Deletion of Cyclophilin D Impairs β-Oxidation and Promotes Glucose Metabolism.

Michele Tavecchio,Sofia Lisanti,Lucia R Languino,Michael J Bennett,Dario C Altieri

doi:10.1038/srep15981

Abstract

Cyclophilin D (CypD) is a mitochondrial matrix protein implicated in cell death, but a potential role in bioenergetics is not understood. Here, we show that loss or depletion of CypD in cell lines and mice induces defects in mitochondrial bioenergetics due to impaired fatty acid β-oxidation. In turn, CypD loss triggers a global compensatory shift towards glycolysis, with transcriptional upregulation of effectors of glucose metabolism, increased glucose consumption and higher ATP production. In vivo, the glycolytic shift secondary to CypD deletion is associated with expansion of insulin-producing β-cells, mild hyperinsulinemia, improved glucose tolerance, and resistance to high fat diet-induced liver damage and weight gain. Therefore, CypD is a novel regulator of mitochondrial bioenergetics, and unexpectedly controls glucose homeostasis, in vivo.

Highlights

We began this study by profiling the metabolome of wild type (WT) or Cyclophilin D (CypD) knockout (KO) mouse embryonic fibroblasts (MEFs), characterized in recent studies[12]
This response was accompanied by increased levels of lactate and glucose, suggestive of heightened glucose metabolism, and overall higher ATP production in CypD KO MEFs, compared to WT cultures (Fig. 2F)
We have identified a novel role of the mitochondrial matrix protein, CypD8 in glucose metabolism, insulin production and liver protection in response to high-fat diet, in vivo

Summary

Introduction

This response was accompanied by increased levels of lactate and glucose, suggestive of heightened glucose metabolism, and overall higher ATP production in CypD KO MEFs, compared to WT cultures (Fig. 2F). Consistent with defective mitochondrial β -oxidation, CypD KO hepatocytes exhibited significantly reduced oxygen consumption, compared to WT cultures (Fig. 3A).

Results

Conclusion