CISD2
CDGSH iron-sulfur domain-containing protein 2 (Endoplasmic reticulum intermembrane small protein) (MitoNEET-related 1 protein) (Miner1) (Nutrient-deprivation autophagy factor-1) (NAF-1) [CDGSH2] [ERIS] [ZCD2]
Publications[править]
- Accumulating evidence has demonstrated a significant association between microglia-driven inflammation in the brain and neurodegenerative dementia. We previously showed a significant decline in CISD2 expression in mice models with advanced age. Moreover, we observed that the knockdown of CISD2 led to remarkable inflammation and mitochondrial dysfunction in neural cells. In the present study, we investigated whether CISD2 attenuation influences anti-inflammatory effects and M1-M2 polarization in microglia. : The knockdown of CISD2 expression by siRNA (siCISD2) in EOC microglial cells was performed to mimic the age-driven decline of CISD2 expression. The extent of the inflammatory reaction, polarization in the M1/M2 spectrum, and NFκB activation were verified in EOC microglial cells exhibiting CISD2 deficiency. : In the cellular model of microglia, loss of CISD2 function mediated by siCISD2 exhibited a significant augmentation of proinflammatory signaling, as well as reduced expression levels of Arg-1, Ym1, IL-10, and BCL2. Attenuation of CISD2 expression led to a decrease in the proportion of the M2 phenotype of microglia (compared to M1). Enhanced DNA-binding activity of the NFκB p65 subunit was confirmed in cells transfected with siCISD2, as demonstrated by enzyme-linked immunosorbent assay (ELISA). : To the best of our knowledge, this is the first report examining the following phenomena: (1) anti-inflammatory effects of CISD2 in microglia [i]via[/i] NFκB regulation; and (2) microglial CISD2 assistance in the restoration of M2 microglia phenotype. The anti-inflammatory effects of CISD2 in microglia eventually augment anti-apoptotic effects, which provides a rationale for the development of potential therapeutic target for neurodegenerative diseases and neurodegenerative dementia.
Keywords
- CISD2
- M1/M2 microglia polarization
- aging
- anti-inflammatory effects
- neurodegenerative disease and dementia
Inflammation and mitochondrial dysfunction have been linked to trauma, neurodegeneration, and aging. Impairment of CISD2 expression may trigger the aforementioned pathological conditions in neural cells. We previously reported that curcumin attenuates the downregulation of CISD2 in animal models of spinal cord injury and lipopolysaccharide (LPS)-treated neuronal cells. In this study, we investigate (1) the role of [i]CISD2[/i] and (2) how curcumin regulates CISD2 in the aging process. The serial expression of CISD2 and the efficacy of curcumin treatment were evaluated in old (104 weeks) mice and long-term cultures of neural cells (35 days in vitro, [i]DIV[/i]). LPS-challenged neural cells (with or without siCISD2 transfection) were used to verify the role of curcumin on CISD2 underlying mitochondrial dysfunction. In the brain and spinal cord of mice aged P2, 8, 25, and 104 weeks, we observed a significant decrease in CISD2 expression with age. Curcumin treatment in vivo and in vitro was shown to upregulate CISD2 expression; attenuate inflammatory response in neural cells. Moreover, curcumin treatment elevated CISD2 expression levels and prevented mitochondrial dysfunction in LPS-challenged neural cells. The beneficial effects of curcumin in either non-stressed or LPS-challenged cells that underwent siCISD2 transfection were significantly lower than in respective groups of cells that underwent scrambled siRNA-transfection. We hypothesize that the protective effects of curcumin treatment in reducing cellular inflammation associated trauma, degenerative, and aging processes can be partially attributed to elevated CISD2 expression. We observed a reduction in the protective effects of curcumin against injury-induced inflammation and mitochondrial dysfunction in cells where CISD2 expression was reduced by siCISD2.
MeSH Terms
- Aging
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
- Apoptosis
- Autophagy-Related Proteins
- Carrier Proteins
- Cell Line, Tumor
- Cell Survival
- Curcumin
- Gene Expression Regulation
- Gene Knockdown Techniques
- Humans
- Inflammation
- Membrane Proteins
- Mice
- Mitochondria
- Nerve Tissue Proteins
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
Keywords
- CISD2
- CISD2-dependent manner
- aging
- curcumin
- neurodegeneration
- trauma
CISD2, an evolutionarily conserved novel gene, plays a crucial role in lifespan control and human disease. Mutations in human CISD2 cause type 2 Wolfram syndrome, a rare neurodegenerative and metabolic disorder associated with a shortened lifespan. Significantly, the CISD2 gene is located within a region on human chromosome 4q where a genetic component for human longevity has been mapped through a comparative genome analysis of centenarian siblings. We created Cisd2 knockout (loss-of-function) and transgenic (gain-of-function) mice to study the role of Cisd2 in development and pathophysiology, and demonstrated that Cisd2 expression affects lifespan in mammals. In the Cisd2 knockout mice, Cisd2 deficiency shortens lifespan and drives a panel of premature aging phenotypes. Additionally, an age-dependent decrease of Cisd2 expression has been detected during normal aging in mice. Interestingly, in the Cisd2 transgenic mice, we demonstrated that a persistent level of Cisd2 expression over the different stages of life gives the mice a long-lived phenotype that is linked to an extension in healthy lifespan and a delay in age-associated diseases. At the cellular level, Cisd2 deficiency leads to mitochondrial breakdown and dysfunction accompanied by cell death with autophagic features. Recent studies revealed that Cisd2 may function as an autophagy regulator involved in the Bcl-2 mediated regulation of autophagy. Furthermore, Cisd2 regulates Ca(2 ) homeostasis and Ca(2 ) has been proposed to have an important regulatory role in autophagy. Finally, it remains to be elucidated if and how the regulation in Ca(2 ) homeostasis, autophagy and lifespan are interconnected at the molecular, cellular and organism levels.
MeSH Terms
- Animals
- Autophagy
- Calcium Signaling
- Homeostasis
- Humans
- Longevity
- Nerve Tissue Proteins
Keywords
- aging
- longevity
- mitochondria
- mitochondria-associated ER membranes
- type 2 Wolfram syndrome