Mitochondrial compromise is a fundamental contributor to pancreatic β-cell failure in diabetes. Previous studies have demonstrated a broader role for tumor suppressor p53 that extends to the modulation of mitochondrial homeostasis. However, the role of islet p53 in glucose homeostasis has not yet been evaluated. Here we show that p53 deficiency protects against the development of diabetes in streptozotocin (STZ)-induced type 1 and db/db mouse models of type 2 diabetes. Glucolipotoxicity stimulates NADPH oxidase via receptor for advanced-glycation end products and Toll-like receptor 4. This oxidative stress induces the accumulation of p53 in the cytosolic compartment of pancreatic β-cells in concert with endoplasmic reticulum stress. Cytosolic p53 disturbs the process of mitophagy through an inhibitory interaction with Parkin and induces mitochondrial dysfunction. The occurrence of mitophagy is maintained in STZ-treated p53 −/− mice that exhibit preserved glucose oxidation capacity and subsequent insulin secretion signaling, leading to better glucose tolerance. These protective effects are not observed when Parkin is deleted. Furthermore, pifithrin-α, a specific inhibitor of p53, ameliorates mitochondrial dysfunction and glucose intolerance in both STZ-treated and db/db mice. Thus, an intervention with cytosolic p53 for a mitophagy deficiency may be a therapeutic strategy for the prevention and treatment of diabetes.

We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.

D-Amino acids are enantiomers of L-amino acids and have recently been recognized as biomarkers and bioactive substances in mammals, including humans. In the present study, we investigated functions of the novel mammalian mitochondrial protein 9030617O03Rik and showed decreased expression under conditions of heart failure. Genomic sequence analyses showed partial homology with a bacterial aspartate/glutamate/hydantoin racemase. Subsequent determinations of all free amino acid concentrations in 9030617O03Rik-deficient mice showed high accumulations of D-glutamate in heart tissues. This is the first time that a significant amount of D-glutamate was detected in mammalian tissue. Further analysis of D-glutamate metabolism indicated that 9030617O03Rik is a D-glutamate cyclase that converts D-glutamate to 5-oxo-D-proline. Hence, this protein is the first identified enzyme responsible for mammalian D-glutamate metabolism, as confirmed in cloning analyses. These findings suggest that D-glutamate and 5-oxo-D-proline have bioactivities in mammals through the metabolism by D-glutamate cyclase.

Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure. The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.