Uzhachenko Roman, Boyd Kelli, Olivares-Villagomez Danyvid, Zhu Yueming, Goodwin J Shawn, Rana Tanu, Shanker Anil, Tan Winston J T, Bondar Tanya, Medzhitov Ruslan, Ivanova Alla V
Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Aging (Albany NY). 2017 Mar 26;9(3):627-649. doi: 10.18632/aging.101213.
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.
能量生成减少和氧化应激增加被认为是衰老及衰老相关病症的主要促成因素。线粒体钙稳态的作用也已被强调为影响不同病理状况的一个重要因素。在此，我们提供证据表明，一种维持线粒体稳态的小线粒体蛋白Fus1的缺失会导致早衰、衰老相关病症及存活率降低。我们发现，Fus1基因敲除（Fus1KO）小鼠出现多种早衰迹象，包括脊柱后凸、活力缺乏、无法积累脂肪、应激耐受能力降低以及过早死亡。其他显著的病理变化包括精子数量减少、成体干细胞重新填充组织的能力受损以及慢性炎症。在分子水平上，我们证明Fus1基因敲除细胞的线粒体具有较低的储备呼吸能力（在突然需要能量的情况下产生额外能量的能力），并且细胞钙反应的动力学显著改变。我们最近对Fus1基因敲除小鼠早期听力和记忆丧失的研究，结合此处呈现的新数据表明，由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蛋白以及依赖Fus1的途径和过程可能代表了抗衰老策略的新工具和新靶点。
