Contribution of NRF2 to sulfur metabolism and mitochondrial activity.

NF-E2-related factor 2 (NRF2) plays a crucial role in the maintenance of cellular homeostasis by regulating various enzymes and proteins that are involved in the redox reactions utilizing sulfur. While substantial impacts of NRF2 on mitochondrial activity have been described, the precise mechanism by which NRF2 regulates mitochondrial function is still not fully understood. Here, we demonstrated that NRF2 increased intracellular persulfides by upregulating the cystine transporter xCT encoded by Slc7a11, a well-known NRF2 target gene. Persulfides have been shown to play an important role in mitochondrial function. Supplementation with glutathione trisulfide (GSSSG), which is a form of persulfide, elevated the mitochondrial membrane potential (MMP), increased the oxygen consumption rate (OCR) and promoted ATP production. Persulfide-mediated mitochondrial activation was shown to require the mitochondrial sulfur oxidation pathway, especially sulfide quinone oxidoreductase (SQOR). Consistently, NRF2-mediated mitochondrial activation was also dependent on SQOR activity. This study clarified that the facilitation of persulfide production and sulfur metabolism in mitochondria by increasing cysteine availability is one of the mechanisms for NRF2-dependent mitochondrial activation.

Repeated Attacks of Dizziness Caused by a Rare Mitochondrial Encephalomyopathy.

Cases of dizziness caused by multiple sclerosis are commonly reported, but those caused by mitochondrial encephalomyopathy have been rarely reported. Particularly, the description of eye nystagmography (ENG) using caloric and optokinetic nystagmus tests has not been reported to date. We encountered the case of a 40-year-old woman with mitochondrial encephalomyopathy who visited us with the chief complaint of dizziness. At first, we considered multiple sclerosis based on the magnetic resonance imaging (MRI) findings and dizziness. Repeated attacks of dizziness and serum lactic acid levels suggested mitochondrial encephalomyopathy. A muscle biopsy confirmed the diagnosis. ENG findings suggested central vestibular disorder of the cerebellum and brainstem. This case suggests that we should not rule out the differential diagnosis of a very rare mitochondrial encephalomyopathy in patients who experience dizziness with MRI findings indicative of multiple sclerosis.

XBP1-FoxO1 interaction regulates ER stress-induced autophagy in auditory cells.

The purpose of this study was to clarify the relationship among X-box-binding protein 1 unspliced, spliced (XBP1u, s), Forkhead box O1 (FoxO1) and autophagy in the auditory cells under endoplasmic reticulum (ER) stress. In addition, the relationship between ER stress that causes unfolded protein response (UPR) and autophagy was also investigated. The present study reported ER stress induction by tunicamycin treatment that resulted in IRE1α-mediated XBP1 mRNA splicing and autophagy. XBP1 mRNA splicing and FoxO1 were found to be involved in ER stress-induced autophagy. This inference was based on the observation that the expression of LC3-II was suppressed by knockdown of IRE1α, XBP1 or FoxO1. In addition, XBP1u was found to interact with XBP1s in auditory cells under ER stress, functioning as a negative feedback regulator that was based on two important findings. Firstly, there was a significant inverse correlation between XBP1u and XBP1s expressions, and secondly, the expression of XBP1 protein showed different dynamics compared to the XBP1 mRNA level. Furthermore, our results regarding the relationship between XBP1 and FoxO1 by small interfering RNA (siRNA) paradoxically showed negative regulation of FoxO1 expression by XBP1. Our findings revealed that the XBP1-FoxO1 interaction regulated the ER stress-induced autophagy in auditory cells.