SUMMARY Cardiac contractility is mediated by variable flux in intracellular calcium (Ca2+), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu−/− mice display no overt baseline phenotype and are protected against mCa2+-overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu−/− mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca2+-dependent metabolism during acute stress.

Mitochondrial calcium ( m Ca 2+ ) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial 1 . Slc8b1 encodes the mitochondrial Na + /Ca 2+ exchanger (NCLX), which is proposed to be the primary mechanism for m Ca 2+ extrusion in excitable cells 2,3 . Here we show that tamoxifen-induced deletion of Slc8b1Reprints and permissions information is available at www.nature.com/reprints.

SUMMARY It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here we show thata thyroid hormone surge activates the IGF-1/IGF1-R/Akt pathway on postnatal day-15andinitiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ~40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day15 is intermediate between that observed at postnatal day-2 and -21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases.

Impairments in neuronal intracellular calcium (i Ca 2+) handling may contribute to Alzheimer's disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (m Ca 2+) signaling is a key regulator of both of these processes. Here, we report remodeling of the m Ca 2+ exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired m Ca 2+ efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na + /Ca 2+ exchanger (NCLX, Slc8b1 gene) accelerated memory decline and increased amyloidosis and tau pathology. Further, genetic rescue of neuronal NCLX in 3xTg-AD mice is sufficient to impede AD-associated pathology and memory loss. We show that m Ca 2+ overload contributes to AD progression by promoting superoxide generation, metabolic dysfunction and neuronal cell death. These results provide a link between the calcium dysregulation and metabolic dysfunction hypotheses of AD and suggest m Ca 2+ exchange as potential therapeutic target in AD.

Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. Am J Physiol Heart Circ Physiol 304: H1215-H1224, 2013. First published March 11, 2013 doi:10.1152/ajpheart.00796.2012.-Hydrogen sulfide (H2S) therapy protects nondiabetic animals in various models of myocardial injury, including acute myocardial infarction and heart failure. Here, we sought to examine whether H2S therapy provides cardioprotection in the setting of type 2 diabetes. H2S therapy in the form of sodium sulfide (Na2S) beginning 24 h or 7 days before myocardial ischemia significantly decreased myocardial injury in db/db diabetic mice (12 wk of age). In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, we focused on the role of nuclear factor E2-related factor (Nrf2) signaling. Our results indicate that diabetes does not alter the ability of H2S to increase the nuclear localization of Nrf2, but does impair aspects of Nrf2 signaling. Specifically, the expression of NADPH quinine oxidoreductase 1 was increased after the acute treatment, whereas the expression of hemeoxygenase-1 (HO-1) was only increased after 7 days of treatment. This discrepancy was found to be the result of an increased nuclear expression of Bach1, a known repressor of HO-1 transcription, which blocked the binding of Nrf2 to the HO-1 promoter. Further analysis revealed that 7 days of Na2S treatment overcame this impairment by removing Bach1 from the nucleus in an Erk1/2-dependent manner. Our findings demonstrate for the first time that exogenous administration of Na2S attenuates myocardial ischemia-reperfusion injury in db/db mice, suggesting the potential therapeutic effects of H2S in treating a heart attack in the setting of type 2 diabetes. hydrogen sulfide; type 2 diabetes; myocardial infarction; nuclear factor E2-related factor