Mitophagy is programmed selective autophagy of mitochondria and is important for mitochondrial quality control and cellular homeostasis. Mitochondrial dysfunction and impaired mitophagy are closely associated with various diseases, including heart failure and diabetes. To better understand the pathophysiological role of mitophagy, we generated doxycycline-inducible mitophagy mice using a synthetic mitophagy adaptor protein consisting of an outer mitochondrial membrane targeting sequence and an engineered LIR. To evaluate the activation of mitophagy upon doxycycline treatment, we also generated mitophagy reporter mito-QC mice in which mitochondria tandemly express mCherry and GFP, and only GFP signals are lost in acidic lysosomes subjected to mitophagy. With the ROSA26 promoter-driven rtTA, mitophagy was observed at least in heart, liver, and skeletal muscle. We investigated the relationship between mitophagy activation and pressure overload heart failure or high fat diet-induced obesity. Unexpectedly, we were unable to confirm the protective effect of mitophagy in these two pathological models. Further titration of the level of mitophagy induction is required to demonstrate the potency of the protective effects of mitophagy in disease models.

中文翻译：

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诱导线粒体自噬小鼠的产生

线粒体自噬是线粒体的程序性选择性自噬，对于线粒体质量控制和细胞稳态非常重要。线粒体功能障碍和线粒体自噬受损与多种疾病密切相关，包括心力衰竭和糖尿病。为了更好地了解线粒体自噬的病理生理学作用，我们使用由线粒体外膜靶向序列和工程化 LIR 组成的合成线粒体自噬接头蛋白生成了强力霉素诱导的线粒体自噬小鼠。为了评估强力霉素治疗后线粒体自噬的激活情况，我们还生成了线粒体自噬报告基因 mito-QC 小鼠，其中线粒体串联表达 mCherry 和 GFP，并且在遭受线粒体自噬的酸性溶酶体中仅 GFP 信号丢失。通过 ROSA26 启动子驱动的 rtTA，至少在心脏、肝脏和骨骼肌中观察到线粒体自噬。我们研究了线粒体自噬激活与压力超负荷心力衰竭或高脂肪饮食引起的肥胖之间的关系。出乎意料的是，我们无法证实线粒体自噬在这两种病理模型中的保护作用。需要进一步滴定线粒体自噬诱导水平，以证明线粒体自噬在疾病模型中的保护作用的效力。