Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice
Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice
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DOI：
10.1182/blood-2014-07-586396
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发表时间：
2015-01-01
期刊：
影响因子：
20.3
通讯作者：
Kundu, Mondira
中科院分区：
文献类型：
--
作者：
Li-Harms, XiuJie;Milasta, Sandra;Kundu, Mondira
体细胞线粒体！DNA（mtDNA）突变有助于年龄相关疾病的发病机制，包括骨髓增生异常综合征（MDS）。这些疾病患者中携带mtDNA突变的线粒体的积累表明正常线粒体质量控制系统的失败。mtDNA突变小鼠通过mtDNA聚合酶PolgA的校对功能中的靶向缺陷获得体细胞mtDNA突变，并发展出与MDS患者相似的大红细胞性贫血。我们观察到一个意想不到的缺陷，在清除功能障碍的线粒体在特定阶段，在红系成熟的造血细胞从老年mtDNA突变小鼠。从机制上讲，雷帕霉素信号传导机制靶点的异常激活和mtDNA突变体小鼠中非协调51样激酶（ULK）1的磷酸化导致蛋白酶体介导的ULK 1降解和红系细胞自噬抑制。为了直接评估抑制线粒体自噬对体内携带mtDNA突变的红系细胞线粒体功能的影响，我们从野生型和mtDNA突变小鼠的红系祖细胞中删除Atg 7。自噬的遗传破坏不会导致野生型小鼠贫血，但会加速线粒体呼吸的下降和mtDNA-mutator小鼠大红细胞贫血的发展。这些发现突出了一个病理反馈回路，解释了功能失调的线粒体如何逃避自噬介导的降解，并在易于发生体细胞mtDNA突变的细胞中繁殖，从而导致疾病。
Somatic mitochondria! DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome-mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.