A persistent level of Cisd2 extends healthy lifespan and delays aging in mice

Abstract

The CISD2 gene, which is an evolutionarily conserved novel gene, encodes a transmembrane protein primarily associated with the mitochondrial outer membrane. Significantly, the CISD2 gene is located within the candidate region on chromosome 4q where a genetic component for human longevity has been mapped. Previously, we have shown that Cisd2 deficiency shortens lifespan resulting in premature aging in mice. Additionally, an age-dependent decrease in Cisd2 expression has been detected during normal aging. In this study, we demonstrate that a persistent level of Cisd2 achieved by transgenic expression in mice extends their median and maximum lifespan without any apparent deleterious side effects. Cisd2 also ameliorates age-associated degeneration of the skin, skeletal muscles and neurons. Moreover, Cisd2 protects mitochondria from age-associated damage and functional decline as well as attenuating the age-associated reduction in whole-body energy metabolism. These results suggest that Cisd2 is a fundamentally important regulator of lifespan and provide an experimental basis for exploring the candidacy of CISD2 in human longevity.

Comparative proteomic profiling reveals a role for Cisd2 in skeletal muscle aging

“…Previously, we have shown that there is an age‐dependent decrease in Cisd2 expression levels within the brain and the femoris muscle using C57BL/6 WT mice (Chen et al., 2010; Wu et al., 2012). The mean lifespan of C57BL/6 mice is 25.5 ± 3.9 months ( n  = 50) in our mouse facility.…”

“…The mean lifespan of C57BL/6 mice is 25.5 ± 3.9 months ( n  = 50) in our mouse facility. In the femoris muscle, there was an average 38% and 57% decrease in the Cisd2 protein level during middle age (12‐month‐old [12M]) and during old age (24M), respectively, compared with young (3M) mice (Wu et al., 2012). Strikingly, in the gastrocnemius, there was a much higher decline, namely a ~70% decrease in Cisd2 protein level during middle/old age (Figure 1a,b).…”

“…It should be noted that these DEPs are involved in oxidative phosphorylation within the mitochondria and are all encoded by nuclear genes. Accordingly, in addition to the presence of damaged mtDNA in the naturally aged muscle (Wu et al., 2012), the functional decline affecting mitochondria may also be attributable to the impaired protein synthesis of nuclear‐encoded mitochondrial proteins. Damage to mitochondrial proteins and mtDNA is known to promote ROS generation, and this forms a vicious cycle that increasingly damages cellular molecules.…”

NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth

“…The involvement of mitochondria in cancer cell function could be linked to the enhanced accumulation of iron and reactive oxygen species (ROS) in mitochondria of cancer cells, which is thought to result from the increased metabolic and energetic demands of the transformed phenotype (7). An interesting, recently discovered group of proteins that could link iron and ROS homeostasis with mitochondrial function in cancer cells are NEET proteins (8-15).NEET proteins [mitoNEET (mNT; CISD1), Nutrient-deprivation autophagy factor-1 (NAF-1; CISD2), and CISD3] are a class of iron-sulfur proteins involved in several human pathologies, including diabetes, cystic fibrosis, Wolfram syndrome 2, neurodegeneration, and muscle atrophy (16)(17)(18)(19)(20)(21)(22). mNT and NAF-1 are localized to the outer mitochondrial membrane.…”

“…NEET proteins [mitoNEET (mNT; CISD1), Nutrient-deprivation autophagy factor-1 (NAF-1; CISD2), and CISD3] are a class of iron-sulfur proteins involved in several human pathologies, including diabetes, cystic fibrosis, Wolfram syndrome 2, neurodegeneration, and muscle atrophy (16)(17)(18)(19)(20)(21)(22). mNT and NAF-1 are localized to the outer mitochondrial membrane.…”