Zhao-Qing Shen's research while affiliated with National Chiao Tung University and other places

Publications (16)

Article
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Background The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Metho...
Article
Liver is a pivotal metabolic organ that is responsible for xenobiotic detoxification, protein synthesis, bile production and energetic balance. Aging of the liver manifests as multiple functional and structural alterations [1]. Cisd2, the second member of the CDGSH iron-sulfur domain-containing protein family in mammals, has been shown to serve as...
Article
Full-text available
The liver plays a pivotal role in mammalian aging. However, the mechanisms underlying liver aging remain unclear. Cisd2 is a pro-longevity gene in mice. Cisd2 mediates lifespan and healthspan via regulation of calcium homeostasis and mitochondrial functioning. Intriguingly, the protein level of Cisd2 is significantly decreased by about 50% in the l...
Article
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Background: Age-related changes affecting the ocular surface cause vision loss in the elderly. Cisd2 deficiency drives premature aging in mice as well as resulting in various ocular surface abnormalities. Here we investigate the role of CISD2 in corneal health and disease. Methods: We studied the molecular mechanism underlying the ocular phenoty...
Article
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Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldw...
Article
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Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide evidence that Cisd2 is a molecular target for the development of treatments targeting NAFLD and...
Article
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The ubiquitin–proteasome system (UPS) and autophagy are two major quality control processes whose impairment is linked to a wide variety of diseases. The coordination between UPS and autophagy remains incompletely understood. Here, we show that ubiquitin ligase UBE3C and deubiquitinating enzyme TRABID reciprocally regulate K29/K48-branched ubiquiti...
Article
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Genotoxic insult causes nuclear and mitochondrial DNA damages with macroautophagy/autophagy induction. The role of mitochondrial DNA (mtDNA) damage in the requirement of autophagy for nuclear DNA (nDNA) stability is unclear. Using site-specific DNA damage approaches, we show that specific nDNA damage alone does not require autophagy for repair unle...
Article
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CDGSH Iron Sulfur Domain 2 (CISD2) is the causative gene for the disease Wolfram syndrome 2 (WFS2; MIM 604928), which is an autosomal recessive disorder showing metabolic and neurodegenerative manifestations. CISD2 protein can be localized on the endoplasmic reticulum (ER), outer mitochondrial membrane (OMM) and mitochondria-associated membrane (MA...
Article
Full-text available
CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca²⁺ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 d...
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is the major risk factor leading to hepatocellular carcinoma (HCC). Cisd2 haploinsufficiency in mice causes NAFLD by disrupting Ca²⁺ homeostasis, indicating that CISD2 is a molecular target for the treatment of NAFLD and the prevention of HCC.
Article
Full-text available
Skeletal muscle has emerged as one of the most important tissues involved in regulating systemic metabolism. The gastrocnemius is a powerful skeletal muscle composed of predominantly glycolytic fast-twitch fibers that are preferentially lost among old age. This decrease in gastrocnemius muscle mass is remarkable during aging; however, the underlyin...
Article
Full-text available
CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontan...
Article
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic steatosis (fatty liver) is a vulnerable factor that could lead to liver damage, inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). However, despite the high prevalence of NAFLD, the genetic factor determining the disease progression remain...

Citations

... Most strikingly, in Cisd2 transgenic mice, increased Cisd2 expression delays cardiac aging and ameliorates age-related cardiac dysfunction [24,30]. Consistently, an elevated level of Cisd2 has been found to delay skeletal muscle aging [17], to slow down liver aging [31] and attenuate liver carcinogenesis [23], as well as reducing Alzheimer's-related neuronal loss [32,33]. Collectively, these mouse genetic studies confirm that Cisd2 is a key player that controls lifespan and healthspan. ...
... For instance, the overexpression of Cisd2 in an APP/PS1 transgenic mouse model for AD resulted in a neuroprotective effect, probably by preventing mitochondrial damage [150]. Conversely, a lack of Cisd2 can lead to chronic injury, such as that seen in the cornea of patients with epithelial disease [151]. A vicious cycle of aberrant wound healing, hindered by Ca 2+ dyshomeostasis and mitochondrial dysfunction, leads to the hyperproliferation and exhaustion of the corneal epithelial stem cells [151,152]. ...
... Thus it seems likely that there are other post-transcriptional mechanisms contributing to the resistance of Cisd2TG mice to WD challenge. RNA sequencing and proteomics analysis have provided promising results regarding aspects of natural aging [3,5]. Cisd2 overexpression blocks the significant age-dependent accumulation of liver fat and maintains a young-like transcriptome and proteome expression pattern even at an advanced age. ...
... Similar to Wfs1, a deficiency in Cisd2 leads to elevated cytosolic Ca 2+ levels [146,[161][162][163][164]. Cisd2 also interacts with IP 3 R as well as B-cell lymphoma 2 (Bcl-2), a known modulator of IP 3 R [165,166]. ...
... Thus, the current model of aggrephagy indicates that p62 governs a sequential recruitment of upstream ATG proteins, such as ULK1 complex, VPS34 complex and ATG16L1, followed by a replacement of the ULK1 complex with the ATG8 family proteins for autophagosome expansion. Accordingly, blockage of VPS34 activity impairs aggrephagy to impede the clearance of ubiquitinated protein aggregates [20,21]. ...
... Excessive accumulation of ROS leads to damage to mitochondrial DNA (mtDNA) and mitochondrial structure, and leads to mitochondrial malfunction, which can be repaired by mitochondrial autophagy. However, excessive damage usually affects the whole cell's physiological activity through the caspase-dependent pathway described above [41][42][43]. Recent studies have suggested that the Bcl-2-related ovarian killer protein (BOK) may be involved in regulating the mitochondrial pathway of apoptosis through a pathway independent of Bcl-2-like protein 4/ Apoptosis regulator Bcl-2 (BAX/BCl-2) [44]. ...
... Most strikingly, in Cisd2 transgenic mice, increased Cisd2 expression delays cardiac aging and ameliorates age-related cardiac dysfunction [24,30]. Consistently, an elevated level of Cisd2 has been found to delay skeletal muscle aging [17], to slow down liver aging [31] and attenuate liver carcinogenesis [23], as well as reducing Alzheimer's-related neuronal loss [32,33]. Collectively, these mouse genetic studies confirm that Cisd2 is a key player that controls lifespan and healthspan. ...
... Similar to Wfs1, a deficiency in Cisd2 leads to elevated cytosolic Ca 2+ levels [146,[161][162][163][164]. Cisd2 also interacts with IP 3 R as well as B-cell lymphoma 2 (Bcl-2), a known modulator of IP 3 R [165,166]. ...
... In the H114C mutant both are disrupted [35,44]. The use of the H114C mutant of CISD2 in our inducible system is therefore different from studies of complete knockout [9,13,15,24,[61][62][63][64][65] or knock-down [11,33,36,40,41,53,[66][67][68] of CISD2 and primarily focuses on the potential of CISD2 to be involved in [2Fe-2S] cluster and/or electron transfer reactions. ...
... Cisd2 maintains Ca 2+ homeostasis and mitochondrial function in order to mediate lifespan and healthspan. Our previous studies have revealed that Cisd2 is essential to maintaining intracellular Ca 2+ homeostasis and mitochondrial integrity in multiple organ systems [22][23][24]. The Cisd2 protein is located on the endoplasmic reticulum membrane and outer membrane of mitochondria; these locations may provide a means of endoplasmic reticulum-mitochondrial crosstalk through electron transfer in response to redox stimuli [25]. ...