulation of OXPHOS, inhibition of the PTP, or deletion of CypD increased high order synthasome assembly. In contrast, OXPHOS inhibition or PTP opening increased synthasome disassembly in WT, but not in CypD KO heart mitochondria. CypD activity also correlated with synthasome assembly in other tissues, such as liver and brain. We conclude that CypD not only regulates the PTP, but also regulates the dynamics of synthasome assembly depending on the bioenergetic state of the mitochondria.