Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling

Verena Coleman,Tim J Schulz,Susanne Klaus,Mario Ost,Tilman Grune,Piangkwan Sa-Nguanmoo,Anna P Kipp,Jeannette Koenig

doi:10.1038/s41598-018-20901-4

Verena Coleman, Tim J Schulz + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-20901-4

Copy DOI

Abstract

Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing. However, salutary effects in response to mild mitochondrial perturbations have been reported in multiple organisms, whereas molecular regulators of cell-autonomous stress responses remain elusive. We addressed this question by asking whether the nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor and master regulator of cellular redox status is involved in adaptive physiological responses including muscle mitohormesis. Using a transgenic mouse model with skeletal muscle-specific mitochondrial uncoupling and oxidative phosphorylation (OXPHOS) inefficiency (UCP1-transgenic, TG) we show that additional genetic ablation of Nrf2 abolishes an adaptive muscle NAD(P)H quinone dehydrogenase 1 (NQO1) and catalase induction. Deficiency of Nrf2 also leads to decreased mitochondrial respiratory performance although muscle functional integrity, fiber-type profile and mitochondrial biogenesis were not significantly altered. Importantly, Nrf2 ablation did not abolish the induction of key genes and proteins of muscle integrated stress response including the serine, one-carbon cycle, and glycine synthesis (SOG) pathway in TG mice while further increasing glutathione peroxidase (GPX) activity linked to increased GPX1 protein levels. Conclusively, our results tune down the functions controlled by Nrf2 in muscle mitohormesis and oxidative stress defense during mitochondrial OXPHOS inefficiency.

Highlights

Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing
The genotypes were determined by PCR (Fig. 1A) and further confirmed by enzyme activity analysis of the Nrf[2] target NAD(P)H quinone dehydrogenase 1 (NQO1) as a key readout parameter for Nrf[2] activity[39]
NAD(P) H quinone dehydrogenase 1 (NQO1) activity was markedly decreased in muscle and liver of both nuclear factor erythroid-derived-like 2 (Nrf2)-Ko and transgenic mice (TG)/Nrf2-Ko mice (Figs 1B and C, S1A and S1B)

Summary

Introduction

Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing. Salutary effects in response to mild mitochondrial perturbations have been reported in multiple organisms, whereas molecular regulators of cell-autonomous stress responses remain elusive We addressed this question by asking whether the nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor and master regulator of cellular redox status is involved in adaptive physiological responses including muscle mitohormesis. Consistent with the mitohormesis concept, this was related to an induced endogenous antioxidative defense system[30,31] as well as a robust cell-autonomous transcriptional and metabolic remodeling[32], including components of amino acid starvation response, the serine, one-carbon cycle, and glycine synthesis (SOG) pathway, ER-stress/UPR and integrated stress response (ISR) signaling. Whether Nrf[2] is required for SOG pathway induction and antioxidant response during muscle mitochondrial stress adaptation remains to be elucidated

Objectives

Methods

Results

Conclusion