Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration

Abstract

Aim/hypothesis Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication.Methods We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice). Results Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response. Conclusions/interpretation Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity.

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

“…To examine how manipulating mitochondrial network architecture affects metabolic state we performed targeted metabolite profiling in young adult drp-1 mutants, fzo-1 mutants and drp-1;fzo-1 double mutants. Consistent with fused networks promoting oxidative metabolism and altering protein biosynthesis (Wang et al, 2015), drp-1 mutants have decreased lactate, increased succinate, and increased levels of most amino acids (Figures 6A and S4C). fzo-1 mutant amino acid and acylcarnitine levels are broadly decreased and increased, respectively, suggesting protein and fatty acid metabolism may be perturbed by fragmented networks (Figures 6B and S4C–E).…”

Mitochondria in the Aging Muscles of Flies and Mice: New Perspectives for Old Characters

“…In obese patients, Mfn-2 expression is reduced [76]. Consistently, in skeletal muscle fibers of mice fed a high fat diet, Mfn-1 and Mfn-2 but not Opa1 were decreased, and the proteins governing mitochondrial fission Fis1 and Drp1 were increased [77, 78]. In this sense, mitochondrial dynamics in muscles appears to be sensitive to changes in cell metabolism.…”

“…Moreover, both ER and mitochondria undergo constant remodeling in response to cellular demands [78], changing their architecture but maintaining their organized disposition in the skeletal muscle fibers. In the recent years, the description of Mitochondrial Associated Membranes (MAMs) has been the target of new research.…”

Mitochondrial dynamics, quality control and miRNA regulation in skeletal muscle: implications for obesity and related metabolic disease

“…Hepatic mitochondria were less abundant and displayed a swollen phenotype in the Drp1LiKO mice. However, blood glucose, triacylglycerol and cholesterol were lowered in Drp1LiKO mice associated with a net improvement in glucose tolerance and insulin signalling assessed by intraperitoneal glucose tolerance test [21].…”