Janus a god with two faces: death and survival utilise same mechanisms conserved by evolution

Nicotera, Pierluigi; Petersen, O. H.; Melino, Gerry; Verkhratsky, Alexei

doi:10.1038/sj.cdd.4402161

Cited by 18 publications

(6 citation statements)

References 36 publications

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“…By 12 months, the predominant response of the cystinotic proximal tubule has made a transition from "fight" to "flight". It has been noted that multiple death pathways have developed as a result of evolution, presumably because a single mechanism would be subject to hijacking by opportunistic parasitic organisms (36). Moreover, metabolism and cell death are intertwined: many proteins that mediate metabolic functions act as transducers of cell death-regulatory signals at "metabolic checkpoints" (24).…”

Section: Despite the Profound Morphological Alterations Taking Place mentioning

confidence: 99%

The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis

Galarreta

Forbes

Thornhill

et al. 2015

American Journal of Physiology-Renal Physiology

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Cystinosis is an inherited disorder resulting from a mutation in the CTNS gene, causing progressive proximal tubular cell flattening, the so-called swan-neck lesion (SNL), and eventual renal failure. To determine the role of oxidative stress in cystinosis, histologic sections of kidneys from C57BL/6 Ctns(-/-) and wild-type mice were examined by immunohistochemistry and morphometry from 1 wk to 20 mo of age. Additional mice were treated from 1 to 6 mo with vehicle or mitoquinone (MitoQ), an antioxidant targeted to mitochondria. The leading edge of the SNL lost mitochondria and superoxide production, and became surrounded by a thickened tubular basement membrane. Progression of the SNL as determined by staining with lectin from Lotus tetragonolobus accelerated after 3 mo, but was delayed by treatment with MitoQ (38 ± 4% vs. 28 ± 1%, P < 0.01). Through 9 mo, glomeruli had retained renin staining and intact macula densa, whereas SNL expressed transgelin, an actin-binding protein, but neither kidney injury molecule-1 (KIM-1) nor cell death was observed. After 9 mo, clusters of proximal tubules exhibited localized oxidative stress (4-hydroxynonenal binding), expressed KIM-1, and underwent apoptosis, leading to the formation of atubular glomeruli and accumulation of interstitial collagen. We conclude that nephron integrity is initially maintained in the Ctns(-/-) mouse by adaptive flattening of cells of the SNL through loss of mitochondria, upregulation of transgelin, and thickened basement membrane. This adaptation ultimately fails in adulthood, with proximal tubular disruption, formation of atubular glomeruli, and renal failure. Antioxidant treatment targeted to mitochondria delays initiation of the SNL, and may provide therapeutic benefit in children with cystinosis.

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Section: Despite the Profound Morphological Alterations Taking Place mentioning

confidence: 99%

The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis

Galarreta

Forbes

Thornhill

et al. 2015

American Journal of Physiology-Renal Physiology

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“…Calcium ions are intimately involved not only in physiological signaling but also in triggering various types of cell death (644). Disruption of microglial Ca 2ϩ homeostasis triggers activation of death programs, which are regulated by the microglia activation status.…”

Section: Ca 2؉ Homeostasis and Microglial Cell Deathmentioning

confidence: 99%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,134

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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“…[4][5][6] Therefore, it is not surprising that the very same intracellular signalling cascades are involved both in physiological regulation and in disruption of neural connectivity. 7 As long as both are kept in balance, the brain will function properly; the pathological deregulation of controlled death routines triggers neurodegeneration. In fact, death and survival represent one of the facets of overall brain homeostasis, and the fundamental question of what distinguishes homeostasis from dyshomeostasis and death at every level from the individual synapse to the brain as a whole represents the core of our understanding of brain physiology and brain diseases.…”

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confidence: 99%