Mitochondrial cyclophilin D ablation is associated with the activation of Akt/p70S6K pathway in the mouse kidney

Jelena Klawitter,Jost Klawitter,Uwe Christians,Joshua M Thurman,Alexander Pennington

doi:10.1038/s41598-017-10076-9

Jelena Klawitter, Jost Klawitter + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-10076-9

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Journal: Scientific Reports	Publication Date: Sep 5, 2017
Citations: 13	License type: open-access

Affiliation: University of Colorado Denver

Abstract

The mitochondrial matrix protein cyclophilin D (CypD) is an essential component of the mitochondrial permeability transition pore (MPTP). Here we characterized the effects of CypD ablation on bioenergetics in the kidney. CypD loss triggers a metabolic shift in Ppif−/− male and female mouse kidneys towards glycolysis and Krebs cycle activity. The shift is accompanied by increased glucose consumption and a transcriptional upregulation of effectors of glucose metabolism in the kidney. These included activation of Akt, AMPK (only in males) and p70S6K kinases. Gender specific differences between the Ppif−/− male and female mouse kidneys were observed including activation of pro-surviving ERK1/2 kinase and inhibited expression of pro-apoptotic and pro-fibrotic JNK and TGFβ1 proteins in Ppif−/− females. They also showed the highest expression of phosphorylated-ERK1/2 and Akt S473 proteins of all four investigated animal groups. Furthermore, Ppif−/− females showed higher lactate concentrations and ATP/ADP-ratios in the kidney than males. These metabolic and transcriptional modifications could provide an additional level of protection to Ppif−/− females. In summary, loss of mitochondrial CypD results in a shift in bioenergetics and in activation of glucose-metabolism regulating Akt/AMPK/p70S6 kinase pathways that is expected to affect the capability of Ppif−/− mice kidneys to react to stimuli and injury.

Highlights

In response to oxidative or other cellular stresses, mitochondrial permeability transition is accompanied by pathological and non-specific mPT pore opening in the inner membrane of mitochondria. mPTP can serve as a target to prevent cell death under pathological conditions such as cardiac and brain ischemia/reperfusion (I/R) injury, myocardial infarction, stroke, and diabetes[1,2,3]
In the heart, cyclophilin D (CypD) ablation is associated with elevated levels of mitochondrial matrix Ca2+ that in turn leads to increased glucose oxidation relative to fatty acids
We hypothesized that CypD deletion will lead to the alteration of cellular metabolism and related signaling pathways including AKT and

Summary

Introduction

In response to oxidative or other cellular stresses, mitochondrial permeability transition is accompanied by pathological and non-specific mPT pore (mPTP) opening in the inner membrane of mitochondria. mPTP can serve as a target to prevent cell death under pathological conditions such as cardiac and brain ischemia/reperfusion (I/R) injury, myocardial infarction, stroke, and diabetes[1,2,3]. In the heart, CypD ablation is associated with elevated levels of mitochondrial matrix Ca2+ that in turn leads to increased glucose oxidation relative to fatty acids. This metabolic switch limits the heart’s ability to adapt during stress[11, 13]. We hypothesized that CypD deletion will lead to the alteration of cellular metabolism and related signaling pathways including AKT and www.nature.com/scientificreports/ Both clinical and experimental observations support the concept that female kidneys are less susceptible to I/R injury[20, 21], and that women show a slower progression rate of renal disease[22]. We compared the effects of CypD deletion in kidneys from male and female mice

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