Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

Alison Burkart,Xiarong Shi,My Chouinard,Silvia Corvera

doi:10.1074/jbc.m110.134106

Alison Burkart, Xiarong Shi + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m110.134106

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Abstract

The unfolded protein response (UPR) is a homeostatic signaling mechanism that balances the protein folding capacity of the endoplasmic reticulum (ER) with the secretory protein load of the cell. ER protein folding capacity is dependent on the abundance of chaperones, which is increased in response to UPR signaling, and on a sufficient ATP supply for their activity. An essential branch of the UPR entails the splicing of XBP1 mRNA to form the XBP1 transcription factor. XBP1 has been shown to be required during adipocyte differentiation, enabling mature adipocytes to secrete adiponectin, and during differentiation of B cells into antibody-secreting plasma cells. Here we find that adenylate kinase 2 (AK2), a mitochondrial enzyme that regulates adenine nucleotide interconversion within the intermembrane space, is markedly induced during adipocyte and B cell differentiation. Depletion of AK2 by RNAi impairs adiponectin secretion in 3T3-L1 adipocytes, IgM secretion in BCL1 cells, and the induction of the UPR during differentiation of both cell types. These results reveal a new mechanism by which mitochondria support ER function and suggest that specific mitochondrial defects may give rise to impaired UPR signaling. The requirement for AK2 for UPR induction may explain the pathogenesis of the profound hematopoietic defects of reticular dysgenesis, a disease associated with mutations of the AK2 gene in humans.

Highlights

Stress, a global response is triggered that can lead to apoptosis and is linked to multiple human pathologies [1,2,3,4,5]
unfolded protein response (UPR) Induction Correlates with Mitochondrial Biogenesis and Remodeling in 3T3-L1 Cells—Consistent with previous findings [18], we find that the levels of XBP1 and several proteins involved in protein folding, such as BiP and ERO1a, are up-regulated early during adipocyte differentiation (Fig. 1A)
Effect of Tfam Depletion on UPR Induction—We have previously shown that siRNA-mediated depletion of Tfam, a nuclearencoded transcription factor for mitochondrial DNA, leads to impaired respiratory chain function [29] without changes in overall mitochondrial mass

Summary

Introduction

Stress, a global response is triggered that can lead to apoptosis and is linked to multiple human pathologies [1,2,3,4,5]. Taken together these data indicate that decreased respiratory chain function through Tfam depletion does not significantly impair the induction of the UPR induced by differentiation in 3T3-L1 cells. To determine whether impaired respiratory chain function would affect the acute induction of the UPR in fully differentiated cells, we examined the effects of tunicamycin, which blocks N-linked glycosylation, causing the rapid accumulation of unfolded proteins.

Results

Conclusion