Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Pathology, University of Kansas Medical Center, Kansas City, KS, USA.
Cell Rep. 2023 Oct 31;42(10):113291. doi: 10.1016/j.celrep.2023.113291. Epub 2023 Oct 19.
Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.
功能失调的线粒体可通过多种途径被清除，如自噬体选择性自噬过程，即线粒体自噬。在此，我们鉴定了一种细胞内混合的线粒体-溶酶体细胞器（称为线粒体-溶酶体相关细胞器[MLRO]），其在肝细胞去分化过程中独立于经典的线粒体自噬来调节线粒体动态平衡。MLRO 是一种电子致密的细胞器，具有单层或双层膜，同时具有线粒体和溶酶体标记物。从机制上讲，MLRO 可能是通过 PARKIN、ATG5 和 DRP1 非依赖性过程由线粒体衍生小泡（MDV）与溶酶体融合形成的，其受转录因子 EB（TFEB）的负调控，并与线粒体蛋白降解和肝细胞去分化有关。MLRO 是半乳糖凝集素-3 阳性的，使人联想到受损的溶酶体，并且可以通过过表达 TFEB 被清除，从而减弱肝细胞去分化。总之，本研究结果表明，MLRO 可能作为一种独立于经典自噬/线粒体自噬的细胞去分化的线粒体质量控制的替代机制。
