Wang C-H, Kao C-H, Chen Y-F, Wei Y-H, Tsai T-F
Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University , Taipei , Taiwan.
Free Radic Res. 2014 Sep;48(9):1109-14. doi: 10.3109/10715762.2014.936431. Epub 2014 Jul 29.
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.
CISD2是一个在进化上保守的新基因，在寿命控制和人类疾病中起关键作用。人类CISD2基因的突变会导致2型沃夫勒姆综合征，这是一种罕见的神经退行性和代谢性疾病，与寿命缩短有关。值得注意的是，CISD2基因位于人类4号染色体上的一个区域，通过对百岁老人兄弟姐妹的比较基因组分析，已在该区域定位了人类长寿的遗传成分。我们创建了Cisd2基因敲除（功能丧失）和转基因（功能获得）小鼠，以研究Cisd2在发育和病理生理学中的作用，并证明Cisd2的表达会影响哺乳动物的寿命。在Cisd2基因敲除小鼠中，Cisd2的缺乏会缩短寿命并引发一系列早衰表型。此外，在小鼠正常衰老过程中检测到Cisd2表达随年龄增长而下降。有趣的是，在Cisd2转基因小鼠中，我们证明在生命的不同阶段持续高水平表达Cisd2会使小鼠具有长寿表型，这与健康寿命的延长和与年龄相关疾病的延迟有关。在细胞水平上，Cisd2的缺乏会导致线粒体分解和功能障碍，并伴有具有自噬特征的细胞死亡。最近的研究表明，Cisd2可能作为一种自噬调节因子，参与Bcl-2介导的自噬调节。此外，Cisd2调节Ca(2+)稳态，并且有人提出Ca(2+)在自噬中具有重要的调节作用。最后，Ca(2+)稳态、自噬和寿命之间的调节在分子、细胞和生物体水平上是否以及如何相互关联仍有待阐明。
