Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.
Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.
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DOI：
10.18632/aging.101213
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发表时间：
2017-03-26
期刊：
影响因子：
--
通讯作者：
Ivanova AV
中科院分区：
文献类型：
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作者：
Uzhachenko R;Boyd K;Olivares-Villagomez D;Zhu Y;Goodwin JS;Rana T;Shanker A;Tan WJ;Bondar T;Medzhitov R;Ivanova AV
能量产生减少和氧化应激增加被认为是衰老和衰老相关病理学的主要贡献者。线粒体钙稳态的作用也被强调为影响不同病理状况的重要因素。在这里，我们提出的证据表明，一个小的线粒体蛋白Fus1的损失，维持线粒体的稳态导致过早衰老，衰老相关的病理，并降低生存。我们发现，Fus1KO小鼠出现多种早期衰老迹象，包括脊柱后凸，缺乏活力，无法积累脂肪，耐受压力的能力降低和过早死亡。其他突出的病理变化包括精子计数低，成体干细胞重建组织的能力受损，以及慢性炎症。在分子水平上，我们证明了Fus1 KO细胞的线粒体具有较低的储备呼吸能力（在突然的能量需求情况下产生额外能量的能力），并显示出细胞钙响应的显著改变的动力学。我们最近对Fus1基因敲除小鼠早期听力和记忆丧失的研究，结合本文提出的新数据表明，Fus1控制的钙和能量稳态可能是其衰老调节活动的核心。因此，Fus1蛋白和Fus1依赖的途径和过程可能代表抗衰老策略的新工具和靶点。
Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response. Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.