Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation
Xiaowen Ma,
Sharon Manley,
Hui Qian,
Yuan Li,
Chen Zhang,
Kevin Li,
Benjamin Ding,
Fengli Guo,
Allen Chen,
Xing Zhang,
Meilian Liu,
Meihua Hao,
Benjamin Kugler,
E. Matthew Morris,
John Thyfault,
Ling Yang,
Hiromi Sesaki,
Hong-Min Ni,
Heidi McBride,
Wen-Xing Ding
Affiliations
Xiaowen Ma
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Sharon Manley
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Hui Qian
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Yuan Li
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Chen Zhang
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Kevin Li
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Benjamin Ding
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Fengli Guo
Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Pathology, University of Kansas Medical Center, Kansas City, KS, USA
Allen Chen
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Xing Zhang
Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
Meilian Liu
Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
Meihua Hao
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Benjamin Kugler
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
E. Matthew Morris
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
John Thyfault
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
Ling Yang
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Hiromi Sesaki
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Hong-Min Ni
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
Heidi McBride
Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Wen-Xing Ding
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA; Corresponding author
Summary: 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.
