Cisd2 slows down liver aging and attenuates age‐related metabolic dysfunction in male mice

Abstract

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Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2

“…Downregulation of Nrf2 could result from decreased abundance of nuclear Nrf2 protein (caused by epigenetic suppression of NFE2L2 expression, diminished translation of Nrf2 mRNA, or destabilisation of Nrf2 protein) or from decreased Nrf2 transactivation activity (caused by mis-localisation of Nrf2 within the nucleus, failure to recruit co-activators, increased recruitment of corepressors, or competition for binding to ARE sequences in gene promoter regions by other transcription factors). It is possible that the downregulation of Nrf2 during NASH is akin to accelerated aging because the livers of old mice (i.e., at 26 months of age) exhibit a NAFLD-like phenotype, including an age-associated dysregulation of Nrf2, which can be exacerbated by liver-specific knockout of the prolongevity gene encoding the iron-sulfur cluster protein Cisd2 [381]. That said, the mechanisms involved in age-associated loss of Nrf2 activity are poorly understood.…”

Dysregulated Ca2+ Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer’s Disease and Wolfram Syndrome

“…An additional mode of action of Cisd2 in the regulation of cytosolic [Ca 2+ ] could occur via modulating SERCA activity. Indeed, findings from murine Cisd2 KO fibroblasts [ 172 ], hepatocytes from heterozygous Cisd2 KO mice [ 173 ] and cardiomyocytes from Cisd2 KO mice [ 162 ] suggest that ER [Ca 2+ ] is decreased when lacking Cisd2. Additionally, Cisd2 interacted with SERCA2b [ 173 ] and SERCA2a [ 162 ].…”

“…Indeed, findings from murine Cisd2 KO fibroblasts [ 172 ], hepatocytes from heterozygous Cisd2 KO mice [ 173 ] and cardiomyocytes from Cisd2 KO mice [ 162 ] suggest that ER [Ca 2+ ] is decreased when lacking Cisd2. Additionally, Cisd2 interacted with SERCA2b [ 173 ] and SERCA2a [ 162 ]. On the contrary, in WS2 patients’ lymphoblastoids [ 174 ] and Cisd2 KO murine myoblasts [ 164 ], the ER [Ca 2+ ] was increased, while the findings in other cell types reported unchanged ER [Ca 2+ ] upon loss of Cisd2 [ 164 , 165 ].…”

Understanding the Unique Microenvironment in the Aging Liver

“…As we known, the main causes of aging are DNA damage, telomeres shortening, epigenic alterations, and impairment of proteostasis (2). The aged liver is usually accompanied with failure of regeneration, metabolic dysfunction, redox imbalance, and development of chronic or malignant liver diseases (3)(4)(5)(6). The impairment of regenerative capacity in the aged liver is affected by both intracellular factors and extracellular factors (7).…”