Adaptive Downregulation of Mitochondrial Function in Down Syndrome

Helguera, Pablo; Seiglie, Jaqueline; Rodriguez, Jose Pindado; Hanna, Michael A.; Helguera, Gustavo; Busciglio, Jorge

doi:10.1016/j.cmet.2012.12.005

Cited by 139 publications

(136 citation statements)

References 24 publications

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“…Previous work showed that multiple cellular functions are sensitive to mitochondrial failure in DS cells (Coskun et al, 2016; Helguera et al, 2013). To assess the potential functional recovery afforded by mCAT, we analyzed cellular proliferation and motility in a wound‐healing assay.…”

Section: Resultsmentioning

confidence: 97%

“…We recently reported chronic downregulation of mitochondrial activity in DS cells as an adaptive response to minimize oxidative damage and preserve basic cellular functions (Busciglio et al, 2002; Helguera et al, 2013). We further examined mitochondrial function and structure in DS HF and Dp16 MEF.…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondria are organized as dynamic networks of interconnected branched tubules of different lengths and shape, reflecting the organelle functionality (Friedman & Nunnari, 2014). As chronic oxidative stress in trisomic cells results in morphological changes in the mitochondrial network (Helguera et al, 2013), we asked whether structural changes could be tracked in DS HF and Dp16 MEF. Mitochondria were visualized using mitochondria‐targeted yellow fluorescent protein (mitoYFP).…”

Section: Resultsmentioning

confidence: 99%

“…Transcriptome analysis showed an Nrf2‐associated antioxidant response in DS cells (Helguera et al, 2013). Consistent with the notion that accumulation of Nrf2 is indicative of cells under stress adjusting to neutralize oxidative damage (Niture et al, 2014; Zhang et al, 2004), we found a marked increase in Nrf2 protein levels in DS HF and Dp16 MEF cellular homogenates (Figure 3a,c) (probed with SC722 antibody, see Methods, Supporting Information Figures S5A–C and S7B,C) and strong immunofluorescent signal for pNrf2ser40 (pNrf2) in the nuclei of DS cells (see Methods, Figure 3b; Supporting Information Figures S6A and S7D,E), consistent with the presence of chronic oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

“…An expanding number of studies have reported the presence of chronic oxidative stress and mitochondrial dysfunction in DS at both the cellular and organismal levels (Annerén & Epstein, 1987; Busciglio & Yankner, 1995; Antonarakis et al, 2004; Lott & Dierssen, 2012; Campos et al, 2011). Recently, we reported that decreased mitochondrial activity, increased ROS and mitochondrial fragmentation in DS cells are associated with transcriptional activation of the nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) signaling pathway (Helguera et al, 2013). Nrf2, a master regulator of antioxidant response elements (ARE), is a cytoplasmic protein constitutively synthesized and rapidly degraded after ubiquination mediated by its repressor, Kelch like‐ECH‐associated protein 1 (Keap1)(Itoh et al, 1999; Nguyen et al, 2009; Zhang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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SummaryMounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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Co‐occurring Down syndrome and SUCLA2‐related mitochondrial depletion syndrome

Couser

Marchuk

Smith

et al. 2017

American J of Med Genetics Pt A

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Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21.

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Single‐cell landscape analysis reveals systematic senescence in mammalian Down syndrome

Chen,

Xiao,

Zhang

et al. 2023

Clinical & Translational Med

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Background Down syndrome (DS), which is characterized by various malfunctions, is the most common chromosomal disorder. As the DS population continues to grow and most of those with DS live beyond puberty, early‐onset health problems have become apparent. However, the cellular landscape and molecular alterations have not been thoroughly studied. Methods This study utilized single‐cell resolution techniques to examine DS in humans and mice, spanning seven distinct organs. A total of 71 934 mouse and 98 207 human cells were analyzed to uncover the molecular alterations occurring in different cell types and organs related to DS, specifically starting from the fetal stage. Additionally, SA‐β‐Gal staining, western blot, and histological study were employed to verify the alterations. Results In this study, we firstly established the transcriptomic profile of the mammalian DS, deciphering the cellular map and molecular mechanism. Our analysis indicated that DS cells across various types and organs experienced senescence stresses from as early as the fetal stage. This was marked by elevated SA‐β‐Gal activity, overexpression of cell cycle inhibitors, augmented inflammatory responses, and a loss of cellular identity. Furthermore, we found evidence of mitochondrial disturbance, an increase in ribosomal protein transcription, and heightened apoptosis in fetal DS cells. This investigation also unearthed a regulatory network driven by an HSA21 gene, which leads to genome‐wide expression changes. Conclusion The findings from this study offer significant insights into the molecular alterations that occur in DS, shedding light on the pathological processes underlying this disorder. These results can potentially guide future research and treatment development for DS.

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Adaptive Downregulation of Mitochondrial Function in Down Syndrome

Cited by 139 publications

References 24 publications

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Co‐occurring Down syndrome and SUCLA2‐related mitochondrial depletion syndrome

Single‐cell landscape analysis reveals systematic senescence in mammalian Down syndrome

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