Liver-targeted Nano-MitoPBN normalizes glucose metabolism by improving mitochondrial redox balance.

Recent advances in Nanomedicine provide promising disease treatment through improved drug delivery efficiency, but clinical applications have encountered difficulties, largely due to the majority of injected nanoparticle is sequestered in liver. In contrast, liver cells seem to be a perfect target for nanoparticles. Here we generated a new formula of liposome encapsulated Nano-MitoPBN as a liver mitochondrial-targeting free radical scavenger. We found that Nano-MitoPBN mainly accumulated in hepatocytes and scavenged hepatic mitochondrial superoxide/hydrogen peroxide generated from mono-electron leak of electron transport chain (ETC) complex I and III. Due to micro-compartmentalization, Nano-MitoPBN increased mitochondrial state 3 respiratory rate and respiratory control ratio (RCR), resulting in decreased NADH:NAD+ ratio, improved mitochondrial oxidative energy coupling and ATP synthesis, thus alleviating ROS-induced mitochondrial dysfunction. The functional mitochondria promoted the substrate oxidation by the liver, resulting in increased glycolysis and TCA cycle, which directly speeds glucose decomposition, thus decreasing the peripheral blood glucose level and improving the impaired glucose tolerance in diabetic animals. Our study suggests the potential of liver mitochondrial targeting antioxidative nanomedicines for diabetes mellitus.

Short-term high salt intake impairs hepatic mitochondrial bioenergetics and biosynthesis in SIRT3 knockout mice.

High salt intake (HS) is an important factor in the development of many metabolic diseases. The liver is the metabolic center in the body. However, the effect of short-term HS on the liver mitochondria and its mechanism are still unclear. In this study, we investigated the effects of short-term HS on liver mitochondrial function. We found that HS reduced Sirtuin3 (SIRT3) protein level, increasing protein carbonylation in mice liver. HS intake decreased ATP production, mitochondrial transcription factor A (TFAM), and complex I level. SIRT3 knockout (SKO) mice exhibited similar results with HS-treated wild-type mice but with a less extent of carbonylation and ATP reduction. Our study shows that short-term HS led to increased hepatic oxidative state, impaired mitochondrial biosynthesis, and bioenergetics. HS-treated mice could still maintain hepatic glucose homeostasis by compensatory activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK). However, in HS-treated SKO mice, AMPK was not activated, instead, the glycogen synthase activity increased, which caused an exceptionally increased glycogen accumulation. This study provides evidence that short-term HS intake could cause the early hepatic metabolic changes, highlighting the importance of controlling salt intake especially in those patients with defects in SIRT3. Highlights High salt intake down-regulates SIRT3 protein level and increases oxidation. High salt intake activates AMPK via AMP-dependent pathway. High salt intake impairs energy metabolism. High salt combined with SIRT3 knockout results in glycogen accumulation.