Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis

Burkhalter, Martin D.; Sridhar, Arthi; Sampaio, Pedro; Jacinto, Raquel; Burczyk, Martina S.; Donow, Cornelia; Angenendt, Max; Hempel, Maja; Walther, Paul; Pennekamp, Petra; Omran, Heymut; Lopes, Susana S.; Ware, Stephanie M.; Philipp, Melanie

doi:10.1172/jci98890

Cited by 48 publications

(45 citation statements)

References 61 publications

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“…Impairment of mitochondrial function results in longer cilia, while shorter cilia are generated when organelle activity is enhanced. Interestingly, he also found a significant reduction in mtDNA in a cohort of heterotaxy patients [160]. Some important reports have provided proof of an association between autophagy and cilia length; in detail, cilia elongation depends on mTOR pathway suppression and thus autophagy activation, which enables suppression of proteasomal degradation of the proteins that constitute cilia [162][163][164].…”

Section: Congenital Heart Diseasementioning

confidence: 95%

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Mitophagy in Cardiovascular Diseases

Morciano

Patergnani

Bonora

et al. 2020

JCM

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Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes.

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Section: Congenital Heart Diseasementioning

confidence: 95%

“…Recently, some authors [160,161] have found that anomalies in cilia function are implicated in CHDs. Cilia are hair-like organelles that can be found on the surfaces of different types of cells.…”

Section: Congenital Heart Diseasementioning

confidence: 99%

Mitophagy in Cardiovascular Diseases

Morciano

Patergnani

Bonora

et al. 2020

JCM

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“…The impairment of mitochondrial function has been involved in a variety of pathological conditions and diseases. For example, mitochondrial dysfunction could provoke heterotaxy via aberrant ciliogenesis and reduced the beating of cilia [29]. Our finding showed that the expression of mitochondrial biogenesis markers such as NRF1, NRF2, TFAM and COX4 were decreased in the epithelium of nasal polyp.…”

Section: Discussionmentioning

confidence: 58%

“…In addition to the number of mitochondria, the function of mitochondria is also critical for the beating of cilia [29]. Flow cytometry analysis revealed a depolarization of the mitochondrial membrane in Si-WDPCP HSECs and U0126-treated HSECs (Figure 5A-B).…”

Section: Wdpcp Stabilized Mitochondrial Function Through the Mapk/erkmentioning

confidence: 99%

WDPCP modulates cilia beating through MAPK/ERK pathway in chronic rhinosinusitis

Tian

Zhong

et al. 2020

Preprint

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Background: Cilia loss and dysfunction is one of the typical pathological features of chronic rhinosinusitis. Tryptophan-aspartic acid (W-D) repeat containing planar cell polarity effector (WDPCP) has been proven to be an essential element for ciliogenesis in human nasal epithelium, but its role in the beating of cilia remains unclear. Cilia beating requires energy from the mitochondria, which is regulated by the MAPK/ERK pathway. In this study, we sought to investigate the role of WDPCP and its underlying mechanism behind the dysfunction in the beating of cilia in chronic rhinosinusitis.Methods: We demonstrated WDPCP expression in the epithelium of nasal polyps. We also investigated the MAPK/ERK pathway in primary human sinonasal epithelial cells to explore the function of WDPCP. The air-liquid interface culture system was used as a model to verify the role of WDPCP and the MAPK/ERK pathway in the beating of cilia.Results: With the dysfunction of cilia beating, we observed a low expression of WDPCP in the epithelium of nasal polyps. Within the in vitro study, we found that WDPCP was critical for mitochondrial biogenesis and mitochondrial function in human sinonasal epithelial cells, possibly due to the activation of the MAPK/ERK pathway. The mitochondrial dysfunction caused by U0126 or lacking WDPCP could be partially recovered by dexamethasone.Conclusion: The low expression of WDPCP in nasal epithelium could affect mitochondria via the MAPK/ERK pathway, which may contribute to the dysfunction in the beating of cilia in chronic rhinosinusitis.

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“…In this issue of the JCI, Burkhalter et al (5) suggest a mechanism linking cilia and mitochondria in the development of multisystem heterotaxy syndromes. Using both pharmacological and genetic tools, they show that longer cilia are produced when mitochondrial function is impaired and shorter cilia are produced with enhanced mitochondrial function.…”

Section: Mitochondrial Dysfunction Cilial Length and Heterotaxymentioning

confidence: 99%

Cilia, mitochondria, and cardiac development

Chaudhry¹,

Henderson²

2019

Journal of Clinical Investigation

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Over the last 350 years, since the discovery of motile cilia, progressive advances in microscopy and structural and molecular biology have revealed much about the structure of motile cilia and how their oscillations provide locomotion for spermatozoa or propulsion along epithelial surfaces (1). In contrast, nonmotile cilia provide a range of sensing functions. For example, the light-sensing outer segments of retinal rod and cone cells are modified cilia, and ciliated hair cells within the cochlea are responsible for detecting sound. The nonmotile primary cilium functions as a cellular signaling hub and its role in development and disease is now emerging. Receptors for important signaling pathways are clustered on its membrane, which appears to be the site of canonical signaling. The best-known example is the Sonic hedgehog signaling pathway. Receptors for platelet-derived growth factor (PDGF) and canonical Wnt signaling, among others, are also suggested to localize to the ciliary signaling hub (2). Together, motile and immotile cilia play an important role in the establishment of the left-right axis in the developing vertebrate embryo (Figure 1

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Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis

Cited by 48 publications

References 61 publications

Mitophagy in Cardiovascular Diseases

Mitophagy in Cardiovascular Diseases

WDPCP modulates cilia beating through MAPK/ERK pathway in chronic rhinosinusitis

Cilia, mitochondria, and cardiac development

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