Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels

Fu, Xiaolong; Wan, Peifeng; Lu, Ling; Wan, Ying; Liu, Ziyi; Hong, Guodong; Cao, Shengda; Bi, Xiuli; Zhou, Jing; Qiao, Ruifeng; Guo, Siwei; Yu, Xiao; Wang, Bingzheng; Miao, Chang; Li, Wen; Li, Peipei; Zhang, Aizhen; Sun, Jing; Chai, Renjie; Gao, Jiangang

doi:10.1002/advs.202300402

Cited by 7 publications

(1 citation statement)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The BK channel has also been implicated in the regulation of tumor cell proliferation [19][20][21], gene expression [22], airway inflammation [23,24], hormone secretion [25,26], and cell volume [27]. Furthermore, it is considered a promising therapeutic target for hearing loss [28]. Currently, the BK channel is considered to have either no or little roles in the function of immune cells [29].…”

Section: Introductionmentioning

confidence: 99%

The BK Channel Limits the Pro-Inflammatory Activity of Macrophages

Chen,

Markov,

Gigon

et al. 2024

Cells

View full text Add to dashboard Cite

Macrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the KCa1.1 or BK channel, in regulating neurotransmitter release and smooth muscle contraction is well known, its potential involvement in immune regulation remains unclear. We employed BK-knockout macrophages and noted that the absence of a BK channel promotes the polarization of macrophages towards a pro-inflammatory phenotype known as M1 macrophages. Specifically, the absence of the BK channel resulted in a significant increase in the secretion of the pro-inflammatory cytokine IL-6 and enhanced the activity of extracellular signal-regulated kinases 1 and 2 (Erk1/2 kinases), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the transcription factor ATF-1 within M1 macrophages. Additionally, the lack of the BK channel promoted the activation of the AIM2 inflammasome without affecting the activation of the NLRC4 and NLRP3 inflammasomes. To further investigate the role of the BK channel in regulating AIM2 inflammasome activation, we utilized BK channel inhibitors, such as paxilline and iberiotoxin, along with the BK channel activator NS-11021. Pharmacological inactivation of the BK channel increased, and its stimulation inhibited IL-1β production following AIM2 inflammasome activation in wild-type macrophages. Moreover, wild-type macrophages displayed increased calcium influx when activated with the AIM2 inflammasome, whereas BK-knockout macrophages did not due to the impaired extracellular calcium influx upon activation. Furthermore, under conditions of a calcium-free medium, IL-1β production following AIM2 inflammasome activation was increased in both wild-type and BK-knockout macrophages. This suggests that the BK channel is required for the influx of extracellular calcium in macrophages, thus limiting AIM2 inflammasome activation. In summary, our study reveals a regulatory role of the BK channel in macrophages under inflammatory conditions.

show abstract

Section: Introductionmentioning

confidence: 99%

The BK Channel Limits the Pro-Inflammatory Activity of Macrophages

Chen,

Markov,

Gigon

et al. 2024

Cells

View full text Add to dashboard Cite

show abstract

Recent Progress in Generation of Inner Ear Organoid

Zong,

Liu,

Zhang

et al. 2024

Advanced Biology

View full text Add to dashboard Cite

Inner ear organoids play a crucial role in hearing research. In comparison to other animal models and 2D cell culture systems, inner ear organoids offer significant advantages for studying the mechanisms of inner ear development and exploring novel approaches to disease treatment. Inner ear organoids derived from human cells are more closely resemble normal human organs in development and function. The 3D culture system of the inner ear organoid enhances cell–cell interactions and mimics the internal environment. In this review, the progress and limitations of organoid culture methods derived from tissue‐specific progenitors and pluripotent stem cells (PSCs) are summarized, which may offer new insights into generating organoids that closely resemble the inner ear in terms of morphology and function.

show abstract

Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels

Wan

et al. 2023

Advanced Science

Self Cite

View full text Add to dashboard Cite

The peroxisome is a ubiquitous organelle in rodent cells and plays important roles in a variety of cell types and tissues. It is previously indicated that peroxisomes are associated with auditory function, and patients with peroxisome biogenesis disorders (PBDs) are found to have hearing dysfunction, but the specific role of peroxisomes in hearing remains unclear. In this study, two peroxisome‐deficient mouse models (Atoh1‐Pex5−/− and Pax2‐Pex5−/−) are established and it is found that peroxisomes mainly function in the hair cells of cochleae. Furthermore, peroxisome deficiency‐mediated negative effects on hearing do not involve mitochondrial dysfunction and oxidative damage. Although the mammalian target of rapamycin complex 1 (mTORC1) signaling is shown to function through peroxisomes, no changes are observed in the mTORC1 signaling in Atoh1‐Pex5−/‐ mice when compared to wild‐type (WT) mice. However, the expression of large‐conductance, voltage‐, and Ca2+‐activated K+ (BK) channels is less in Atoh1‐Pex5−/− mice as compared to the WT mice, and the administration of activators of BK channels (NS‐1619 and NS‐11021) restores the auditory function in knockout mice. These results suggest that peroxisomes play an essential role in cochlear hair cells by regulating BK channels. Hence, BK channels appear as the probable target for treating peroxisome‐related hearing diseases such as PBDs.

show abstract

Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels

Cited by 7 publications

References 80 publications

The BK Channel Limits the Pro-Inflammatory Activity of Macrophages

The BK Channel Limits the Pro-Inflammatory Activity of Macrophages

Recent Progress in Generation of Inner Ear Organoid

Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels

Contact Info

Product

Resources

About