Nix-mediated mitophagy regulates platelet activation and life span

Abstract

Key Points• Nix controls platelet activation/arterial thrombosis, regulating platelet mitochondria quality/activity in (patho)physiological settings.• Knockout of Nix increases the life span of platelets by inhibiting autophagic degradation of the mitochondrial protein Bcl-xL. 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 a IIb b 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 2/2 platelets. Transplantation of wildtype (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.

The mitophagy receptor FUN14 domain-containing 1 (FUNDC1): A promising biomarker and potential therapeutic target of human diseases

“… 66 , 67 In addition, whether other mitophagy receptors such as Nix is implicated in phosphorylation regulation and diseases also should be explored. 68 , 69 …”

Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

“…Programmed mitophagy plays a crucial role in physiological contexts which require the activation of the planned clearance of mitochondria as an element of their developmental programs, including tissue differentiation and protection processes [ 32 , 33 ]. In this regard, mitochondrial degradation was implicated in erythrocyte maturation through NIP3-like protein X (NIX/BNIP3L) activity and platelet activation [ 34 , 35 ]. In addition, the mitophagy-dependent selective clearance of paternal mitochondrial DNA (mtDNA) ensures the inheritance of the maternal mtDNA, following fertilization [ 36 ].…”

Potential Roles of NIX/BNIP3L Pathway in Rat Traumatic Brain Injury

“…There are many studies that agree with the neuroprotective effect of autophagy [34][35][36] . As a mitophagy receptor, NIX is involved in mitophagy by many pathways 37 , and its related mitophagy participates in the pathological process of many diseases as well. Whether the increased autophagy was due to NIX-mediated mitophagy was not clear until now and needed further research.…”