PMID- 31391167 OWN - NLM STAT- MEDLINE DCOM- 20200731 LR - 20231013 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 3 IP - 15 DP - 2019 Aug 13 TI - Nix-mediated mitophagy regulates platelet activation and life span. PG - 2342-2354 LID - 10.1182/bloodadvances.2019032334 [doi] AB - Platelet activation requires fully functional mitochondria, which provide a vital energy source and control the life span of platelets. Previous reports have shown that both general autophagy and selective mitophagy are critical for platelet function. However, the underlying mechanisms remain incompletely understood. Here, we show that Nix, a previously characterized mitophagy receptor that plays a role in red blood cell maturation, also mediates mitophagy in platelets. Genetic ablation of Nix impairs mitochondrial quality, platelet activation, and FeCl(3)-induced carotid arterial thrombosis without affecting the expression of platelet glycoproteins (GPs) such as GPIb, GPVI, and alpha(IIb)beta(3) Metabolic analysis revealed decreased mitochondrial membrane potential, enhanced mitochondrial reactive oxygen species level, diminished oxygen consumption rate, and compromised adenosine triphosphate production in Nix (-/-) platelets. Transplantation of wild-type (WT) bone marrow cells or transfusion of WT platelets into Nix-deficient mice rescued defects in platelet function and thrombosis, suggesting a platelet-autonomous role (acting on platelets, but not other cells) of Nix in platelet activation. Interestingly, loss of Nix increases the life span of platelets in vivo, likely through preventing autophagic degradation of the mitochondrial protein Bcl-xL. Collectively, our findings reveal a novel mechanistic link between Nix-mediated mitophagy, platelet life span, and platelet physiopathology. Our work suggests that targeting platelet mitophagy Nix might provide new antithrombotic strategies. CI - (c) 2019 by The American Society of Hematology. FAU - Zhang, Weilin AU - Zhang W AD - State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. FAU - Ma, Qi AU - Ma Q AD - State Key Laboratory of Membrane Biology and. AD - Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China. FAU - Siraj, Sami AU - Siraj S AUID- ORCID: 0000-0002-4595-0232 AD - State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. AD - Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. FAU - Ney, Paul A AU - Ney PA AD - Department of Cell and Molecular Biology and. AD - Lindsley Kimball Research Institute, New York Blood Center, New York, NY. FAU - Liu, Junling AU - Liu J AD - Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University, Shanghai, China. FAU - Liao, Xudong AU - Liao X AD - Case Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH. AD - Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH. FAU - Yuan, Yefeng AU - Yuan Y AD - Beijing Key Laboratory for Genetics of Birth Defects and. AD - MOE Key Laboratory of Major Diseases in Children, Center for Medical Genetics, Beijing Pediatric Research Institute, Beijing Children's Hospital/Capital Medical University/National Center for Children's Health, Beijing, China. AD - Shunyi Women and Children's Hospital of Beijing Children's Hospital, Beijing, China; and. FAU - Li, Wei AU - Li W AD - Beijing Key Laboratory for Genetics of Birth Defects and. AD - MOE Key Laboratory of Major Diseases in Children, Center for Medical Genetics, Beijing Pediatric Research Institute, Beijing Children's Hospital/Capital Medical University/National Center for Children's Health, Beijing, China. AD - Shunyi Women and Children's Hospital of Beijing Children's Hospital, Beijing, China; and. FAU - Liu, Lei AU - Liu L AD - State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. FAU - Chen, Quan AU - Chen Q AUID- ORCID: 0000-0001-7539-8728 AD - State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. AD - Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (BNIP3L protein, human) RN - 0 (Biomarkers) RN - 0 (Membrane Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Tumor Suppressor Proteins) SB - IM MH - Animals MH - Biomarkers MH - Bleeding Time MH - Blood Platelets/*metabolism/ultrastructure MH - Carotid Artery Thrombosis/etiology/metabolism/pathology MH - Cell Survival/genetics MH - Humans MH - Immunophenotyping MH - Membrane Proteins/genetics/*metabolism MH - Mice MH - Mice, Knockout MH - Mitochondria/genetics/metabolism/ultrastructure MH - *Mitophagy MH - Phenotype MH - *Platelet Activation/genetics MH - Platelet Function Tests MH - Proto-Oncogene Proteins/genetics/*metabolism MH - Tumor Suppressor Proteins/genetics/*metabolism PMC - PMC6693007 COIS- Conflict-of-interest disclosure: The authors declare no competing financial interests. EDAT- 2019/08/09 06:00 MHDA- 2020/08/01 06:00 PMCR- 2019/08/07 CRDT- 2019/08/09 06:00 PHST- 2019/01/26 00:00 [received] PHST- 2019/05/14 00:00 [accepted] PHST- 2019/08/09 06:00 [entrez] PHST- 2019/08/09 06:00 [pubmed] PHST- 2020/08/01 06:00 [medline] PHST- 2019/08/07 00:00 [pmc-release] AID - bloodadvances.2019032334 [pii] AID - 2019/032334 [pii] AID - 10.1182/bloodadvances.2019032334 [doi] PST - ppublish SO - Blood Adv. 2019 Aug 13;3(15):2342-2354. doi: 10.1182/bloodadvances.2019032334.